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c -0.58 -3.366 -1.343 -2.339 -1.343 -0.974 c -1.343 -0.254 l -1.343 1.344 -0.538 2.116 0.837 2.116 c 2.331 2.116 3.018 1.248 3.018 -0.36 c 3.018 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.936 -1.768 c h f Q EMC Q BT /T1_1 1 Tf 8 0 0 8 107.1653 750.5894 Tm ( )Tj /T1_2 1 Tf 0.278 0.25 Td ( \(2023\) 7:4)Tj ET BT /Span <>BDC /T1_2 1 Tf 38.328 Tw 8 0 0 8 107.1653 750.5894 Tm 4.93 0.25 Td ( )Tj EMC ET BT /T1_2 1 Tf 8 0 0 8 455.4453 752.5894 Tm (www)Tj 8 0 0 8 107.1653 750.5894 Tm 45.703 0.25 Td [(.hemaspher)18(ejour)-18(nal.com)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.038 Tw 7.5 0 0 7.5 51 727.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 727.1221 Tm (91.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 727.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 727.1221 Tm (Damianaki )Tj 7.5 0 0 7.5 51 727.1221 Tm 7.057 0 Td [(A,)37( Stagakis E,)37( Mavroudi I,)37( et al.)37( Minor populations of par)]TJ 0 Tw 25.41 0 Td (-)Tj 0.122 Tw -30.467 -1.2 Td [(oxysmal )1(nocturnal )1(hemoglobinuria-type )1(cells )1(in )1(patients )1(with )1(chronic )]TJ 0 Tw 0 -1.2 TD [(idiopathic neutropenia.)37( )]TJ /T1_4 1 Tf (Eur J Haematol)Tj /T1_3 1 Tf [(.)37( 2016;97:538\226546.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.279 Tw 7.5 0 0 7.5 51 700.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 700.1221 Tm (92.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 700.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 700.1221 Tm (Hirokazu Kanegane H,)Tj 7.5 0 0 7.5 51 727.1221 Tm 12.524 -3.6 Td [( Hoshino )37(A,)37( Okano )37(T)111(,)37( et al.)37( Flow cytome)]TJ 0 Tw (-)Tj 0.015 Tw -10.524 -1.2 Td [(try-based diagnosis of primary immunode\037ciency diseases.)37( )]TJ /T1_4 1 Tf [(Allerg)12(ol Int)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2018;67:43\22654.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.156 Tw 7.5 0 0 7.5 51 673.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 673.1221 Tm (93.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 673.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 673.1221 Tm (Kennedy )Tj 7.5 0 0 7.5 51 727.1221 Tm 6.175 -7.2 Td [(AL,)37( Myers KC,)37( Bowman J)24(,)37( et al.)37( Distinct genetic pathways )]TJ 0.374 Tw -4.175 -1.2 Td (de\037ne pre-malignant versus compensatory clonal hematopoiesis in )Tj 0 Tw T* [(Shwachman-Diamond syndrome.)37( )]TJ /T1_4 1 Tf (Nat Commun)Tj /T1_3 1 Tf [(.)37( 2021;12:1334.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.027 Tw 7.5 0 0 7.5 51 646.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 646.1221 Tm (94.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 646.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 646.1221 Tm (Malcovati )Tj 7.5 0 0 7.5 51 727.1221 Tm 6.639 -10.8 Td [(L,)37( )1(Gall\354 )38(A,)37( )38(T)67(ravaglino )1(E,)37( )1(et )1(al.)37( )1(Clinical )1(signi\037cance )1(of )1(somatic )]TJ -0.054 Tw -4.639 -1.2 Td [(mutation )1(in )1(unexplained )1(blood )1(cytopenia.)37( )]TJ /T1_4 1 Tf 0 Tw 18.085 0 Td (Blood)Tj /T1_3 1 Tf -0.054 Tw [(.)37( )1(2017;129:3371\2263378.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.009 Tw 7.5 0 0 7.5 51 628.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 628.1221 Tm (95.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 628.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 628.1221 Tm (Gall\354 )Tj 7.5 0 0 7.5 51 727.1221 Tm 4.344 -13.2 Td [(A,)37( )37(T)98(odisco G,)37( Catamo E,)37( et al.)37( Relationship between clone metrics )]TJ 0 Tw -2.344 -1.2 Td [(and clinical outcome in clonal cytopenia.)37( )]TJ /T1_4 1 Tf (Blood)Tj /T1_3 1 Tf [(.)37( 2021;138:965\226976.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.104 Tw 7.5 0 0 7.5 51 610.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 610.1221 Tm (96.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 610.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 610.1221 Tm (Jaiswal S,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.027 -15.6 Td [( Fontanillas P)129(,)37( Flannick J)24(,)37( et al.)37( )37(Age-related clonal hematopoiesis )]TJ -0.047 Tw -4.027 -1.2 Td [(associated with adverse outcomes.)37( )]TJ /T1_4 1 Tf (N Engl J Med)Tj /T1_3 1 Tf [(.)37( 2014;371:2488\2262498.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.035 Tw 7.5 0 0 7.5 51 592.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 592.1221 Tm (97.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 592.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 592.1221 Tm (Genovese G,)Tj 7.5 0 0 7.5 51 727.1221 Tm 7.373 -18 Td [( K\344hler )37(AK,)37( Handsaker RE,)37( et al.)37( Clonal hematopoiesis and )]TJ 0.098 Tw -5.373 -1.2 Td [(blood-cancer risk inferred from blood DNA sequence.)37( )]TJ /T1_4 1 Tf (N Engl J Med)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2014;371:2477\2262487.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.02 Tw 7.5 0 0 7.5 51 565.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 565.1221 Tm (98.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 565.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 565.1221 Tm (Zink F)Tj 7.5 0 0 7.5 51 727.1221 Tm 4.838 -21.6 Td [(,)37( Stacey SN,)37( Norddahl GL,)37( et al.)37( Clonal hematopoiesis,)37( with and )]TJ 0.123 Tw -2.838 -1.2 Td [(without candidate driver mutations,)37( is common in the elderly)92(.)37( )]TJ /T1_4 1 Tf 0 Tw (Blood)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2017;130:742\226752.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.054 Tw 7.5 0 0 7.5 51 538.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 538.1221 Tm (99.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 61.245 538.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 538.1221 Tm (List )Tj 7.5 0 0 7.5 51 727.1221 Tm 3.906 -25.2 Td [(AF)129(,)37( )1(Sandberg )37(AA,)37( Doll )1(DC.)37( )1(Myelodysplastic Syndromes.)37( In: )1(Greer )]TJ 0.057 Tw -1.906 -1.2 Td [(JP)129(,)37( ed.)37( )]TJ /T1_4 1 Tf [(W)18(introbe\222)74(s Clinical Hematolog)18(y)]TJ /T1_3 1 Tf [(.)37( 12th ed.)37( Baltimore: Lippincott )]TJ 0 Tw T* [(W)18(illiams & )37(W)18(ilkins; 2008.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.029 Tw 7.5 0 0 7.5 51 511.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 511.1221 Tm (100.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 511.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 511.1221 Tm (Dong F)Tj 7.5 0 0 7.5 51 727.1221 Tm 5.067 -28.8 Td [(,)37( Brynes RK,)37( )37(T)37(idow N,)37( et al.)37( Mutations )1(in the gene for the granu)]TJ 0 Tw (-)Tj -0.013 Tw -3.067 -1.2 Td (locyte colony-stimulating-factor receptor in patients with acute myeloid\ )Tj 0.183 Tw T* [(leukemia preceded by severe congenital neutropenia.)37( )]TJ /T1_4 1 Tf (N Engl J Med)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (1995;333:487\226493.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.045 Tw 7.5 0 0 7.5 51 475.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 475.1221 Tm (101.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 475.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 475.1221 Tm (Shimamura )Tj 7.5 0 0 7.5 51 727.1221 Tm 7.229 -33.6 Td [(A.)37( Molecular alterations governing predisposition to myel)]TJ 0 Tw (-)Tj 0.045 Tw -5.229 -1.2 Td [(odysplastic syndromes: Insights from Shwachman-Diamond syndrome.)37( )]TJ /T1_4 1 Tf 0 Tw T* [(Best Pr)45(act Res Clin Haematol)]TJ /T1_3 1 Tf [(.)37( 2021;34:101252.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.002 Tw 7.5 0 0 7.5 51 448.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 448.1221 Tm (102.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 448.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 448.1221 Tm (Berends C,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.628 -37.2 Td [( Maggen C,)37( Lok C)30(AR,)37( et al.)37( Maternal and neonatal outcome )]TJ 0.044 Tw -4.628 -1.2 Td [(after the use of G-CSF for cancer treatment during pregnancy)92(.)37( )]TJ /T1_4 1 Tf 0 Tw [(Cancer)12(s )]TJ T* (\(Basel\))Tj /T1_3 1 Tf [(.)37( 2021;13:1214.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.152 Tw 7.5 0 0 7.5 51 421.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 421.1221 Tm (103.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 421.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 421.1221 Tm (Dale DC,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.171 -40.8 Td [( Bolyard )37(AA.)37( )37(An update on the diagnosis and treatment of )]TJ 0 Tw -4.171 -1.2 Td [(chronic idiopathic neutropenia.)37( )]TJ /T1_4 1 Tf (Curr Opin Hematol)Tj /T1_3 1 Tf [(.)37( 2017;24:46\22653.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.124 Tw 7.5 0 0 7.5 51 403.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 403.1221 Tm (104.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 403.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 403.1221 Tm (W)Tj 7.5 0 0 7.5 51 727.1221 Tm 2.914 -43.2 Td [(ang C)30(Y)129(,)37( Lai )37(YJ)24(,)37( Hwang KS,)37( et al.)37( Successful treatment with granu)]TJ 0 Tw (-)Tj 0.058 Tw -0.914 -1.2 Td (locyte-colony stimulating factor for ritodrine-induced neutropenia in a \ )Tj 0 Tw T* [(twin pregnancy)92(.)37( )]TJ /T1_4 1 Tf [(T)74(aiw)24(an J Obstet Gynecol)]TJ /T1_3 1 Tf [(.)37( 2016;55:738\226740.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.057 Tw 7.5 0 0 7.5 51 376.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 376.1221 Tm (105.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 376.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 376.1221 Tm (Boxer LA,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.35 -46.8 Td [( Bolyard )37(AA,)37( Kelley ML,)37( et al.)37( Use of granulocyte colony-stim)]TJ 0 Tw (-)Tj 0.145 Tw -4.35 -1.2 Td [(ulating factor during pregnancy in women with chronic neutropenia.)37( )]TJ /T1_4 1 Tf 0 Tw T* (Obstet Gynecol)Tj /T1_3 1 Tf [(.)37( 2015;125:197\226203.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.179 Tw 7.5 0 0 7.5 51 349.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 349.1221 Tm (106.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 349.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 349.1221 Tm (Zeidler C,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.531 -50.4 Td [( Grote U)30(A,)37( Nickel )37(A,)37( et )1(al.)37( Outcome and management of )]TJ 0.217 Tw -4.531 -1.2 Td (pregnancies in severe chronic neutropenia patients by the European )Tj 0.371 Tw T* [(Branch of the Severe Chronic Neutropenia International Registry)92(.)37( )]TJ /T1_4 1 Tf 0 Tw T* (Haematologica)Tj /T1_3 1 Tf [(.)37( 2014;99:1395\2261402.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.054 Tw 7.5 0 0 7.5 51 313.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 313.1221 Tm (107.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 313.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 313.1221 Tm (Pessach I,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.183 -55.2 Td [( Shimoni )37(A,)37( Nagler )37(A.)37( Granulocyte-colony stimulating factor )]TJ -0.041 Tw -4.183 -1.2 Td (for hematopoietic stem cell donation from healthy female donors during )Tj 0.216 Tw T* (pregnancy and lactation: what do we know? )Tj /T1_4 1 Tf (Hum Reprod Update)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2013;19:259\226267.)Tj ET BT /Span <>BDC /T1_3 1 Tf -0.05 Tw 7.5 0 0 7.5 51 277.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 277.1221 Tm (108.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 277.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 277.1221 Tm (Dagli )Tj 7.5 0 0 7.5 51 727.1221 Tm 4.525 -60 Td [(AI,)37( Lee PJ)24(,)37( Correia CE,)37( et al.)37( Pregnancy in glycogen storage disease )]TJ -0.03 Tw -2.525 -1.2 Td [(type Ib: gestational care and report of \037rst successful deliveries.)37( )]TJ /T1_4 1 Tf (J Inherit )Tj 0 Tw T* (Metab Dis)Tj /T1_3 1 Tf [(.)37( 2010;33:S151\226S157.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.122 Tw 7.5 0 0 7.5 51 250.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 250.1221 Tm (109.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 250.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 250.1221 Tm (Dale DC,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.141 -63.6 Td [( Cottle )37(TE,)37( Fier CJ)24(,)37( et al.)37( Severe chronic neutropenia: treat)]TJ 0 Tw (-)Tj 0.243 Tw -4.141 -1.2 Td (ment and follow-up of patients in the Severe Chronic Neutropenia )Tj 0 Tw T* [(International Registry)92(.)37( )]TJ /T1_4 1 Tf (Am J Hematol)Tj /T1_3 1 Tf [(.)37( 2003;72:82\22693.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.252 Tw 7.5 0 0 7.5 51 223.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 223.1221 Tm (110.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 223.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 223.1221 Tm (Dale DC,)Tj 7.5 0 0 7.5 51 727.1221 Tm 6.271 -67.2 Td [( Makaryan )37(V)129(.)37( ELANE-Related Neutropenia.)37( 2002 Jun 17 )]TJ 0.06 Tw -4.271 -1.2 Td [([updated 2018 )37(Aug 23].)37( In: )37(Adam MP)129(,)37( )37(Ardinger HH,)37( Pagon RA,)37( et al,)37( )]TJ 0 Tw T* [(ed.)37( )]TJ /T1_4 1 Tf 0.153 Tw 1.672 0 Td (GeneReviews\256 [Internet])Tj /T1_3 1 Tf [(.)37( Seattle,)37( )37(W)98(A: University of )37(W)86(ashington,)37( )]TJ 0 Tw -1.672 -1.2 Td (Seattle; 1993\2262020.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.06 Tw 7.5 0 0 7.5 51 187.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 187.1221 Tm (111.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 187.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 187.1221 Tm (Abe )Tj 7.5 0 0 7.5 51 727.1221 Tm 4.022 -72 Td [(T)111(,)37( )37(Azuma H,)37( )37(W)86(atanabe )37(A,)37( et al.)37( )37(A patient with cyclic neutropenia )]TJ 0.186 Tw -2.022 -1.2 Td (complicated by severe persistent neutropenia successfully delivered a )Tj 0 Tw T* [(healthy baby)92(.)37( )]TJ /T1_4 1 Tf (Intern Med)Tj /T1_3 1 Tf [(.)37( 2000;39:663\226666.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.175 Tw 7.5 0 0 7.5 51 160.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 160.1221 Tm (112.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 160.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 160.1221 Tm (Hollis )Tj 7.5 0 0 7.5 51 727.1221 Tm 5.029 -75.6 Td [(VS,)37( )1(Holloway )1(JA,)37( )1(Harris )1(S,)37( )1(et )1(al.)37( )1(Comparison )1(of )1(venous )1(and )]TJ 0.265 Tw -3.029 -1.2 Td [(capillary )1(differential )1(leukocyte )1(counts )1(using )1(a )1(standard )1(hematology )]TJ 0.234 Tw T* [(analyzer and a novel micro\036uidic impedance cytometer)111(.)37( )]TJ /T1_4 1 Tf (PLoS One)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2012;7:e43702.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.389 Tw 7.5 0 0 7.5 51 124.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 124.1221 Tm (113.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 124.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 124.1221 Tm (Scheffer)Tj 7.5 0 0 7.5 51 727.1221 Tm 5.388 -80.4 Td [(-Mendoza S,)37( Espinosa-Padilla SE,)37( L\363pez-Herrera G,)37( et al.)37( )]TJ 0.114 Tw -3.388 -1.2 Td [(Reference )1(values )1(of leukocyte and )1(lymphocytes populations )1(in )1(umbil)]TJ 0 Tw (-)Tj 0.149 Tw T* [(ical cord and capillary blood in healthy Mexican newborns.)37( )]TJ /T1_4 1 Tf 0 Tw [(Allerg)12(ol )]TJ T* (Immunopathol \(Madr\))Tj /T1_3 1 Tf [(.)37( 2020;48:295\226305.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.037 Tw 7.5 0 0 7.5 51 88.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 88.1221 Tm (114.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 65.415 88.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 88.1221 Tm (Lambert RM,)Tj 7.5 0 0 7.5 51 727.1221 Tm 7.869 -85.2 Td [( Baer )37(VL,)37( )37(W)18(iedmeier SE,)37( et al.)37( Isolated elevated blood neu)]TJ 0 Tw (-)Tj 0.144 Tw -5.869 -1.2 Td (trophil concentration at altitude does not require NICU admission if )Tj 0 Tw T* [(appropriate reference ranges are used.)37( )]TJ /T1_4 1 Tf [(J P)74(erinatol)]TJ /T1_3 1 Tf [(.)37( 2009;29:822\226825.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.046 Tw 7.5 0 0 7.5 312 727.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 727.1221 Tm (115.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 727.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 727.1221 Tm (Kling PJ)Tj 7.5 0 0 7.5 51 727.1221 Tm 40.287 0 Td [(,)37( Hutter JJ)24(.)37( Hematologic abnormalities in severe neonatal necro)]TJ 0 Tw (-)Tj -3.487 -1.2 Td [(tizing enterocolitis: 25 years later)111(.)37( )]TJ /T1_4 1 Tf [(J P)74(erinatol)]TJ /T1_3 1 Tf [(.)37( 2003;23:523\226530.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.227 Tw 7.5 0 0 7.5 312 709.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 709.1221 Tm (116.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 709.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 709.1221 Tm (Pachlopnik Schmid JM,)Tj 7.5 0 0 7.5 51 727.1221 Tm 47.442 -2.4 Td [( Kuehni CE,)37( Strippoli MP)129(,)37( et al.)37( .)37( Maternal )]TJ 0.032 Tw -10.642 -1.2 Td [(tobacco smoking and decreased leukocytes,)37( including dendritic cells,)37( in )]TJ 0 Tw T* [(neonates.)37( )]TJ /T1_4 1 Tf [(P)74(ediatr Res)]TJ /T1_3 1 Tf [(.)37( 2007;61:462\226466.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.035 Tw 7.5 0 0 7.5 312 682.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 682.1221 Tm (117.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 682.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 682.1221 Tm (La Nasa M,)Tj 7.5 0 0 7.5 51 727.1221 Tm 41.86 -6 Td [( Gaughan J)24(,)37( Cardonick E.)37( Incidence of neonatal neutropenia )]TJ 0.095 Tw -5.06 -1.2 Td (and leukopenia after in utero exposure to chemotherapy for maternal )Tj 0 Tw T* [(cancer)111(.)37( )]TJ /T1_4 1 Tf (Am J Clin Oncol)Tj /T1_3 1 Tf [(.)37( 2019;42:351\226354.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.018 Tw 7.5 0 0 7.5 312 655.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 655.1221 Tm (118.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 655.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 655.1221 Tm (Feiterna-Sperling C,)Tj 7.5 0 0 7.5 51 727.1221 Tm 45.358 -9.6 Td [( )37(W)74(eizsaecker K,)37( B\374hrer C,)37( et al.)37( Hematologic effects )]TJ -0.035 Tw -8.558 -1.2 Td [(of maternal antiretroviral therapy and transmission prophylaxis in HIV)92(-)]TJ 0.092 Tw T* [(1-exposed uninfected newborn infants.)37( )]TJ /T1_4 1 Tf [(J )37(Acquir Immune De\037c Syndr)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2007;45:43\22651.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.459 Tw 7.5 0 0 7.5 312 619.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 619.1221 Tm (119.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 619.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 619.1221 Tm (Fraser SH,)Tj 7.5 0 0 7.5 51 727.1221 Tm 41.78 -14.4 Td [( )37(T)86(udehope DI.)37( Neonatal neutropenia and thrombocy)]TJ 0 Tw (-)Tj 0.346 Tw -4.98 -1.2 Td [(topenia following maternal hypertension.)37( )]TJ /T1_4 1 Tf [(J P)111(aediatr Child Health)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (1996;32:31\22634.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.1 Tw 7.5 0 0 7.5 312 592.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 592.1221 Tm (120.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 592.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 592.1221 Tm (Christensen RD)Tj 7.5 0 0 7.5 51 727.1221 Tm 43.679 -18 Td [(,)37( Henry E,)37( )37(W)18(iedmeier SE,)37( et al.)37( Low blood neutrophil )]TJ -0.041 Tw -6.879 -1.2 Td (concentrations among extremely low birth weight neonates: data from a )Tj 0 Tw T* [(multihospital health-care system.)37( )]TJ /T1_4 1 Tf [(J P)74(erinatol)]TJ /T1_3 1 Tf [(.)37( 2006;26:682\226687.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.066 Tw 7.5 0 0 7.5 312 565.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 565.1221 Tm (121.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 565.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 565.1221 Tm (Blanco E,)Tj 7.5 0 0 7.5 51 727.1221 Tm 40.941 -21.6 Td [( Johnston DL.)37( Neutropenia in infants with hemolytic disease )]TJ 0 Tw -4.141 -1.2 Td [(of the newborn.)37( )]TJ /T1_4 1 Tf [(P)74(ediatr Blood Cancer)]TJ /T1_3 1 Tf [(.)37( 2012;58:950\226952.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.107 Tw 7.5 0 0 7.5 312 547.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 547.1221 Tm (122.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 547.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 547.1221 Tm (Koenig )Tj 7.5 0 0 7.5 51 727.1221 Tm 40.24 -24 Td [(JM,)37( )1(Hunter )1(DD)55(,)37( )1(Christensen )1(RD)55(.)37( )1(Neutropenia )1(in )1(donor )1(\(ane)]TJ 0 Tw (-)Tj 0.025 Tw -3.44 -1.2 Td [(mic\) )1(twins )1(involved )1(in )1(the )1(twin-twin )1(transfusion )1(syndrome.)37( )]TJ /T1_4 1 Tf [(J )1(P)74(erinatol)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (1991;11:355\226358.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.024 Tw 7.5 0 0 7.5 312 520.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 520.1221 Tm (123.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 520.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 520.1221 Tm (Engle )Tj 7.5 0 0 7.5 51 727.1221 Tm 39.454 -27.6 Td [(WD)55(,)37( Rosenfeld CR.)37( Neutropenia in high-risk neonates.)37( )]TJ /T1_4 1 Tf [(J P)74(ediatr)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -2.654 -1.2 Td (1984;105:982\226986.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.009 Tw 7.5 0 0 7.5 312 502.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 502.1221 Tm (124.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 502.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 502.1221 Tm (Del )Tj 7.5 0 0 7.5 51 727.1221 Tm 38.55 -30 Td [(V)74(ecchio )37(A,)37( Christensen RD)55(.)37( Neonatal neutropenia: what diagnostic )]TJ 0.035 Tw -1.75 -1.2 Td (evaluation is needed and when is treatment recommended? )Tj /T1_4 1 Tf [(Earl)18(y Hum )]TJ 0 Tw T* (Dev)Tj /T1_3 1 Tf [(.)37( 2012;88\(Suppl 2\):S19\226S24.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.044 Tw 7.5 0 0 7.5 312 475.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 475.1221 Tm (125.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 475.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 475.1221 Tm (Alexandropoulou O)Tj 7.5 0 0 7.5 51 727.1221 Tm 45.514 -33.6 Td [(,)37( Kossiva L,)37( Haliotis F)129(,)37( et al.)37( )37(T)67(ransient neutropenia )]TJ 0.018 Tw -8.714 -1.2 Td (in children with febrile illness and associated infectious agents: 2 yea\ rs\222 )Tj 0 Tw T* [(follow-up.)37( )]TJ /T1_4 1 Tf [(Eur J P)74(ediatr)]TJ /T1_3 1 Tf [(.)37( 2013;172:811\226819.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.048 Tw 7.5 0 0 7.5 312 448.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 448.1221 Tm (126.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 448.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 448.1221 Tm (Pembrey L,)Tj 7.5 0 0 7.5 51 727.1221 Tm 41.603 -37.2 Td [( Newell ML,)37( )37(T)98(ovo P)55(A; European Paediatric Hepatitis C )37(V)37(irus )]TJ 0.109 Tw -4.803 -1.2 Td [(Network.)37( )37(Age-related lymphocyte and neutrophil levels in children of )]TJ 0 Tw T* [(hepatitis C-infected women.)37( )]TJ /T1_4 1 Tf [(P)74(ediatr Infect Dis J)]TJ /T1_3 1 Tf [(.)37( 2008;27:800\226807.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.02 Tw 7.5 0 0 7.5 312 421.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 421.1221 Tm (127.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 421.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 421.1221 Tm (Hu J)Tj 7.5 0 0 7.5 51 727.1221 Tm 38.813 -40.8 Td [(,)37( Doucette K,)37( Hartling L,)37( et al.)37( )37(T)67(reatment of hepatitis C in children: )]TJ 0 Tw -2.013 -1.2 Td [(a systematic review)92(.)37( )]TJ /T1_4 1 Tf (PLoS One)Tj /T1_3 1 Tf [(.)37( 2010;5:e11542.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.112 Tw 7.5 0 0 7.5 312 403.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 403.1221 Tm (128.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 403.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 403.1221 Tm (Farruggia P)Tj 7.5 0 0 7.5 51 727.1221 Tm 41.786 -43.2 Td [(.)37( Immune neutropenias of infancy and childhood.)37( )]TJ /T1_4 1 Tf [(W)67(orld J )]TJ 0 Tw -4.986 -1.2 Td [(P)74(ediatr)]TJ /T1_3 1 Tf [(.)37( 2016;12:142\226148.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.005 Tc -0.26 Tw 7.5 0 0 7.5 312 385.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51 727.1221 Tm 34.813 -45.6 Td (129.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.265 385.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 385.1221 Tm (Zupa)Tj /T1_5 1 Tf 0 Tc 0 Tw 7.5 0 0 7.5 51 727.1221 Tm 39.114 -45.6 Td (\034)Tj /T1_3 1 Tf -0.005 Tc -0.077 Tw 0.519 0 Td [(ska B,)37( Uhrynowska M,)37( Guz K,)37( et al.)37( )37(The risk of antibody formation)-5( )]TJ -0.027 Tw -2.833 -1.2 Td [(against )1(HNA1a and )1(HNA1b )1(granulocyte )1(antigens )1(during )1(pregnancy )1(and)-5( )]TJ 0 Tw T* [(its relation to neonatal neutropenia.)37( )]TJ /T1_4 1 Tf [(T)55(r)45(ansfus Med)]TJ /T1_3 1 Tf [(.)37( 2001;11:377\226382.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0 Tc -0.017 Tw 7.5 0 0 7.5 312 358.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 358.1221 Tm (130.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 358.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 358.1221 Tm (Bux J)Tj 7.5 0 0 7.5 51 727.1221 Tm 39.149 -49.2 Td [(,)37( Jung KD)55(,)37( Kauth )37(T)111(,)37( et al.)37( Serological and clinical aspects of granu)]TJ 0 Tw (-)Tj -0.01 Tw -2.349 -1.2 Td [(locyte antibodies leading to alloimmune neonatal neutropenia.)37( )]TJ /T1_4 1 Tf 0 Tw [(T)55(r)45(ansfus )]TJ T* (Med)Tj /T1_3 1 Tf [(.)37( 1992;2:143\226149.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.055 Tw 7.5 0 0 7.5 312 331.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 331.1221 Tm (131.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 331.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 331.1221 Tm (Rodwell RL,)Tj 7.5 0 0 7.5 51 727.1221 Tm 42.209 -52.8 Td [( Gray PH,)37( )37(T)86(aylor KM,)37( et al.)37( Granulocyte colony stimulating )]TJ 0.044 Tw -5.409 -1.2 Td [(factor )1(treatment for alloimmune )1(neonatal neutropenia.)37( )]TJ /T1_4 1 Tf 24.168 0 Td [(Arc)12(h )1(Dis )1(Child )]TJ 0 Tw -24.168 -1.2 Td [(F)12(etal Neonatal Ed)]TJ /T1_3 1 Tf [(.)37( 1996;75:F57\226F58.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.27 Tw 7.5 0 0 7.5 312 304.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 304.1221 Tm (132.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 304.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 304.1221 Tm (Desenfants )Tj 7.5 0 0 7.5 51 727.1221 Tm 42.033 -56.4 Td [(A,)37( Jeziorski E,)37( Plan O)55(,)37( et al.)37( Intravenous immunoglob)]TJ 0 Tw (-)Tj 0.36 Tw -5.233 -1.2 Td (ulins for neonatal alloimmune neutropenia refractory to recombi)Tj 0 Tw (-)Tj 0.294 Tw T* [(nant human granulocyte colony-stimulating factor)111(.)37( )]TJ /T1_4 1 Tf [(Am J P)74(erinatol)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2011;28:461\226466.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.202 Tw 7.5 0 0 7.5 312 268.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 268.1221 Tm (133.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 268.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 268.1221 Tm (Bedu )Tj 7.5 0 0 7.5 51 727.1221 Tm 39.41 -61.2 Td [(A,)37( Baumann C,)37( Rohrlich P)129(,)37( et al.)37( Failure of granulocyte colo)]TJ 0 Tw (-)Tj 0.191 Tw -2.61 -1.2 Td [(ny-stimulating factor in alloimmune neonatal neutropenia.)37( )]TJ /T1_4 1 Tf [(J P)74(ediatr)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (1995;127:508\226509.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.112 Tw 7.5 0 0 7.5 312 241.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 241.1221 Tm (134.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 241.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 241.1221 Tm (Maheshwari )Tj 7.5 0 0 7.5 51 727.1221 Tm 42.543 -64.8 Td [(A,)37( Christensen RD)55(,)37( Calhoun D)60(A.)37( Resistance to recombi)]TJ 0 Tw (-)Tj 0.09 Tw -5.743 -1.2 Td (nant human granulocyte colony-stimulating factor in neonatal alloim)Tj 0 Tw (-)Tj 0.197 Tw T* (mune neutropenia associated with anti-human neutrophil antigen-2a )Tj 0 Tw T* [(\(NB1\) antibodies.)37( )]TJ /T1_4 1 Tf [(P)74(ediatrics)]TJ /T1_3 1 Tf [(.)37( 2002;109:e64.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.033 Tw 7.5 0 0 7.5 312 205.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 205.1221 Tm (135.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 205.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 205.1221 Tm (Seguier )Tj 7.5 0 0 7.5 51 727.1221 Tm 40.155 -69.6 Td [(J)24(,)37( Barlogis )37(V)129(,)37( Croisille L,)37( et al.)37( Severe transitory neonatal neutro)]TJ 0 Tw (-)Tj 0.032 Tw -3.356 -1.2 Td [(penia associated with maternal autoimmune or idiopathic neutropenia.)37( )]TJ /T1_4 1 Tf 0 Tw T* (J Clin Immunol)Tj /T1_3 1 Tf [(.)37( 2019;39:200\226206.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.081 Tw 7.5 0 0 7.5 312 178.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 178.1221 Tm (136.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 178.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 178.1221 Tm (Davoren )Tj 7.5 0 0 7.5 51 727.1221 Tm 40.845 -73.2 Td [(A,)37( Saving K,)37( McFarland JG,)37( et al.)37( Neonatal neutropenia and )]TJ 0.121 Tw -4.045 -1.2 Td (bacterial sepsis associated with placental transfer of maternal neutro)Tj 0 Tw (-)Tj T* [(phil-speci\037c autoantibodies.)37( )]TJ /T1_4 1 Tf [(T)55(r)45(ansfusion)]TJ /T1_3 1 Tf [(.)37( 2004;44:1041\2261046.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.227 Tw 7.5 0 0 7.5 312 151.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 151.1221 Tm (137.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 151.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 151.1221 Tm (Fung )Tj 7.5 0 0 7.5 51 727.1221 Tm 39.437 -76.8 Td [(YL,)37( Pitcher LA,)37( )37(T)86(aylor K,)37( et al.)37( Managing passively acquired )]TJ 0.517 Tw -2.637 -1.2 Td [(autoimmune neonatal neutropenia: a case study)92(.)37( )]TJ /T1_4 1 Tf [(T)55(r)45(ansfus Med)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2005;15:151\226155.)Tj ET BT /Span <>BDC /T1_3 1 Tf -0.018 Tw 7.5 0 0 7.5 312 124.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 124.1221 Tm (138.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 124.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 124.1221 Tm (Juul )Tj 7.5 0 0 7.5 51 727.1221 Tm 38.838 -80.4 Td [(SE,)37( )1(Calhoun )1(D)60(A,)37( )1(Christensen )1(RD)55(.)37( )75(\223Idiopathic )1(neutropenia\224)74( )1(in )1(very )]TJ 0 Tw -2.038 -1.2 Td [(low birthweight infants.)37( )]TJ /T1_4 1 Tf [(Acta P)111(aediatr)]TJ /T1_3 1 Tf [(.)37( 1998;87:963\226968.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.108 Tw 7.5 0 0 7.5 312 106.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 106.1221 Tm (139.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 106.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 106.1221 Tm (Omar S)Tj 7.5 0 0 7.5 51 727.1221 Tm 40.21 -82.8 Td [(A,)37( Salhadar )37(A,)37( )37(W)86(ooliever DE,)37( et al.)37( Late-onset neutropenia in )]TJ 0 Tw -3.41 -1.2 Td [(very low birth weight infants.)37( )]TJ /T1_4 1 Tf [(P)74(ediatrics)]TJ /T1_3 1 Tf [(.)37( 2000;106:E55.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.181 Tw 7.5 0 0 7.5 312 88.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 88.1221 Tm (140.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 326.415 88.1221 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 88.1221 Tm (V)Tj 7.5 0 0 7.5 51 727.1221 Tm 37.449 -85.2 Td [(etter)55(-Laracy S,)37( Balliu PR,)37( Salinas JA,)37( et al.)37( Late-onset neutropenia: )]TJ 0.111 Tw -0.649 -1.2 Td [(de\037ning limits of neutrophil count in very low birth weight infants.)37( )]TJ /T1_4 1 Tf 0 Tw (J )Tj T* [(P)74(erinatol)]TJ /T1_3 1 Tf [(.)37( 2014;34:22\22626.)]TJ ET q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 785 0 obj <> endobj 786 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 285.052 24.0881 Tm (14)Tj ET q 0 g /GS0 gs /Fm1 Do Q BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 36 727.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 727.1221 Tm (38.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 727.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 727.1221 Tm (Curtis BR.)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.519 0 Td ( Non-chemotherapy drug-induced neutropenia: key points to )Tj 0.122 Tw -4.519 -1.2 Td [(manage the challenges.)37( )]TJ /T1_2 1 Tf [(Hematolog)18(y )37(Am Soc Hematol Educ Progr)45(am)]TJ /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw 0 -1.2 TD (2017;2017:187\226193.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.008 Tw 7.5 0 0 7.5 36 700.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 700.1221 Tm (39.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 700.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 700.1221 Tm (V)Tj 7.5 0 0 7.5 36 727.1221 Tm 2.686 -3.6 Td [(illalba NL,)37( )37(Alonso-Ortiz MB,)37( Maouche )37(Y)129(,)37( et al.)37( Idiosyncratic drug-in)]TJ 0 Tw (-)Tj 0.053 Tw -0.686 -1.2 Td [(duced neutropenia and agranulocytosis in elderly patients.)37( )]TJ /T1_2 1 Tf (J Clin Med)Tj /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2020;9:1808.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.224 Tw 7.5 0 0 7.5 36 673.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 673.1221 Tm (40.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 673.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 673.1221 Tm (Bux J)Tj 7.5 0 0 7.5 36 727.1221 Tm 4.59 -7.2 Td [(,)37( Behrens G,)37( Jaeger G,)37( et al.)37( Diagnosis and clinical course of )]TJ 0.31 Tw -2.59 -1.2 Td [(autoimmune neutropenia in infancy: analysis of 240 cases.)37( )]TJ /T1_2 1 Tf 0 Tw (Blood)Tj /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (1998;91:181\226186.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.258 Tw 7.5 0 0 7.5 36 646.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 646.1221 Tm (41.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 646.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 646.1221 Tm (Farruggia P)Tj 7.5 0 0 7.5 36 727.1221 Tm 7.132 -10.8 Td [(,)37( Fioredda F)129(,)37( Puccio G,)37( et al.)37( Idiopathic neutropenia of )]TJ 0.182 Tw -5.132 -1.2 Td [(infancy: )1(data )1(from )1(the )1(Italian )1(Neutropenia )1(Registry)92(.)37( )]TJ /T1_2 1 Tf 23.919 0 Td [(Am )1(J )1(Hematol)]TJ /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -23.919 -1.2 Td (2019;94:216\226222.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.097 Tw 7.5 0 0 7.5 36 619.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 619.1221 Tm (42.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 619.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 619.1221 Tm (Fioredda F)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.639 -14.4 Td [(,)37( Rotulo GA,)37( Farruggia P)129(,)37( et al.)37( Late-onset and long-lasting )]TJ 0.265 Tw -4.639 -1.2 Td (autoimmune neutropenia: an analysis from the Italian Neutropenia )Tj 0 Tw T* [(Registry)92(.)37( )]TJ /T1_2 1 Tf -0.037 Tw (Blood Adv)Tj /T1_1 1 Tf 0 Tw [(.)37( 2020;4:5644\2265649.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.001 Tw 7.5 0 0 7.5 36 592.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 592.1221 Tm (43.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 592.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 592.1221 Tm (Lima CS,)Tj 7.5 0 0 7.5 36 727.1221 Tm 5.963 -18 Td [( Paula EV)129(,)37( )37(T)86(akahashi )37(T)111(,)37( et al.)37( Causes of incidental neutropenia )]TJ 0 Tw -3.963 -1.2 Td [(in adulthood.)37( )]TJ /T1_2 1 Tf (Ann Hematol)Tj /T1_1 1 Tf [(.)37( 2006;85:705\226709.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 36 574.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 574.1221 Tm (44.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 574.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 574.1221 Tm (Osamu Hirata O)Tj 7.5 0 0 7.5 36 727.1221 Tm 9.278 -20.4 Td [(,)37( Okada S,)37( )37(T)67(sumura M,)37( et al.)37( Mosaicism of an ELANE )]TJ -0.008 Tw -7.278 -1.2 Td (mutation in an asymptomatic mother in a familial case of cyclic neutro)Tj 0 Tw (-)Tj T* [(penia.)37( )]TJ /T1_2 1 Tf (J Clin Immunol)Tj /T1_1 1 Tf [(.)37( 2015;35:512\226516.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.166 Tw 7.5 0 0 7.5 36 547.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 547.1221 Tm (45.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 547.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 547.1221 Tm (Peng HW)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.205 -24 Td [(,)37( Chou CF)129(,)37( Liang DC.)37( Hereditary cyclic neutropenia in the )]TJ 0.085 Tw -4.205 -1.2 Td [(male members of a Chinese family with inverted )37(Y chromosome.)37( )]TJ /T1_2 1 Tf (Br J )Tj 0 Tw T* (Haematol)Tj /T1_1 1 Tf [(.)37( 2000;110:438\226440.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.203 Tw 7.5 0 0 7.5 36 520.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 520.1221 Tm (46.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 520.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 520.1221 Tm (Boutakoglou E,)Tj 7.5 0 0 7.5 36 727.1221 Tm 8.891 -27.6 Td [( )1(Klimiankou M,)37( )38(T)67(saknakis G,)37( et al.)37( Identi\037cation of )]TJ 0.243 Tw -6.891 -1.2 Td [(GFI1 mutations in adult patients with congenital neutropenia.)37( )]TJ /T1_2 1 Tf 0 Tw (Ann )Tj T* (Hematol)Tj /T1_1 1 Tf [(.)37( 2022;101:2771\2262773.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.113 Tw 7.5 0 0 7.5 36 493.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 493.1221 Tm (47.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 493.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 493.1221 Tm (Nikolouzakis )Tj 7.5 0 0 7.5 36 727.1221 Tm 8.134 -31.2 Td [(TK,)37( Spyridakis K,)37( )37(Tzardi M,)37( et al.)37( Chronic neutropenic )]TJ 0.08 Tw -6.134 -1.2 Td (colitis with complete colonic obstruction in a patient with severe con)Tj 0 Tw (-)Tj 0.124 Tw T* [(genital neutropenia associated with G6PC3 mutations.)37( )]TJ /T1_2 1 Tf (Ann Hematol)Tj /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2022;101:1583\2261585.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.339 Tw 7.5 0 0 7.5 36 457.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 457.1221 Tm (48.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 457.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 457.1221 Tm (Kostman R.)Tj 7.5 0 0 7.5 36 727.1221 Tm 7.468 -36 Td [( Infantile genetic agranulocytosis.)37( )]TJ /T1_2 1 Tf [(Acta P)111(aediatr Scand)]TJ /T1_1 1 Tf 0 Tw ( )Tj -5.468 -1.2 Td (1956;45\(Suppl 105\):1\22678.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.093 Tw 7.5 0 0 7.5 36 439.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 439.1221 Tm (49.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 439.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 439.1221 Tm (Kostman R.)Tj 7.5 0 0 7.5 36 727.1221 Tm 7.222 -38.4 Td [( Infantile genetic agranulocytosis.)37( )37(A review with presenta)]TJ 0 Tw (-)Tj -5.222 -1.2 Td [(tion of ten new cases.)37( )]TJ /T1_2 1 Tf [(Acta P)111(aediatr Scand)]TJ /T1_1 1 Tf [(.)37( 1975;64:362\226368.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.161 Tw 7.5 0 0 7.5 36 421.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 421.1221 Tm (50.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 421.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 421.1221 Tm (Y)Tj 7.5 0 0 7.5 36 727.1221 Tm 2.636 -40.8 Td [(e )37(Y)129(,)37( Carlsson G,)37( )37(W)86(ondimu B,)37( et al.)37( Mutations in the ELANE gene )]TJ -0.004 Tw -0.636 -1.2 Td (are associated with development of periodontitis in patients with severe\ )Tj 0 Tw T* [(congenital neutropenia.)37( )]TJ /T1_2 1 Tf (J Clin Immunol)Tj /T1_1 1 Tf [(.)37( 2011;31:936\226945.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.15 Tw 7.5 0 0 7.5 36 394.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 394.1221 Tm (51.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 394.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 394.1221 Tm (Roques G,)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.67 -44.4 Td [( Munzer M,)37( Barthez MA,)37( et al.)37( Neurological \037ndings and )]TJ 0.211 Tw -4.67 -1.2 Td (genetic alterations in patients with Kostmann syndrome and HAX1 )Tj 0 Tw T* [(mutations.)37( )]TJ /T1_2 1 Tf [(P)74(ediatr Blood Cancer)]TJ /T1_1 1 Tf [(.)37( 2014;61:1041\2261048.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.132 Tw 7.5 0 0 7.5 36 367.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 367.1221 Tm (52.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 367.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 367.1221 Tm (James RM,)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.927 -48 Td [( Kinsey SE.)37( )37(The investigation and management of chronic )]TJ 0 Tw -4.927 -1.2 Td [(neutropenia in children.)37( )]TJ /T1_2 1 Tf [(Arc)12(h Dis Child)]TJ /T1_1 1 Tf [(.)37( 2006;91:852\226858.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.04 Tw 7.5 0 0 7.5 36 349.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 349.1221 Tm (53.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 349.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 349.1221 Tm (Skokowa J)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.685 -50.4 Td [(,)37( Steinemann D)55(,)37( Katsman-Kuipers JE,)37( et al.)37( Cooperativity of )]TJ -0.118 Tw -4.685 -1.2 Td [(R)30(UNX1 )1(and CSF3R mutations in severe congenital neutropenia: a unique )]TJ 0 Tw T* [(pathway in myeloid leukemogenesis.)37( )]TJ /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 2014;123:2229\2262237.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.022 Tw 7.5 0 0 7.5 36 322.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 322.1221 Tm (54.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 322.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 322.1221 Tm (Olofsen )Tj 7.5 0 0 7.5 36 727.1221 Tm 5.644 -54 Td [(P)55(A,)37( )38(T)98(ouw IP)129(.)37( )1(R)30(UNX1 Mutations in )1(the )1(leukemic progression )1(of )]TJ 0 Tw -3.645 -1.2 Td [(severe congenital neutropenia.)37( )]TJ /T1_2 1 Tf (Mol Cells)Tj /T1_1 1 Tf [(.)37( 2020;43:139\226144.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.071 Tw 7.5 0 0 7.5 36 304.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 304.1221 Tm (55.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 304.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 304.1221 Tm (Klimiankou M,)Tj 7.5 0 0 7.5 36 727.1221 Tm 8.56 -56.4 Td [( Sabine Mellor)55(-Heineke S,)37( Zeidler C,)37( et al.)37( Role of CSF3R )]TJ 0.128 Tw -6.56 -1.2 Td [(mutations )1(in )1(the )1(pathomechanism of )1(congenital )1(neutropenia and )1(sec)]TJ 0 Tw (-)Tj -0.07 Tw T* [(ondary )1(acute )1(myeloid )1(leukemia.)37( )]TJ /T1_2 1 Tf -0.107 Tw [(Ann )-36(N )1(Y )1(Acad )-36(Sci)]TJ /T1_1 1 Tf -0.07 Tw [(.)37( )1(2016;1370:119\226125.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.039 Tw 7.5 0 0 7.5 36 277.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 277.1221 Tm (56.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 277.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 277.1221 Tm (Olofsen P)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.207 -60 Td [(A,)37( Fatrai S,)37( van Strien PMH,)37( et al.)37( Malignant transformation )]TJ -0.012 Tw -4.207 -1.2 Td [(involving CXX)55(C4 mutations identi\037ed in a leukemic progression model )]TJ 0 Tw T* [(of severe congenital neutropenia.)37( )]TJ /T1_2 1 Tf (Cell Rep Med)Tj /T1_1 1 Tf [(.)37( 2020;1:100074.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.057 Tw 7.5 0 0 7.5 36 250.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 250.1221 Tm (57.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 250.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 250.1221 Tm (Beekman R,)Tj 7.5 0 0 7.5 36 727.1221 Tm 7.241 -63.6 Td [( )37(V)86(alkhof MG,)37( Sanders MA,)37( et al.)37( Sequential gain of muta)]TJ 0 Tw (-)Tj -0.004 Tw -5.241 -1.2 Td (tions in severe congenital neutropenia progressing to acute myeloid leu)Tj 0 Tw (-)Tj T* [(kemia.)37( )]TJ /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 2012;119:5071\2265077.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.028 Tw 7.5 0 0 7.5 36 223.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 223.1221 Tm (58.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 223.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 223.1221 Tm (Link DC.)Tj 7.5 0 0 7.5 36 727.1221 Tm 5.992 -67.2 Td ( Mechanisms of leukemic transformation in congenital neutro)Tj 0 Tw (-)Tj -3.992 -1.2 Td [(penia.)37( )]TJ /T1_2 1 Tf (Curr Opin Hematol)Tj /T1_1 1 Tf [(.)37( 2019;26:34\22640.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.109 Tw 7.5 0 0 7.5 36 205.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 205.1221 Tm (59.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 205.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 205.1221 Tm (Klimiankou M,)Tj 7.5 0 0 7.5 36 727.1221 Tm 8.74 -69.6 Td [( Kandabarau S,)37( Zeidler C,)37( et al.)37( )37(Accumulation of spe)]TJ 0 Tw (-)Tj 0.115 Tw -6.74 -1.2 Td (ci\037c somatic leukemia-associated mutations in congenital neutropenia \ )Tj 0.13 Tw T* (precedes malignant transformation - new preconditions for treatment )Tj 0 Tw T* [(decisions.)37( )]TJ /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 2022;140\(Supplement 1\):994\226995.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.156 Tw 7.5 0 0 7.5 36 169.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 169.1221 Tm (60.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 169.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 169.1221 Tm (T)Tj 7.5 0 0 7.5 36 727.1221 Tm 2.599 -74.4 Td [(saknakis )1(G,)37( Gall\354 )37(A,)37( Papadakis )1(S,)37( )1(et )1(al.)37( Incidence and )1(prognosis )1(of )]TJ 0.142 Tw -0.599 -1.2 Td [(clonal hematopoiesis in patients with chronic idiopathic neutropenia.)37( )]TJ /T1_2 1 Tf 0 Tw T* (Blood)Tj /T1_1 1 Tf [(.)37( 2021;138:1249\2261257.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.111 Tw 7.5 0 0 7.5 36 142.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 142.1221 Tm (61.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 142.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 142.1221 Tm (W)Tj 7.5 0 0 7.5 36 727.1221 Tm 2.926 -78 Td [(elte K,)37( Boxer LA.)37( Severe chronic neutropenia: pathophysiology and )]TJ 0 Tw -0.926 -1.2 Td [(therapy)92(.)37( )]TJ /T1_2 1 Tf (Semin Hematol)Tj /T1_1 1 Tf [(.)37( 1997;34:267\226278.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.041 Tw 7.5 0 0 7.5 36 124.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 124.1221 Tm (62.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 124.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 124.1221 Tm (V)Tj 7.5 0 0 7.5 36 727.1221 Tm 2.637 -80.4 Td [(alent P)129(,)37( Orazi )37(A,)37( Steensma DP)129(,)37( et al.)37( Proposed minimal diagnostic crite)]TJ 0 Tw (-)Tj 0.051 Tw -0.637 -1.2 Td (ria for myelodysplastic syndromes \(MDS\) and potential pre-MDS con)Tj 0 Tw (-)Tj T* [(ditions.)37( )]TJ /T1_2 1 Tf (Oncotarget)Tj /T1_1 1 Tf [(.)37( 2017;8:73483\22673500.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.046 Tw 7.5 0 0 7.5 36 97.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 97.1221 Tm (63.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 97.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 97.1221 Tm (W)Tj 7.5 0 0 7.5 36 727.1221 Tm 2.926 -84 Td [(esters )37(TM,)37( Ireland R,)37( Kern )37(W)129(,)37( et al.)37( Standardization of \036ow cytome)]TJ 0 Tw (-)Tj 0.082 Tw -0.926 -1.2 Td (try in myelodysplastic syndromes: a report from an international con)Tj 0 Tw (-)Tj 0.183 Tw T* [(sortium and the European LeukemiaNet )37(W)86(orking Group.)37( )]TJ /T1_2 1 Tf 0 Tw [(Leuk)12(emia)]TJ /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2012;26:1730\2261741.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.023 Tw 7.5 0 0 7.5 36 61.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 36.0975 61.1221 Tm (64.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 46.245 61.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 51 61.1221 Tm (Koene HR,)Tj 7.5 0 0 7.5 36 727.1221 Tm 6.82 -88.8 Td [( Kleijer M,)37( Roos D)55(,)37( et al.)37( Fc gamma RIIIB gene duplication: )]TJ 0.025 Tw -4.82 -1.2 Td (evidence for presence and expression of three distinct FC gamma RIIIB )Tj 0 Tw T* [(genes in NA\(1+,2+\)SH\(+\) individuals.)37( )]TJ /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 1998;91:673\226679.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.012 Tw 7.5 0 0 7.5 297 727.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 727.1221 Tm (65.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 727.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 727.1221 Tm (Bruin M,)Tj 7.5 0 0 7.5 36 727.1221 Tm 40.697 0 Td [( Dassen )37(A,)37( Pajkrt D)55(,)37( et al.)37( Primary autoimmune neutropenia in )]TJ -0.016 Tw -3.897 -1.2 Td [(children: a study of neutrophil antibodies and clinical course.)37( )]TJ /T1_2 1 Tf [(V)86(ox Sang)]TJ /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2005;88:52\22659.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.144 Tw 7.5 0 0 7.5 297 700.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 700.1221 Tm (66.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 700.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 700.1221 Tm (Sella R,)Tj 7.5 0 0 7.5 36 727.1221 Tm 40.185 -3.6 Td [( Flomenblit L,)37( Goldstein I,)37( et al.)37( Detection of anti-neutrophil )]TJ 0.06 Tw -3.385 -1.2 Td [(antibodies in autoimmune neutropenia of infancy: a multicenter study)92(.)37( )]TJ /T1_2 1 Tf 0 Tw T* [(Isr Med )37(Assoc J)]TJ /T1_1 1 Tf [(.)37( 2010;12:91\22696.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.043 Tw 7.5 0 0 7.5 297 673.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 673.1221 Tm (67.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 673.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 673.1221 Tm (Audrain )Tj 7.5 0 0 7.5 36 727.1221 Tm 40.591 -7.2 Td [(M,)37( )1(Martin J)24(,)37( )1(Fromont P)129(,)37( )1(et al.)37( )37(Autoimmune )1(neutropenia )1(in )1(chil)]TJ 0 Tw (-)Tj -0.038 Tw -3.791 -1.2 Td [(dren: analysis of 116 cases.)37( )]TJ /T1_2 1 Tf -0.075 Tw [(P)74(ediatr Allerg)18(y )-37(Immunol)]TJ /T1_1 1 Tf -0.038 Tw [(.)37( 2011;22:494\226496.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.161 Tw 7.5 0 0 7.5 297 655.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 655.1221 Tm (68.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 655.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 655.1221 Tm (Kobayashi M,)Tj 7.5 0 0 7.5 36 727.1221 Tm 43.037 -9.6 Td [( Nakamura K,)37( Kawaguchi H,)37( et al.)37( Signi\037cance of the )]TJ 0.057 Tw -6.237 -1.2 Td (detection of antineutrophil antibodies in children with chronic neutro)Tj 0 Tw (-)Tj T* [(penia.)37( )]TJ /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 2002;99:3468\2263471.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.133 Tw 7.5 0 0 7.5 297 628.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 628.1221 Tm (69.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 628.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 628.1221 Tm (Lindqvist H,)Tj 7.5 0 0 7.5 36 727.1221 Tm 42.343 -13.2 Td [( Carlsson G,)37( Moell J)24(,)37( et al.)37( Neutropenia in childhood: a )]TJ -0.002 Tw -5.543 -1.2 Td [(5-year )1(experience at a tertiary )1(center)111(.)37( )]TJ /T1_2 1 Tf [(Eur )1(J P)74(ediatr)]TJ /T1_1 1 Tf [(.)37( 2015;174:801\226807.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.054 Tw 7.5 0 0 7.5 297 610.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 610.1221 Tm (70.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 610.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 610.1221 Tm (Angelino G,)Tj 7.5 0 0 7.5 36 727.1221 Tm 41.932 -15.6 Td [( Caruso R,)37( D\222Argenio P)129(,)37( et al.)37( Etiology)92(,)37( clinical outcome,)37( and )]TJ 0.03 Tw -5.132 -1.2 Td [(laboratory features in children with neutropenia: analysis of 104 cases.\ )37( )]TJ /T1_2 1 Tf -0.037 Tw T* [(P)74(ediatr Allerg)18(y )-37(Immunol)]TJ /T1_1 1 Tf 0 Tw [(.)37( 2014;25:283\226289.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.055 Tw 7.5 0 0 7.5 297 583.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 583.1221 Tm (71.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 583.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 583.1221 Tm (Porretti L,)Tj 7.5 0 0 7.5 36 727.1221 Tm 41.153 -19.2 Td [( Farruggia P)129(,)37( Colombo FS,)37( et al.)37( Diagnostic value of cell bound )]TJ 0.055 Tw -4.353 -1.2 Td [(and circulating neutrophil antibody detection in pediatric neutropenia.)37( )]TJ /T1_2 1 Tf 0 Tw T* [(P)74(ediatr Blood Cancer)]TJ /T1_1 1 Tf [(.)37( 2018;65:e26904.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.099 Tw 7.5 0 0 7.5 297 556.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 556.1221 Tm (72.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 556.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 556.1221 Tm (Hartman KR,)Tj 7.5 0 0 7.5 36 727.1221 Tm 42.806 -22.8 Td [( )37(W)50(right DG.)37( Identi\037cation of autoantibodies speci\037c for )]TJ 0.169 Tw -6.006 -1.2 Td [(the )1(neutrophil )1(adhesion )1(glycoproteins )1(CD11b/CD18 )1(in )1(patients )1(with )]TJ 0 Tw T* [(autoimmune neutropenia.)37( )]TJ /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 1991;78:1096\2261104.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.438 Tw 7.5 0 0 7.5 297 529.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 529.1221 Tm (73.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 529.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 529.1221 Tm (Logue GL,)Tj 7.5 0 0 7.5 36 727.1221 Tm 41.813 -26.4 Td [( Shastri KA,)37( Laughlin M,)37( et al.)37( Idiopathic neutrope)]TJ 0 Tw (-)Tj 0.275 Tw -5.013 -1.2 Td [(nia: antineutrophil antibodies and clinical correlations.)37( )]TJ /T1_2 1 Tf (Am J Med)Tj /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (1991;90:211\226216.)Tj ET BT /Span <>BDC /T1_1 1 Tf -0.002 Tw 7.5 0 0 7.5 297 502.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 502.1221 Tm (74.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 502.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 502.1221 Tm (de Fontbrune FS,)Tj 7.5 0 0 7.5 36 727.1221 Tm 44.153 -30 Td [( Moignet )37(A,)37( Blandine Beaupain B,)37( et al.)37( Severe chronic )]TJ -0.022 Tw -7.353 -1.2 Td [(primary )1(neutropenia in )1(adults: report on a )1(series of 108 patients.)37( )]TJ /T1_2 1 Tf 0 Tw 27.946 0 Td (Blood)Tj /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -27.946 -1.2 Td (2015;126:1643\2261650.)Tj ET BT /Span <>BDC /T1_1 1 Tf -0.053 Tw 7.5 0 0 7.5 297 475.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 475.1221 Tm (75.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 475.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 475.1221 Tm (Bux J)Tj 7.5 0 0 7.5 36 727.1221 Tm 39.113 -33.6 Td [(,)37( Chapman J)24(.)37( Report on the second international granulocyte serol)]TJ 0 Tw (-)Tj -2.313 -1.2 Td [(ogy workshop.)37( )]TJ /T1_2 1 Tf [(T)55(r)45(ansfusion)]TJ /T1_1 1 Tf [(.)37( 1997;37:977\226983.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.05 Tw 7.5 0 0 7.5 297 457.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 457.1221 Tm (76.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 457.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 457.1221 Tm (Schulz U,)Tj 7.5 0 0 7.5 36 727.1221 Tm 40.869 -36 Td [( Reil )37(A,)37( Kiefel )37(V)129(,)37( et al.)37( Evaluation of a new microbeads assay )]TJ 0 Tw -4.069 -1.2 Td [(for granulocyte antibody detection.)37( )]TJ /T1_2 1 Tf [(T)55(r)45(ansfusion)]TJ /T1_1 1 Tf [(.)37( 2017;57:70\22681.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.031 Tw 7.5 0 0 7.5 297 439.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 439.1221 Tm (77.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 439.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 439.1221 Tm (Farruggia P)Tj 7.5 0 0 7.5 36 727.1221 Tm 41.705 -38.4 Td [(,)37( Dufour C.)37( Diagnosis and management of primary autoim)]TJ 0 Tw (-)Tj -0.054 Tw -4.905 -1.2 Td [(mune neutropenia in children: insights for clinicians.)37( )]TJ /T1_2 1 Tf -0.091 Tw [(Ther Adv )-37(Hematol)]TJ /T1_1 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2015;6:15\22624.)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.036 Tw 7.5 0 0 7.5 297 412.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 412.1221 Tm (78.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 412.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 412.1221 Tm (Boxer LA,)Tj 7.5 0 0 7.5 36 727.1221 Tm 41.243 -42 Td [( Bolyard )37(AA,)37( Marrero )37(TM,)37( et al.)37( Is there a role for anti-neu)]TJ 0 Tw (-)Tj 0.002 Tw -4.443 -1.2 Td [(trophil )1(antibody )1(testing )1(in predicting )1(spontaneous )1(resolution )1(of neutro)]TJ 0 Tw (-)Tj T* (penia in young children? )Tj /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 2015;126:2211\2262211.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.014 Tw 7.5 0 0 7.5 297 385.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 385.1221 Tm (79.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 385.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 385.1221 Tm (Dobrewa )Tj 7.5 0 0 7.5 36 727.1221 Tm 41.028 -45.6 Td [(W)129(,)37( Madzio J)24(,)37( Babol-Pokora K,)37( et al.)37( )37(A high prevalence of neu)]TJ 0 Tw (-)Tj -0.006 Tw -4.228 -1.2 Td (trophil-speci\037c antibodies in ELANE-mutated severe congenital neutro)Tj 0 Tw (-)Tj T* [(penia.)37( )]TJ /T1_2 1 Tf [(P)74(ediatr Blood Cancer)]TJ /T1_1 1 Tf [(.)37( 2023;70:e30247.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.024 Tw 7.5 0 0 7.5 297 358.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 358.1221 Tm (80.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 358.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 358.1221 Tm (W)Tj 7.5 0 0 7.5 36 727.1221 Tm 37.714 -49.2 Td [(oloszynek )1(JR,)37( )1(Rothbaum )1(RJ)24(,)37( )1(Rawls )38(AS,)37( )1(et )1(al.)37( )1(Mutations )1(of )1(the )1(SBDS )]TJ -0.02 Tw -0.914 -1.2 Td [(gene )1(are )1(present )1(in most patients with )1(Shwachman-Diamond syndrome.)37( )]TJ /T1_2 1 Tf 0 Tw T* (Blood)Tj /T1_1 1 Tf [(.)37( 2004;104:3588\2263590.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.02 Tw 7.5 0 0 7.5 297 331.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 331.1221 Tm (81.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 331.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 331.1221 Tm (Richards S,)Tj 7.5 0 0 7.5 36 727.1221 Tm 41.673 -52.8 Td [( )37(Aziz N,)37( Bale S,)37( et al.)37( Standards and guidelines for the inter)]TJ 0 Tw 25.594 0 Td (-)Tj 0.344 Tw -30.467 -1.2 Td (pretation of sequence variants: a joint consensus recommendation )Tj 0.156 Tw T* [(of the )37(American College of Medical Genetics and Genomics and the )]TJ 0 Tw T* [(Association for Molecular Pathology)92(.)37( )]TJ /T1_2 1 Tf (Genet Med)Tj /T1_1 1 Tf [(.)37( 2015;17:405\226424.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.087 Tw 7.5 0 0 7.5 297 295.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 295.1221 Tm (82.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 295.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 295.1221 Tm (Kluk MJ)Tj 7.5 0 0 7.5 36 727.1221 Tm 40.642 -57.6 Td [(,)37( Lindsley R)74(C,)37( )37(Aster JC,)37( et al.)37( )37(V)86(alidation and implementation )]TJ 0.086 Tw -3.842 -1.2 Td (of a custom next-generation sequencing clinical assay for hematologic )Tj 0 Tw T* [(malignancies.)37( )]TJ /T1_2 1 Tf (J Mol Diagn)Tj /T1_1 1 Tf [(.)37( 2016;18:507\226515.)]TJ ET BT /Span <>BDC /T1_1 1 Tf -0.043 Tw 7.5 0 0 7.5 297 268.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 268.1221 Tm (83.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 268.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 268.1221 Tm (Lucas F)Tj 7.5 0 0 7.5 36 727.1221 Tm 39.963 -61.2 Td [(,)37( Michaels PD)55(,)37( )37(W)86(ang D)55(,)37( et al.)37( Mutational analysis of hematologic )]TJ -0.021 Tw -3.163 -1.2 Td (neoplasms in 164 paired peripheral blood and bone marrow samples by )Tj 0 Tw T* [(next-generation sequencing.)37( )]TJ /T1_2 1 Tf -0.037 Tw (Blood Adv)Tj /T1_1 1 Tf 0 Tw [(.)37( 2020;4:4362\2264365.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.017 Tw 7.5 0 0 7.5 297 241.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 241.1221 Tm (84.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 241.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 241.1221 Tm (Atallah-Y)Tj 7.5 0 0 7.5 36 727.1221 Tm 40.954 -64.8 Td [(unes S)30(A,)37( Ready )37(A,)37( Newburger PE.)37( Benign ethnic neutropenia.)37( )]TJ /T1_2 1 Tf 0 Tw -4.154 -1.2 Td (Blood Rev)Tj /T1_1 1 Tf [(.)37( 2019;37:100586.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.01 Tw 7.5 0 0 7.5 297 223.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 223.1221 Tm (85.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 223.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 223.1221 Tm (Fragiadaki I,)Tj 7.5 0 0 7.5 36 727.1221 Tm 42.275 -67.2 Td [( Papadakis S,)37( Sevastaki G,)37( et al.)37( Increased frequency of the )]TJ 0.091 Tw -5.475 -1.2 Td [(single nucleotide polymorphism of the D)60(AR)74(C/A)37(CKR1 gene associated )]TJ 0.051 Tw T* (with ethnic neutropenia in a cohort of European patients with chronic )Tj 0 Tw T* [(idiopathic neutropenia.)37( )]TJ /T1_2 1 Tf (Am J Hematol)Tj /T1_1 1 Tf [(.)37( 2020;95:E163\226E166.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.004 Tw 7.5 0 0 7.5 297 187.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 187.1221 Tm (86.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 187.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 187.1221 Tm (Lamy )Tj 7.5 0 0 7.5 36 727.1221 Tm 39.488 -72 Td [(T)111(,)37( Moignet )37(A,)37( Loughran )37(TP)129(.)37( LGL leukemia: from pathogenesis to )]TJ 0 Tw -2.688 -1.2 Td [(treatment.)37( )]TJ /T1_2 1 Tf (Blood)Tj /T1_1 1 Tf [(.)37( 2017;129:1082\2261094.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.223 Tw 7.5 0 0 7.5 297 169.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 169.1221 Tm (87.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 169.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 169.1221 Tm (Mu\361oz-Garc\355a )Tj 7.5 0 0 7.5 36 727.1221 Tm 43.635 -74.4 Td [(N,)37( )1(Mor\341n-Plata )1(F)18(J)24(,)37( )38(V)37(illamor )1(N,)37( )1(et )1(al.)37( )1(High-sensitive )]TJ 0.191 Tw -6.835 -1.2 Td [(TRBC1-based \036ow cytometric assessment of )37(T)104(-cell clonality in )37(T)]TJ /T1_3 1 Tf 0 Tw (\037\036)Tj /T1_1 1 Tf (-)Tj T* [(large granular lymphocytic leukemia.)37( )]TJ /T1_2 1 Tf [(Cancer)12(s \(Basel\))]TJ /T1_1 1 Tf [(.)37( 2022;14:408.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.178 Tw 7.5 0 0 7.5 297 142.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 142.1221 Tm (88.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 142.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 142.1221 Tm (Della Porta MG,)Tj 7.5 0 0 7.5 36 727.1221 Tm 44.343 -78 Td [( Picone C,)37( Pascutto C,)37( et al.)37( Multicenter validation )]TJ 0.068 Tw -7.543 -1.2 Td (of a reproducible \036ow cytometric score for the diagnosis of low-grade\ )Tj -0.002 Tw T* [(myelodysplastic syndromes: results of a European LeukemiaNET study)92(.)37( )]TJ /T1_2 1 Tf 0 Tw T* (Haematologica)Tj /T1_1 1 Tf [(.)37( 2012;97:1209\2261217.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.061 Tw 7.5 0 0 7.5 297 106.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 106.1221 Tm (89.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 106.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 106.1221 Tm (van Dongen JJM,)Tj 7.5 0 0 7.5 36 727.1221 Tm 44.443 -82.8 Td [( Lhermitte L,)37( B\366ttcher S,)37( et al.)37( EuroFlow consortium )]TJ 0.004 Tw -7.643 -1.2 Td [(\(EU-FP6,)37( LSHB-CT)104(-2006-018708\).)37( EuroFlow antibody panels for stan)]TJ 0 Tw (-)Tj 0.198 Tw T* [(dardized )1(n-dimensional )1(\036ow cytometric )1(immunophenotyping of )1(nor)]TJ 0 Tw 30.467 0 Td (-)Tj -0.054 Tw -30.467 -1.2 Td [(mal,)37( reactive and malignant leukocytes.)37( )]TJ /T1_2 1 Tf 0 Tw [(Leuk)12(emia)]TJ /T1_1 1 Tf -0.054 Tw [(.)37( 2012;26:1908\2261975.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 0.041 Tw 7.5 0 0 7.5 297 70.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 297.0975 70.1221 Tm (90.)Tj ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 307.245 70.1221 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 312 70.1221 Tm (W)Tj 7.5 0 0 7.5 36 727.1221 Tm 37.726 -87.6 Td [(esters )37(TM,)37( )37(Alhan C,)37( )37(V)37(isser)55(-W)18(isselaar HA,)37( et al.)37( Dysplasia and PNH-)]TJ 0.271 Tw -0.926 -1.2 Td [(type cells in bone marrow aspirates of myelodysplastic syndromes.)37( )]TJ /T1_2 1 Tf 0.4 Tw T* (Cytometry B Clin Cytom)Tj /T1_1 1 Tf [(.)37( 2021:1\22611.)37( doi: 10.1002/cyto.b.22038.)37( )]TJ 0 Tw T* (Online ahead of print.)Tj 0 0 0 0 k /GS0 gs 9 0 0 9 3.6695 450.2461 Tm [(A)37(Q16)]TJ 60.889 -44.791 Td [(A)37(Q17)]TJ ET q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 787 0 obj <> endobj 788 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 300.052 24.0881 Tm (13)Tj ET /PlacedGraphic /MC0 BDC q 1 0 0 1 55.0115967 759.9024048 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 0 -2.901 l -2.529 -2.901 l -2.529 0 l -4.011 0 l -4.011 -7.304 l -2.529 -7.304 l -2.529 -4.151 l 0 -4.151 l 0 -7.304 l 1.481 -7.304 l 1.481 0 l h f Q q 51 750.589 56.165 9.41 re W n q 1 0 0 1 58.9167023 755.8701019 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.307 0.974 0.053 0.604 0 0 c 2.942 -2.466 m 2.571 -3.112 1.958 -3.366 1.005 -3.366 c -0.582 -3.366 -1.344 -2.339 -1.344 -0.974 c -1.344 -0.254 l -1.344 1.344 -0.54 2.116 0.835 2.116 c 2.33 2.116 3.016 1.248 3.016 -0.36 c 3.016 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 67.2454071 752.5995941 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -1.344 0 l -1.344 3.101 l -1.344 3.947 -1.672 4.223 -2.148 4.223 c -2.625 4.223 -2.984 3.863 -2.984 3.111 c -2.984 0 l -4.339 0 l -4.339 5.291 l -3.016 5.291 l -3.016 4.848 l -2.815 5.122 -2.435 5.387 -1.842 5.387 c -1.207 5.387 -0.688 5.144 -0.36 4.678 c 0.013 5.135 0.574 5.396 1.164 5.387 c 2.317 5.387 2.995 4.687 2.995 3.312 c 2.995 -0.001 l 1.64 -0.001 l 1.64 3.101 l 1.64 3.895 1.366 4.223 0.825 4.223 c 0.339 4.223 0 3.863 0 3.111 c h f Q q 1 0 0 1 74.0608063 754.7783051 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -0.889 0 l -1.439 0 -1.683 -0.18 -1.683 -0.593 c -1.683 -1.005 -1.375 -1.186 -0.91 -1.186 c -0.296 -1.186 0.003 -0.921 0.003 -0.201 c h -1.047 0.996 m 0 0.996 l 0 1.304 l 0 1.896 -0.179 2.086 -0.941 2.086 c -1.46 2.086 -1.714 2.012 -1.937 1.663 c -2.889 2.326 l -2.499 2.972 -1.906 3.205 -0.814 3.205 c 0.55 3.205 1.323 2.802 1.323 1.289 c 1.323 -2.182 l 0 -2.182 l 0 -1.717 l -0.212 -2.076 -0.529 -2.277 -1.143 -2.277 c -2.244 -2.277 -3.005 -1.696 -3.005 -0.617 c -3.005 0.51 -2.159 0.996 -1.047 0.996 c f Q q 1 0 0 1 80.4425964 758.0068054 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.317 0.498 -0.698 0.741 -1.439 0.741 c -2.103 0.741 -2.466 0.435 -2.466 -0.062 c -2.466 -0.635 -2 -0.889 -1.026 -1.132 c 0.497 -1.513 1.186 -2.084 1.186 -3.373 c 1.186 -4.568 0.381 -5.5 -1.333 -5.5 c -2.614 -5.5 -3.502 -5.15 -4.148 -4.304 c -3.016 -3.521 l -2.625 -4.008 -2.18 -4.251 -1.429 -4.251 c -0.582 -4.251 -0.296 -3.881 -0.296 -3.436 c -0.296 -2.928 -0.603 -2.643 -1.791 -2.335 c -3.229 -1.954 -3.948 -1.268 -3.948 -0.061 c -3.948 1.094 -3.187 1.993 -1.451 1.993 c -0.289 1.993 0.592 1.602 1.11 0.797 c h f Q q 1 0 0 1 85.7776031 754.9795074 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 0 0.55 l 0 1.396 -0.265 1.862 -0.931 1.862 c -1.577 1.862 -1.873 1.439 -1.873 0.666 c -1.873 0.002 l -1.873 -0.76 -1.693 -1.331 -0.931 -1.331 c -0.202 -1.337 -0.001 -0.761 -0.001 0.002 c h 1.354 -0.083 m 1.354 -1.459 0.656 -2.476 -0.709 -2.476 c -1.26 -2.476 -1.63 -2.369 -1.871 -2.168 c -1.871 -4.39 l -3.228 -4.39 l -3.228 2.914 l -1.874 2.914 l -1.874 2.564 l -1.62 2.85 -1.239 3.009 -0.699 3.009 c 0.524 3.007 1.354 2.149 1.354 0.637 c h f Q q 1 0 0 1 88.0207977 759.902298 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.352 0 l 1.352 -2.424 l 1.554 -2.159 1.925 -1.916 2.538 -1.916 c 3.606 -1.916 4.475 -2.424 4.475 -3.991 c 4.475 -7.304 l 3.132 -7.304 l 3.132 -4.202 l 3.132 -3.377 2.836 -3.08 2.285 -3.08 c 1.661 -3.08 1.355 -3.495 1.355 -4.191 c 1.355 -7.303 l 0 -7.303 l h f Q q 1 0 0 1 94.7415009 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.659 0 l 1.628 0.687 1.354 0.974 0.846 0.974 c 0.306 0.974 0.052 0.604 0 0 c 2.941 -2.466 m 2.571 -3.112 1.957 -3.366 1.005 -3.366 c -0.583 -3.366 -1.345 -2.339 -1.345 -0.974 c -1.345 -0.254 l -1.345 1.344 -0.541 2.116 0.835 2.116 c 2.329 2.116 3.015 1.248 3.015 -0.36 c 3.015 -0.963 l 0 -0.963 l 0.01 -1.693 0.243 -2.223 0.995 -2.223 c 1.557 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 101.5989075 756.4199066 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.139 0.201 -0.328 0.402 -0.664 0.402 c -1.173 0.402 -1.511 0.032 -1.511 -0.709 c -1.511 -3.82 l -2.868 -3.82 l -2.868 1.471 l -1.545 1.471 l -1.545 1.027 l -1.366 1.292 -1.017 1.566 -0.393 1.566 c 0.232 1.566 0.723 1.29 1.037 0.74 c h f Q q 1 0 0 1 104.1477051 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.309 0.974 0.055 0.604 0 0 c 2.943 -2.466 m 2.572 -3.112 1.959 -3.366 1.007 -3.366 c -0.58 -3.366 -1.343 -2.339 -1.343 -0.974 c -1.343 -0.254 l -1.343 1.344 -0.538 2.116 0.837 2.116 c 2.331 2.116 3.018 1.248 3.018 -0.36 c 3.018 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.936 -1.768 c h f Q EMC Q BT /T1_1 1 Tf 8 0 0 8 107.1653 750.5894 Tm ( )Tj /T1_2 1 Tf 0.278 0.25 Td ( \(2023\) 7:4)Tj ET BT /Span <>BDC /T1_2 1 Tf 38.328 Tw 8 0 0 8 107.1653 750.5894 Tm 4.93 0.25 Td ( )Tj EMC ET BT /T1_2 1 Tf 8 0 0 8 455.4453 752.5894 Tm (www)Tj 8 0 0 8 107.1653 750.5894 Tm 45.703 0.25 Td [(.hemaspher)18(ejour)-18(nal.com)]TJ /T1_3 1 Tf -0.01 Tc 0.046 Tw 9 0 0 9 51 725.9761 Tm [(especially)92(,)37( if neutropenia is associated with concurrent infection,)27( )]TJ 0 Tw 0 -1.111 TD (genetic analysis should also be performed to exclude CN.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_4 1 Tf 0 Tc 8 0 0 8 51 692.388 Tm [(T)92(ransient neutropenia of infants)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.319 Tw 9 0 0 9 61 682.388 Tm [(T)67(ransient )1(neutropenia )1(of )1(infants )1(is )1(typically )1(observed )1(at )]TJ 0.123 Tw -1.111 -1.111 Td (~3\2264 weeks of life in former preterm newborns who suffered )Tj 0.302 Tw T* [(from )1(anemia )1(of )1(prematurity)92(.)]TJ 0 Tw 5.247 0 0 5.247 169.291 665.385 Tm (138\226140)Tj 0.302 Tw 9 0 0 9 189.4184 662.388 Tm [( )1(It )1(is )1(probably )1(related )1(to )]TJ 0.289 Tw -15.38 -1.111 Td [(HSC )1(competition )1(between )1(compensatory )1(erythropoiesis )1(and )]TJ 0 Tw T* (granulocytopoiesis.)Tj 5.247 0 0 5.247 126.0235 645.385 Tm (138\226140)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_4 1 Tf 8 0 0 8 51 618.8 Tm [(Sever)-6(e CN)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.083 Tw 9 0 0 9 61 608.8 Tm (Severe CN syndromes can obviously have their clinical pre)Tj 0 Tw (-)Tj 0.022 Tw -1.111 -1.111 Td [(sentation in neonatal age.)37( For the investigation of isolated neu)]TJ 0 Tw (-)Tj 0.215 Tw T* [(tropenia )1(in neonates )1(without a phenotype )1(suggestive )1(of any )]TJ 0.018 Tw T* [(speci\037c disease/syndrome,)37( it is advisable to pursue the pathway )]TJ 0 Tw T* (described in the \036owchart of Figure\0352.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 7.5 0 0 7.5 51 541.8 Tm (ACKNOWLEDGMENTS)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.037 Tw 1.333 -1.767 Td [(The authors thank Mr Francesco Cerisoli,)37( Ms Sara Roman Galdran,)37( Ms )]TJ 0.011 Tw -1.333 -1.2 Td [(Anastasia Naoum,)37( and Ms Xiamo )37(W)86(ang,)37( staff of the European Hematology )]TJ 0.111 Tw 0 -1.2 TD [(Association \(EHA\) Executive Of\037ce,)37( for their scienti\037c and organizational )]TJ 0.277 Tw T* [(support on the EHA/EuNet-INNOCHR)45(ON Guidelines project.)37( )37(W)74(e also )]TJ 0 Tw T* [(thank Ms Cristina )37(Ardoino for technical support.)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 0 -3.6 TD (AUTHOR CONTRIBUTIONS)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.042 Tw 1.333 -1.767 Td (All authors participated in the meetings for the production of the guide\ )Tj 0 Tw (-)Tj 0.114 Tw -1.333 -1.2 Td [(lines described in the article.)37( )37(All authors contributed in the writing of the )]TJ 0 Tw 0 -1.2 TD (article.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 0 -3.6 TD (DISCLOSURES)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.505 Tw 1.333 -1.767 Td [(FF: )37(Advisory Board honorarium from X4 Pharmaceuticals.)37( PEN: )]TJ 0.115 Tw -1.333 -1.2 Td [(Consultant for X4 Pharmaceuticals.)37( JP: Consultant to Chiesi Canada Ltd.)37( )]TJ 0.127 Tw 0 -1.2 TD [(DCD: Consultant and research support: )37(Amgen,)37( X4Pharma,)37( Emendo Bio; )]TJ -0.075 Tw T* [(data )1(safety )1(monitoring )1(committee: )1(Galderma,)37( )1(Omeros,)37( )1(X4Pharma,)37( )1(Hoffman-)]TJ 0.616 Tw T* [(LaRoche,)37( Insmed; consultant: Boerhinger)55(-Ingelheim,)37( Prolong,Coherus,)37( )]TJ 0.202 Tw T* [(Spectrum,)37( Shire,)37( Seattle Genetics.)37( CD: )37(Advisory Board honorarium from )]TJ 0.141 Tw T* [(Gilead,)37( Novartis,)37( P\037zer)111(,)37( Rockets,)37( Sobi.)37( HAP: )37(Advisory Board honorarium )]TJ 0.019 Tw T* [(from X4 Pharmaceuticals.)37( )37(All the other authors have no con\036icts of interest )]TJ 0 Tw T* [(to disclose.)37( )]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 0 -3.6 TD (SOURCES OF FUNDING)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.264 Tw 1.333 -1.767 Td (This article is based on the work from Cooperation in Science and )Tj 0.155 Tw -1.333 -1.2 Td [(T)86(echnology )1(\(COST\) )38(Action )1(C)30(A18233 )75(\223European )1(Network )1(for )1(Innovative )]TJ 0.058 Tw 0 -1.2 TD [(Diagnosis )1(and treatment of )1(Chronic )1(Neutropenias,)37( )1(EuNet-INNOCHR)45(ON\224)74( )]TJ -0.027 Tw T* [(\(https://www)92(.eunet-innochron.eu/\) supported by COST)111(.)37( PEN and DCD were )]TJ 0 Tw T* [(supported by a NIH R24 )37(AI162637 grant.)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 0 -3.733 TD (REFERENCES)Tj ET BT /Span <>BDC 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.063 Tw 7.5 0 0 7.5 51 204.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 204.54 Tm (1.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 204.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 204.54 Tm (Dale DC.)Tj 7.5 0 0 7.5 51 541.8 Tm 6.082 -44.968 Td [( How I diagnose and treat neutropenia.)37( )]TJ /T1_5 1 Tf (Curr Opin Hematol)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -4.082 -1.2 Td (2016;23:1\2264.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.528 Tw 7.5 0 0 7.5 51 186.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 186.54 Tm (2.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 186.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 186.54 Tm (Furutani E,)Tj 7.5 0 0 7.5 51 541.8 Tm 7.383 -47.368 Td [( Newburger PE,)37( Shimamura )37(A.)37( Neutropenia in the )]TJ 0.398 Tw -5.383 -1.2 Td [(age of genetic testing: )37(Advances and challenges.)37( )]TJ /T1_5 1 Tf (Am J Hematol)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw 0 -1.2 TD (2019;94:384\226393.)Tj ET BT /Span <>BDC /T1_3 1 Tf -0.041 Tw 7.5 0 0 7.5 51 159.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 159.54 Tm (3.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 159.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 159.54 Tm (Skokowa J)Tj 7.5 0 0 7.5 51 541.8 Tm 6.604 -50.968 Td [(,)37( Dale DC,)37( )37(T)98(ouw IP)129(,)37( et al.)37( Severe congenital neutropenias.)37( )]TJ /T1_5 1 Tf 0 Tw (Nat )Tj -4.604 -1.2 Td [(Rev Dis Primer)12(s)]TJ /T1_3 1 Tf [(.)37( 2017;3:17032.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.041 Tw 7.5 0 0 7.5 51 141.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 141.54 Tm (4.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 141.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 141.54 Tm (Donadieu J)Tj 7.5 0 0 7.5 51 541.8 Tm 6.908 -53.368 Td [(,)37( Beaupain B,)37( Fenneteau O)55(,)37( et al.)37( Congenital neutropenia in )]TJ 0.088 Tw -4.908 -1.2 Td [(the era of genomics: classi\037cation,)37( diagnosis,)37( and natural history)92(.)37( )]TJ /T1_5 1 Tf (Br J )Tj 0 Tw T* (Haematol)Tj /T1_3 1 Tf [(.)37( 2017;179:557\226574.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.111 Tw 7.5 0 0 7.5 51 114.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 114.54 Tm (5.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 114.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 114.54 Tm (Klein C.)Tj 7.5 0 0 7.5 51 541.8 Tm 5.63 -56.968 Td ( Children with rare diseases of neutrophil granulocytes: from )Tj -0.045 Tw -3.63 -1.2 Td [(therapeutic orphans to pioneers of individualized medicine.)37( )]TJ /T1_5 1 Tf 0 Tw [(Hematolog)18(y )]TJ T* [(Am Soc Hematol Educ Progr)45(am)]TJ /T1_3 1 Tf [(.)37( 2016;2016:33\22637.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.028 Tw 7.5 0 0 7.5 51 87.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 87.54 Tm (6.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 87.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 87.54 Tm (W)Tj 7.5 0 0 7.5 51 541.8 Tm 2.914 -60.568 Td [(arren )37(A)24(J)24(.)37( Molecular basis of the human ribosomopathy Shwachman-)]TJ 0 Tw -0.914 -1.2 Td [(Diamond syndrome.)37( )]TJ /T1_5 1 Tf (Adv Biol Regul)Tj /T1_3 1 Tf [(.)37( 2018;67:109\226127.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.028 Tw 7.5 0 0 7.5 51 69.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 69.54 Tm (7.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 69.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 69.54 Tm (T)Tj 7.5 0 0 7.5 51 541.8 Tm 2.58 -62.968 Td [(an S,)37( Kermasson L,)37( Hilcenko C,)37( et al.)37( Somatic genetic rescue of a ger)]TJ 0 Tw 29.887 0 Td (-)Tj -30.467 -1.2 Td [(mline ribosome assembly defect.)37( )]TJ /T1_5 1 Tf (Nat Commun)Tj /T1_3 1 Tf [(.)37( 2021;12:5044.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.176 Tw 7.5 0 0 7.5 51 51.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 51.0975 51.54 Tm (8.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 57.075 51.54 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 66 51.54 Tm (Dale DC,)Tj 7.5 0 0 7.5 51 541.8 Tm 6.195 -65.368 Td [( Bolyard )37(AA,)37( Steele LA,)37( et al.)37( Severe Chronic Neutropenia )]TJ -0.121 Tw -4.195 -1.2 Td [(International )1(registry)92(.)37( )1(Registries )1(for )1(study )1(of )1(nonmalignant )1(hematological )]TJ 0.058 Tw 34.8 91.278 Td (diseases: the example of the Severe Chronic Neutropenia International )Tj 0 Tw T* [(Registry)92(.)37( )]TJ /T1_5 1 Tf (Curr Opin Hematol)Tj /T1_3 1 Tf [(.)37( 2020;27:18\22626.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.633 Tw 7.5 0 0 7.5 312 709.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 709.125 Tm (9.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 318.075 709.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 709.125 Tm (Newburger PE.)Tj 7.5 0 0 7.5 51 541.8 Tm 44.008 22.31 Td [( )37(Autoimmune and other acquired neutropenias.)37( )]TJ /T1_5 1 Tf 0 Tw -7.208 -1.2 Td [(Hematolog)18(y )37(Am Soc Hematol Educ Progr)45(am)]TJ /T1_3 1 Tf [(.)37( 2016;2016:38\22642.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.026 Tw 7.5 0 0 7.5 312 691.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 691.125 Tm (10.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 691.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 691.125 Tm (Palmblad J)Tj 7.5 0 0 7.5 51 541.8 Tm 41.525 19.91 Td [(,)37( Dufour C,)37( Papadaki HA.)37( How we diagnose neutropenia in )]TJ 0 Tw -4.725 -1.2 Td [(the adult and elderly patient.)37( )]TJ /T1_5 1 Tf (Haematologica)Tj /T1_3 1 Tf [(.)37( 2014;99:1130\2261133.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.063 Tw 7.5 0 0 7.5 312 673.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 673.125 Tm (11.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 673.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 673.125 Tm (Palmblad J)Tj 7.5 0 0 7.5 51 541.8 Tm 41.562 17.51 Td [(,)37( Nilsson CC,)37( H\366glund P)129(,)37( et al.)37( How we diagnose and treat )]TJ 0 Tw -4.762 -1.2 Td [(neutropenia in adults.)37( )]TJ /T1_5 1 Tf (Expert Rev Hematol)Tj /T1_3 1 Tf [(.)37( 2016;9:479\226487.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.019 Tw 7.5 0 0 7.5 312 655.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 655.125 Tm (12.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 655.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 655.125 Tm (Gibson C,)Tj 7.5 0 0 7.5 51 541.8 Tm 41.135 15.11 Td [( Berliner N.)37( How we evaluate and treat neutropenia in adults.)37( )]TJ /T1_5 1 Tf 0 Tw -4.335 -1.2 Td (Blood)Tj /T1_3 1 Tf [(.)37( 2014;124:1251\2268; quiz 1378.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.096 Tw 7.5 0 0 7.5 312 637.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 637.125 Tm (13.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 637.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 637.125 Tm (Papadaki HA,)Tj 7.5 0 0 7.5 51 541.8 Tm 42.972 12.71 Td [( Mavroudi I,)37( )37(Almeida )37(A,)37( et al.)37( Congenital and acquired )]TJ 0.167 Tw -6.172 -1.2 Td [(chronic neutropenias: challenges,)37( perspectives and implementation of )]TJ 0 Tw T* [(the EuNet-INNOCHR)45(ON action.)37( )]TJ /T1_5 1 Tf (Hemasphere)Tj /T1_3 1 Tf [(.)37( 2020;4:e406.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.005 Tw 7.5 0 0 7.5 312 610.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 610.125 Tm (14.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 610.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 610.125 Tm (Steurer J)Tj 7.5 0 0 7.5 51 541.8 Tm 40.493 9.11 Td [(.)37( )37(The Delphi method: an ef\037cient procedure to generate knowl)]TJ 0 Tw (-)Tj -3.693 -1.2 Td [(edge.)37( )]TJ /T1_5 1 Tf [(Sk)12(elet Radiol)]TJ /T1_3 1 Tf [(.)37( 2011;40:959\226961.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.236 Tw 7.5 0 0 7.5 312 592.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 592.125 Tm (15.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 592.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 592.125 Tm (Fioredda F)Tj 7.5 0 0 7.5 51 541.8 Tm 41.578 6.71 Td [(,)37( Onofrillo D)55(,)37( Farruggia P)129(,)37( et al.)37( Diagnosis and manage)]TJ 0 Tw (-)Tj 0.082 Tw -4.778 -1.2 Td (ment of neutropenia in children: the approach of the Study Group on )Tj 0.176 Tw T* (Neutropenia and Marrow Failure Syndromes of the Pediatric Italian )Tj -0.04 Tw T* [(Hemato-Oncology )37(Association \(Associazione Italiana Emato-Oncologia )]TJ -0.037 Tw T* [(Pediatrica )-37(- AIEOP\).)37( )]TJ /T1_5 1 Tf 0 Tw 9.035 0 Td [(P)74(ediatr Blood Cancer)]TJ /T1_3 1 Tf [(.)37( 2022;69:e29599.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.104 Tw 7.5 0 0 7.5 312 547.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 547.125 Tm (16.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 547.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 547.125 Tm (Schmutz N,)Tj 7.5 0 0 7.5 51 541.8 Tm 41.921 0.71 Td [( Henry E,)37( Jopling J)24(,)37( et al.)37( Expected ranges for blood neu)]TJ 0 Tw (-)Tj 0.106 Tw -5.121 -1.2 Td (trophil concentrations of neonates: the Manroe and Mouzinho charts )Tj 0 Tw T* [(revisited.)37( )]TJ /T1_5 1 Tf [(J P)74(erinatol)]TJ /T1_3 1 Tf [(.)37( 2008;28:275\226281.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.023 Tw 7.5 0 0 7.5 312 520.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 520.125 Tm (17.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 520.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 520.125 Tm (Christensen RD)Tj 7.5 0 0 7.5 51 541.8 Tm 43.556 -2.89 Td [(,)37( Henry E,)37( Jopling J)24(,)37( et al.)37( )37(The CBC: reference ranges for )]TJ 0 Tw -6.756 -1.2 Td [(neonates.)37( )]TJ /T1_5 1 Tf [(Semin P)74(erinatol)]TJ /T1_3 1 Tf [(.)37( 2009;33:3\22611.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.163 Tw 7.5 0 0 7.5 312 502.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 502.125 Tm (18.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 502.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 502.125 Tm (Dale DC.)Tj 7.5 0 0 7.5 51 541.8 Tm 40.982 -5.29 Td [( How I manage children with neutropenia.)37( )]TJ /T1_5 1 Tf (Br J Haematol)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -4.182 -1.2 Td (2017;178:351\226363.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.029 Tw 7.5 0 0 7.5 312 484.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 484.125 Tm (19.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 484.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 484.125 Tm (Newburger PE,)Tj 7.5 0 0 7.5 51 541.8 Tm 43.404 -7.69 Td [( Dale DC.)37( Evaluation and management of patients with )]TJ 0 Tw -6.604 -1.2 Td [(isolated neutropenia.)37( )]TJ /T1_5 1 Tf (Semin Hematol)Tj /T1_3 1 Tf [(.)37( 2013;50:198\226206.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.002 Tw 7.5 0 0 7.5 312 466.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 466.125 Tm (20.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 466.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 466.125 Tm (Khoury JD)Tj 7.5 0 0 7.5 51 541.8 Tm 41.467 -10.09 Td [(,)37( Solary E,)37( )37(Abla O)55(,)37( et al.)37( )37(The 5th edition of the )37(W)86(orld Health )]TJ 0.273 Tw -4.667 -1.2 Td [(Organization Classi\037cation of Haematolymphoid )37(T)86(umours: myeloid )]TJ 0 Tw T* [(and histiocytic/dendritic neoplasms.)37( )]TJ /T1_5 1 Tf [(Leuk)12(emia)]TJ /T1_3 1 Tf [(.)37( 2022;36:1703\2261719.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.01 Tw 7.5 0 0 7.5 312 439.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 439.125 Tm (21.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 439.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 439.125 Tm (Arber D)Tj 7.5 0 0 7.5 51 541.8 Tm 40.305 -13.69 Td [(A,)37( Orazi )37(A,)37( Hasserjian R,)37( et al.)37( International consensus classi\037)]TJ 0 Tw (-)Tj 0.023 Tw -3.505 -1.2 Td (cation of myeloid neoplasms and acute leukemias: integrating morpho)Tj 0 Tw (-)Tj T* [(logic,)37( clinical,)37( and genomic data.)37( )]TJ /T1_5 1 Tf (Blood)Tj /T1_3 1 Tf [(.)37( 2022;140:1200\2261228.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.089 Tw 7.5 0 0 7.5 312 412.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 412.125 Tm (22.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 412.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 412.125 Tm (Greenberg PL,)Tj 7.5 0 0 7.5 51 541.8 Tm 43.075 -17.29 Td [( )37(T)86(uechler H,)37( Schanz J)24(,)37( et al.)37( Cytopenia levels for aiding )]TJ 0.188 Tw -6.275 -1.2 Td [(establishment of the diagnosis of myelodysplastic syndromes.)37( )]TJ /T1_5 1 Tf 0 Tw (Blood)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2016;128:2096\2262097.)Tj ET BT /Span <>BDC /T1_3 1 Tf -0.017 Tw 7.5 0 0 7.5 312 385.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 385.125 Tm (23.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 385.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 385.125 Tm (Palmblad J)Tj 7.5 0 0 7.5 51 541.8 Tm 41.482 -20.89 Td [(,)37( H\366glund P)129(.)37( Ethnic benign neutropenia: a phenomenon \037nds )]TJ 0 Tw -4.682 -1.2 Td [(an explanation.)37( )]TJ /T1_5 1 Tf [(P)74(ediatr Blood Cancer)]TJ /T1_3 1 Tf [(.)37( 2018;65:e27361.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.156 Tw 7.5 0 0 7.5 312 367.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 367.125 Tm (24.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 367.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 367.125 Tm (Thobakgale CF)Tj 7.5 0 0 7.5 51 541.8 Tm 43.496 -23.29 Td [(,)37( Ndung\222u )37(T)111(.)37( Neutrophil counts in persons of )37(African )]TJ 0 Tw -6.696 -1.2 Td [(origin.)37( )]TJ /T1_5 1 Tf (Curr Opin Hematol)Tj /T1_3 1 Tf [(.)37( 2014;21:50\22657.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.014 Tw 7.5 0 0 7.5 312 349.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 349.125 Tm (25.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 349.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 349.125 Tm (Denic S,)Tj 7.5 0 0 7.5 51 541.8 Tm 40.305 -25.69 Td [( Narchi H,)37( Mekaini LA,)37( et al.)37( Prevalence of neutropenia in chil)]TJ 0 Tw (-)Tj -3.505 -1.2 Td [(dren by nationality)92(.)37( )]TJ /T1_5 1 Tf (BMC Hematol)Tj /T1_3 1 Tf [(.)37( 2016;16:15.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.017 Tw 7.5 0 0 7.5 312 331.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 331.125 Tm (26.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 331.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 331.125 Tm (Reich D)Tj 7.5 0 0 7.5 51 541.8 Tm 40.262 -28.09 Td [(,)37( Nalls MA,)37( Kao )37(WHL,)37( et al.)37( Reduced neutrophil count in peo)]TJ 0 Tw (-)Tj -0.021 Tw -3.462 -1.2 Td [(ple of )37(African descent is due to a regulatory variant in the Duffy antigen )]TJ 0 Tw T* [(receptor for chemokines gene.)37( )]TJ /T1_5 1 Tf (PLoS Genet)Tj /T1_3 1 Tf [(.)37( 2009;5:e1000360.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.014 Tw 7.5 0 0 7.5 312 304.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 304.125 Tm (27.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 304.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 304.125 Tm (Merz LE,)Tj 7.5 0 0 7.5 51 541.8 Tm 40.832 -31.69 Td [( )37(Achebe M.)37( )37(When non-whiteness becomes a condition.)37( )]TJ /T1_5 1 Tf 0 Tw (Blood)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -4.032 -1.2 Td (2021;137:13\22615.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.384 Tw 7.5 0 0 7.5 312 286.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 286.125 Tm (28.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 286.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 286.125 Tm (Crosby )Tj 7.5 0 0 7.5 51 541.8 Tm 40.537 -34.09 Td [(WH.)37( How many )74(\223polys\224)74( are enough? )]TJ /T1_5 1 Tf [(Arc)12(h Intern Med)]TJ /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -3.737 -1.2 Td (1969;123:722\226723.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.446 Tw 7.5 0 0 7.5 312 268.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 268.125 Tm (29.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 268.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 268.125 Tm (Dale DC,)Tj 7.5 0 0 7.5 51 541.8 Tm 41.265 -36.49 Td [( Liles C.)37( How many neutrophils are enough? )]TJ /T1_5 1 Tf 0 Tw (Lancet)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw -4.465 -1.2 Td (1998;351:1752\2261753.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.344 Tw 7.5 0 0 7.5 312 250.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 250.125 Tm (30.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 250.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 250.125 Tm (Bodey )Tj 7.5 0 0 7.5 51 541.8 Tm 40.088 -38.89 Td [(GP)129(,)37( )1(Buckley )1(M,)37( )1(Sathe )38(Y)37(S,)37( )1(et )1(al.)37( )1(Quantitative )1(relationships )]TJ 0.027 Tw -3.288 -1.2 Td (between circulating leukocytes and infection in patients with acute leu)Tj 0 Tw (-)Tj T* [(kemia.)37( )]TJ /T1_5 1 Tf (Ann Intern Med)Tj /T1_3 1 Tf [(.)37( 1966;64:328\226340.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.138 Tw 7.5 0 0 7.5 312 223.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 223.125 Tm (31.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 223.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 223.125 Tm (Donadieu J)Tj 7.5 0 0 7.5 51 541.8 Tm 41.805 -42.49 Td [(,)37( Fenneteau O)55(,)37( Beaupain B,)37( et al.)37( Congenital neutropenia: )]TJ 0.095 Tw -5.005 -1.2 Td [(diagnosis,)37( molecular bases and patient management.)37( )]TJ /T1_5 1 Tf (Orphanet J Rare )Tj 0 Tw T* (Dis)Tj /T1_3 1 Tf [(.)37( 2011;6:26.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.217 Tw 7.5 0 0 7.5 312 196.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 196.125 Tm (32.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 196.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 196.125 Tm (T)Tj 7.5 0 0 7.5 51 541.8 Tm 37.38 -46.09 Td [(angye )1(SG,)37( )37(Al-Herz )38(W)129(,)37( Bous\037ha )37(A,)37( )1(et al.)37( Human Inborn )1(Errors of )]TJ 0.183 Tw -0.58 -1.2 Td (Immunity: 2022 Update on the Classi\037cation from the International )Tj 0.061 Tw T* [(Union of Immunological Societies Expert Committee.)37( )]TJ /T1_5 1 Tf (J Clin Immunol)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2022;42:1473\2261507.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.015 Tw 7.5 0 0 7.5 312 160.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 160.125 Tm (33.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 160.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 160.125 Tm (OMIM\256 Online Mendelian Inheritance in Man\256 Updated January 10,)Tj 7.5 0 0 7.5 51 541.8 Tm 67.598 -50.89 Td ( )Tj 0 Tw -30.798 -1.2 Td [(2022.)37( https://www)92(.omim.org/.)]TJ ET BT /Span <>BDC /T1_3 1 Tf -0.022 Tw 7.5 0 0 7.5 312 142.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 142.125 Tm (34.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 142.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 142.125 Tm (Hilcenko )Tj 7.5 0 0 7.5 51 541.8 Tm 41.001 -53.29 Td [(C,)37( )1(Simpson )1(PJ)24(,)37( )1(Finch )38(A)24(J)24(,)37( )1(et )1(al.)37( )38(Aberrant )1(3\222 )1(oligoadenylation )1(of )]TJ 0.014 Tw -4.201 -1.2 Td [(spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia.)37( )]TJ /T1_5 1 Tf 0 Tw T* (Blood)Tj /T1_3 1 Tf [(.)37( 2013;121:1028\2261038.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.211 Tw 7.5 0 0 7.5 312 115.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 115.125 Tm (35.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 115.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 115.125 Tm (Fioredda F)Tj 7.5 0 0 7.5 51 541.8 Tm 41.553 -56.89 Td [(,)37( Dufour C,)37( H\366glund P)129(,)37( et al.)37( )37(Autoimmune neutropenias: )]TJ 0.351 Tw -4.753 -1.2 Td [(update on clinical and biological features in children and adults.)37( )]TJ /T1_5 1 Tf 0 Tw T* (Hemasphere)Tj /T1_3 1 Tf [(.)37( 2022;7:e814.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 0.449 Tw 7.5 0 0 7.5 312 88.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 88.125 Tm (36.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 88.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 88.125 Tm (Andersohn F)Tj 7.5 0 0 7.5 51 541.8 Tm 42.678 -60.49 Td [(,)37( Konzen C,)37( Garbe E.)37( Systematic review: agranulo)]TJ 0 Tw (-)Tj 0.632 Tw -5.878 -1.2 Td [(cytosis induced by nonchemotherapy drugs.)37( )]TJ /T1_5 1 Tf (Ann Intern Med)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2007;146:657\226665.)Tj ET BT /Span <>BDC /T1_3 1 Tf 0.308 Tw 7.5 0 0 7.5 312 61.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 312.0975 61.125 Tm (37.)Tj ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 322.245 61.125 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 327 61.125 Tm (T)Tj 7.5 0 0 7.5 51 541.8 Tm 37.38 -64.09 Td [(esfa D)55(,)37( Keisu M,)37( Palmblad J)24(.)37( Idiosyncratic drug-induced agranu)]TJ 0 Tw (-)Tj 0.411 Tw -0.58 -1.2 Td [(locytosis: possible mechanisms and management.)37( )]TJ /T1_5 1 Tf (Am J Hematol)Tj /T1_3 1 Tf -0.037 Tc 0.037 Tw (. )Tj 0 Tc 0 Tw T* (2009;84:428\226434.)Tj 0 0 0 0 k /GS0 gs 9 0 0 9 25.4915 570.9241 Tm (F2)Tj 60.131 -46.409 Td [(A)37(Q15)]TJ ET q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 789 0 obj <> endobj 790 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 285.052 24.0881 Tm (12)Tj ET q 0 g /GS0 gs /Fm1 Do Q BT /T1_1 1 Tf -0.005 Tc 0.025 Tw 9 0 0 9 36 725.9761 Tm [(appropriate if,)37( some days after a proven infection,)37( the )37(ANC has)-5( )]TJ 0.005 Tw 0 -1.111 TD (normalized.)Tj 5.247 0 0 5.247 81.5035 718.9731 Tm (125)Tj -0.081 Tw 9 0 0 9 90.1768 715.9761 Tm [( Nevertheless,)37( it must be emphasized that occasion)]TJ 0 Tc 0 Tw (-)Tj -0.005 Tc -0.051 Tw -6.02 -1.111 Td [(ally some infections,)37( for example,)37( those caused by HIV or human)-5( )]TJ 0 Tw T* [(hepatitis C virus,)37( can cause a long-lasting neutropenia.)]TJ 0.005 Tw 5.247 0 0 5.247 245.1944 698.9731 Tm (126,127)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_2 1 Tf 0 Tc 0 Tw 8 0 0 8 36 674.9841 Tm (Immune neutropenias)Tj 0 0 0 1 k /GS1 gs /T1_1 1 Tf 0.166 Tw 9 0 0 9 46 664.9841 Tm (Neonatal immune neutropenias can be subclassi\037ed as the )Tj 0 Tw -1.111 -1.111 Td (following:)Tj ET BT /Span <>BDC /T1_1 1 Tf -0.05 Tw 9 0 0 9 36.001 638.9831 Tm ( )Tj EMC ET BT /T1_1 1 Tf 9 0 0 9 48.997 638.9831 Tm (1.)Tj ET BT /Span <>BDC /T1_1 1 Tf 9 0 0 9 56.17 638.9831 Tm ( )Tj EMC ET BT /T1_1 1 Tf 9 0 0 9 60.004 638.9831 Tm (AIN,)Tj 9 0 0 9 46 664.9841 Tm 3.683 -2.889 Td [( )1(which )1(is )1(unusual,)37( )1(but )1(not )1(impossible,)37( )1(at )1(<1 )1(month )1(of )]TJ 0 Tw -2.127 -1.111 Td (age.)Tj 5.247 0 0 5.247 75.4979 631.9811 Tm (41,128)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.287 Tw 9 0 0 9 36 618.9841 Tm ( )Tj EMC ET BT /T1_1 1 Tf 9 0 0 9 48.996 618.9841 Tm (2.)Tj ET BT /Span <>BDC /T1_1 1 Tf 9 0 0 9 56.169 618.9841 Tm ( )Tj EMC ET BT /T1_1 1 Tf 9 0 0 9 60.003 618.9841 Tm (Neonatal alloimmune neutropenia \(NAN\) in which a )Tj 0 Tw T* (genetic mismatch for a polymorphism in one of the genes )Tj 0.344 Tw T* (encoding human neutrophil antigens \(HNA\) between )Tj 0.069 Tw T* (mother and fetus leads to immunization of the pregnant )Tj 0.084 Tw T* (woman,)Tj 9 0 0 9 36 618.9841 Tm 6.13 -4.444 Td ( passage of alloantibodies over the placenta and )Tj 0.149 Tw -3.463 -1.111 Td [(neutropenia in the baby)92(.)]TJ 0 Tw 5.247 0 0 5.247 158.2183 571.9811 Tm (129)Tj 0.149 Tw 9 0 0 9 166.9702 568.9841 Tm ( Indirect antineutrophil anti)Tj 0 Tw (-)Tj 0.176 Tw -11.886 -1.111 Td [(bodies are positive in the mother and in the newborn.)37( )]TJ 0.079 Tw T* (The diagnostic con\037rmation may be obtained through a )Tj 0.037 Tw T* (positive cross-match between maternal sera and paternal )Tj 0.132 Tw T* [(granulocytes \(even if not routinely indicated\).)37( )37(Although )]TJ 0.158 Tw T* (fetomaternal incompatibility is found in about 20% of )Tj -0.041 Tw T* [(pregnant women,)37( alloimmunization in 0.6%\2261% of preg)]TJ 0 Tw (-)Tj -0.027 Tw T* [(nant women,)37( NAN occurs only in 1:6000 newborns.)]TJ 0 Tw 5.247 0 0 5.247 263.0375 501.9811 Tm (129,130)Tj -0.048 Tw 9 0 0 9 46 482.9841 Tm [(Serious infections,)37( mainly of skin and umbilical cord,)37( occur in )]TJ 0.035 Tw -1.111 -1.111 Td (1 out of 5 patients with NAN and the duration of neutropenia )Tj 0.036 Tw T* (is on an average 1\2264 months.)Tj 0 Tw 5.247 0 0 5.247 151.1375 465.9811 Tm (129)Tj 0.036 Tw 9 0 0 9 159.8895 462.9841 Tm [( )37(There are not many studies on )]TJ 0.074 Tw -13.766 -1.111 Td (therapy but a bene\037cial effect of a dose of 10 \033g/kg of G-CSF )Tj 0.054 Tw 29 30.332 Td (has been reported.)Tj 0 Tw 5.247 0 0 5.247 369.4805 728.9731 Tm (130,131)Tj 0.054 Tw 9 0 0 9 388.443 725.9761 Tm [( )37(There is no agreement about the dura)]TJ 0 Tw (-)Tj 0.115 Tw -10.16 -1.111 Td [(tion of G-CSF therapy but,)37( considering that neutropenia lasts )]TJ 0.156 Tw T* (only a few weeks and that there are some reports of serious )Tj 0.061 Tw T* [(infectious complications,)37( G-CSF administration up to recovery )]TJ 0.107 Tw T* [(of )37(ANC should probably be considered.)]TJ 0 Tw 5.247 0 0 5.247 456.5293 688.9731 Tm (131)Tj 0.107 Tw 9 0 0 9 465.2812 685.9761 Tm [( Finally)92(,)37( there are a )]TJ -0.011 Tw -18.698 -1.111 Td [(few )1(cases of )1(total inef\037cacy )1(of G-CSF)]TJ 0 Tw 5.247 0 0 5.247 441.3889 678.9731 Tm (132\226134)Tj -0.011 Tw 9 0 0 9 461.5163 675.9761 Tm [( and )1(in some )1(of them )]TJ 0.174 Tw -18.28 -1.111 Td (intravenous administration of immunoglobulins at 0.8\2261)Tj ET BT /Span <>BDC /T1_1 1 Tf 9 0 0 9 461.5163 675.9761 Tm 7.096 -1.111 Td ( )Tj EMC ET BT /T1_1 1 Tf 9 0 0 9 526.4873 665.9771 Tm (g/kg )Tj 0 Tw -25.499 -1.111 Td (was effective.)Tj 5.247 0 0 5.247 348.9832 658.9731 Tm (132)Tj ET BT /Span <>BDC /T1_1 1 Tf 0.151 Tw 9 0 0 9 297 639.9761 Tm ( )Tj EMC ET BT /T1_1 1 Tf 9 0 0 9 309.996 639.9761 Tm (3.)Tj ET BT /Span <>BDC /T1_1 1 Tf 9 0 0 9 317.169 639.9761 Tm ( )Tj EMC ET BT /T1_1 1 Tf 9 0 0 9 321.003 639.9761 Tm (NAN secondary to maternal )Tj 9 0 0 9 297 639.9761 Tm 15.788 0 Td (AIN is the rarest immune )Tj 0.159 Tw -13.121 -1.111 Td [(neutropenia of early infancy)92(.)37( )37(The duration of this neu)]TJ 0 Tw (-)Tj 0.008 Tw T* (tropenia is on an average the same as the classic NAN.)Tj 0 Tw 5.247 0 0 5.247 534.248 622.9731 Tm (135)Tj 9 0 0 9 543 619.9761 Tm ( )Tj 0.066 Tw -24.667 -1.111 Td [(Among the reported patients,)37( there are 2 pairs of broth)]TJ 0 Tw (-)Tj T* (ers:)Tj 5.247 0 0 5.247 334.4997 602.9731 Tm (136,137)Tj 0.056 Tw 9 0 0 9 353.4622 599.9761 Tm ( in the \037rst pregnancy both the mothers and the )Tj 0.097 Tw -3.607 -1.111 Td [(neonates were )1(not treated with G-CSF and both infants )]TJ 0.085 Tw T* [(suffered )1(from )1(severe )1(infections.)37( )1(During the )1(second )1(preg)]TJ 0 Tw (-)Tj 0.155 Tw T* [(nancies,)37( both mothers were given low-dose G-CSF and )]TJ 0.059 Tw T* [(both newborns did not have neutropenia,)37( with an excel)]TJ 0 Tw (-)Tj 0.119 Tw T* [(lent outcome.)37( )37(W)74(e,)37( therefore,)37( suggest that G-CSF should )]TJ 0 Tw T* (be offered to the mothers.)Tj -0.01 Tc 0.058 Tw -1.556 -1.778 Td [(In conclusion,)37( there are 3 different types of neonatal immune)-10( )]TJ -0.019 Tw -1.111 -1.111 Td [(neutropenia: \(1\) NAN: in this case,)37( it is fundamental to prove the)-10( )]TJ 0.153 Tw T* [(HNA mismatch between the mother and the newborn as well)-10( )]TJ 0.119 Tw T* [(as the presence of indirect antineutrophil antibodies in both of)-10( )]TJ -0.032 Tw T* [(them; \(2\) NAN secondary to maternal )37(AIN: it is easy to diagnose,)27( )]TJ 0.029 Tw T* [(being the mother affected by )37(AIN; and \(3\) )37(AIN with appearance)-10( )]TJ 0.048 Tw T* [(at <1 month of age: this situation is extremely rare and requires)-10( )]TJ -0.021 Tw T* [(exclusion of a false-positive indirect antineutrophil antibody and,)27( )]TJ ET q /GS0 gs 479.9999847 0 0 335.2799988 49.5 96.35495 cm /Im0 Do Q q 1 0 0 1 36 438.5299988 cm 0 0 0 1 K 0.5 w 0 0 m 507 0 l S Q q 1 0 0 1 36 51.75 cm 0 0 0 1 K 0.5 w 0 0 m 507 0 l S Q BT /T1_3 1 Tf 0 Tc -0.028 Tw 7.5 0 0 7.5 36 85 Tm [(Figur)18(e 2.)]TJ ET BT /Span <>BDC /T1_3 1 Tf 7.5 0 0 7.5 66.63 85 Tm ( )Tj EMC ET BT /T1_3 1 Tf 7.5 0 0 7.5 70.38 85 Tm (Flowchart for the investigation of isolated neutr)Tj 7.5 0 0 7.5 36 85 Tm 26.987 0 Td (openia in neonates.)Tj /T1_4 1 Tf [( The \035owchart is r)18(ecommended in cases of isolated neutr)18(openia without a )]TJ -0.04 Tw -26.987 -1.2 Td [(phenotype suggestive of any speci\036c disease/syndr)18(ome. *The neutr)18(openia is de\036ned as true if absolute neutr)18(ophil counts ar)18(e out of range for the corr)18(esponding )]TJ 0.002 Tw 0 -1.2 TD [(gestational age and ther)18(e is no a pr)18(enatal gr)18(owth r)18(etar)18(dation. )]TJ /T1_5 1 Tf [(AIN )1(= )1(autoimmune )1(neutropenia; )1(HDN )1(= )1(Rh-hemolytic )1(disease )1(of )1(the )1(newborn; )1(HNA )1(= )1(human )1(neutrophil )1(antigens; )1(IN )]TJ 0 Tw T* (= idiopathic neutropenia; NAN = neonatal alloimmune neutropenia; NEC = n\ ecrotizing enterocolitis; SGA = small for gestational a)Tj [(ge; )37(TTTS = twin-twin transfusion syndrome)]TJ /T1_4 1 Tf (. )Tj ET q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 791 0 obj <> endobj 792 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 300.052 24.0881 Tm (11)Tj ET /PlacedGraphic /MC0 BDC q 1 0 0 1 55.0115967 759.9024048 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 0 -2.901 l -2.529 -2.901 l -2.529 0 l -4.011 0 l -4.011 -7.304 l -2.529 -7.304 l -2.529 -4.151 l 0 -4.151 l 0 -7.304 l 1.481 -7.304 l 1.481 0 l h f Q q 51 750.589 56.165 9.41 re W n q 1 0 0 1 58.9167023 755.8701019 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.307 0.974 0.053 0.604 0 0 c 2.942 -2.466 m 2.571 -3.112 1.958 -3.366 1.005 -3.366 c -0.582 -3.366 -1.344 -2.339 -1.344 -0.974 c -1.344 -0.254 l -1.344 1.344 -0.54 2.116 0.835 2.116 c 2.33 2.116 3.016 1.248 3.016 -0.36 c 3.016 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 67.2454071 752.5995941 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -1.344 0 l -1.344 3.101 l -1.344 3.947 -1.672 4.223 -2.148 4.223 c -2.625 4.223 -2.984 3.863 -2.984 3.111 c -2.984 0 l -4.339 0 l -4.339 5.291 l -3.016 5.291 l -3.016 4.848 l -2.815 5.122 -2.435 5.387 -1.842 5.387 c -1.207 5.387 -0.688 5.144 -0.36 4.678 c 0.013 5.135 0.574 5.396 1.164 5.387 c 2.317 5.387 2.995 4.687 2.995 3.312 c 2.995 -0.001 l 1.64 -0.001 l 1.64 3.101 l 1.64 3.895 1.366 4.223 0.825 4.223 c 0.339 4.223 0 3.863 0 3.111 c h f Q q 1 0 0 1 74.0608063 754.7783051 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -0.889 0 l -1.439 0 -1.683 -0.18 -1.683 -0.593 c -1.683 -1.005 -1.375 -1.186 -0.91 -1.186 c -0.296 -1.186 0.003 -0.921 0.003 -0.201 c h -1.047 0.996 m 0 0.996 l 0 1.304 l 0 1.896 -0.179 2.086 -0.941 2.086 c -1.46 2.086 -1.714 2.012 -1.937 1.663 c -2.889 2.326 l -2.499 2.972 -1.906 3.205 -0.814 3.205 c 0.55 3.205 1.323 2.802 1.323 1.289 c 1.323 -2.182 l 0 -2.182 l 0 -1.717 l -0.212 -2.076 -0.529 -2.277 -1.143 -2.277 c -2.244 -2.277 -3.005 -1.696 -3.005 -0.617 c -3.005 0.51 -2.159 0.996 -1.047 0.996 c f Q q 1 0 0 1 80.4425964 758.0068054 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.317 0.498 -0.698 0.741 -1.439 0.741 c -2.103 0.741 -2.466 0.435 -2.466 -0.062 c -2.466 -0.635 -2 -0.889 -1.026 -1.132 c 0.497 -1.513 1.186 -2.084 1.186 -3.373 c 1.186 -4.568 0.381 -5.5 -1.333 -5.5 c -2.614 -5.5 -3.502 -5.15 -4.148 -4.304 c -3.016 -3.521 l -2.625 -4.008 -2.18 -4.251 -1.429 -4.251 c -0.582 -4.251 -0.296 -3.881 -0.296 -3.436 c -0.296 -2.928 -0.603 -2.643 -1.791 -2.335 c -3.229 -1.954 -3.948 -1.268 -3.948 -0.061 c -3.948 1.094 -3.187 1.993 -1.451 1.993 c -0.289 1.993 0.592 1.602 1.11 0.797 c h f Q q 1 0 0 1 85.7776031 754.9795074 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 0 0.55 l 0 1.396 -0.265 1.862 -0.931 1.862 c -1.577 1.862 -1.873 1.439 -1.873 0.666 c -1.873 0.002 l -1.873 -0.76 -1.693 -1.331 -0.931 -1.331 c -0.202 -1.337 -0.001 -0.761 -0.001 0.002 c h 1.354 -0.083 m 1.354 -1.459 0.656 -2.476 -0.709 -2.476 c -1.26 -2.476 -1.63 -2.369 -1.871 -2.168 c -1.871 -4.39 l -3.228 -4.39 l -3.228 2.914 l -1.874 2.914 l -1.874 2.564 l -1.62 2.85 -1.239 3.009 -0.699 3.009 c 0.524 3.007 1.354 2.149 1.354 0.637 c h f Q q 1 0 0 1 88.0207977 759.902298 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.352 0 l 1.352 -2.424 l 1.554 -2.159 1.925 -1.916 2.538 -1.916 c 3.606 -1.916 4.475 -2.424 4.475 -3.991 c 4.475 -7.304 l 3.132 -7.304 l 3.132 -4.202 l 3.132 -3.377 2.836 -3.08 2.285 -3.08 c 1.661 -3.08 1.355 -3.495 1.355 -4.191 c 1.355 -7.303 l 0 -7.303 l h f Q q 1 0 0 1 94.7415009 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.659 0 l 1.628 0.687 1.354 0.974 0.846 0.974 c 0.306 0.974 0.052 0.604 0 0 c 2.941 -2.466 m 2.571 -3.112 1.957 -3.366 1.005 -3.366 c -0.583 -3.366 -1.345 -2.339 -1.345 -0.974 c -1.345 -0.254 l -1.345 1.344 -0.541 2.116 0.835 2.116 c 2.329 2.116 3.015 1.248 3.015 -0.36 c 3.015 -0.963 l 0 -0.963 l 0.01 -1.693 0.243 -2.223 0.995 -2.223 c 1.557 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 101.5989075 756.4199066 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.139 0.201 -0.328 0.402 -0.664 0.402 c -1.173 0.402 -1.511 0.032 -1.511 -0.709 c -1.511 -3.82 l -2.868 -3.82 l -2.868 1.471 l -1.545 1.471 l -1.545 1.027 l -1.366 1.292 -1.017 1.566 -0.393 1.566 c 0.232 1.566 0.723 1.29 1.037 0.74 c h f Q q 1 0 0 1 104.1477051 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.309 0.974 0.055 0.604 0 0 c 2.943 -2.466 m 2.572 -3.112 1.959 -3.366 1.007 -3.366 c -0.58 -3.366 -1.343 -2.339 -1.343 -0.974 c -1.343 -0.254 l -1.343 1.344 -0.538 2.116 0.837 2.116 c 2.331 2.116 3.018 1.248 3.018 -0.36 c 3.018 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.936 -1.768 c h f Q EMC Q BT /T1_1 1 Tf 8 0 0 8 107.1653 750.5894 Tm ( )Tj /T1_2 1 Tf 0.278 0.25 Td ( \(2023\) 7:4)Tj ET BT /Span <>BDC /T1_2 1 Tf 38.328 Tw 8 0 0 8 107.1653 750.5894 Tm 4.93 0.25 Td ( )Tj EMC ET BT /T1_2 1 Tf 8 0 0 8 455.4453 752.5894 Tm (www)Tj 8 0 0 8 107.1653 750.5894 Tm 45.703 0.25 Td [(.hemaspher)18(ejour)-18(nal.com)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_3 1 Tf 0 Tw -52.724 -3.181 Td [(Surr)18(ogate markers of transformation into MDS/leukemia)]TJ 0 0 0 1 k /GS1 gs /T1_4 1 Tf -0.03 Tc 0.042 Tw 9 0 0 9 61 717.1401 Tm (The key markers of malignant transformation to MDS or leuke)Tj 0 Tc 0 Tw (-)Tj -0.03 Tc -0.052 Tw -1.111 -1.111 Td [(mia in CN patients are the following: typical dysplastic features in PB)-30( )]TJ -0.006 Tw 0 -1.111 TD [(\(pseudo Pelger)55(-Hu\353t anomaly)92(,)37( hypogranulation,)37( hypersegmentation,)7( )]TJ 0.196 Tw T* [(reticulated )1(nucleus,)37( )1(and )1(ringed-shaped )1(nuclei\) )1(and )1(BM )1(\(defective)-30( )]TJ 0.135 Tw T* [(granulation,)37( maturation arrest at myelocyte stage,)37( and increase in)-30( )]TJ 0.057 Tw T* [(monocytoid forms\); cytogenetic abnormalities; and,)37( high frequency)-30( )]TJ -0.057 Tw T* (of somatic mutations in leukemia-associated driver genes.)Tj 0.03 Tw 5.247 0 0 5.247 256.0154 660.1371 Tm (99)Tj -0.094 Tw 9 0 0 9 261.5352 657.1401 Tm [( The )-37(most)-30( )]TJ -0.053 Tw -23.393 -1.111 Td [(common chromosomal defects in patients with CN at the MDS stage)-30( )]TJ -0.024 Tw T* [(are trisomy 21 and monosomy 7.)37( In CN patients,)37( there is a clear cor)]TJ 0 Tc 0 Tw 27 0 Td (-)Tj -0.03 Tc -0.021 Tw -27 -1.111 Td (relation between the high frequency of somatic )Tj /T1_5 1 Tf 0.03 Tw (CSF3R)Tj /T1_4 1 Tf -0.021 Tw ( and )Tj /T1_5 1 Tf 0.03 Tw [(R)37(UNX1)]TJ /T1_4 1 Tf 0 Tc 0 Tw 27.333 0 Td ( )Tj -0.03 Tc 0.211 Tw -27.333 -1.111 Td (mutations and leukemia development.)Tj 0.03 Tw 5.247 0 0 5.247 195.2467 620.1371 Tm (52\22659)Tj 0.174 Tw 9 0 0 9 208.7524 617.1401 Tm [( T)86(ypical )-37(leukemia-asso)]TJ 0 Tc 0 Tw (-)Tj -0.03 Tc 0.03 Tw -17.528 -1.111 Td (ciated )Tj /T1_5 1 Tf 2.754 0 Td (CSF3R)Tj /T1_4 1 Tf 0.131 Tw [( mutations in CN patients are truncation mutations)-30( )]TJ 0.15 Tw -2.754 -1.111 Td [(in the intracellular part of the receptor)111(,)37( leading to the absence of)-30( )]TJ 0.096 Tw T* [(1,)37( 2,)37( or 3 tyrosine phosphorylation sites.)]TJ 0.03 Tw 5.247 0 0 5.247 201.7351 590.1371 Tm (56,100)Tj 0 Tc 0 Tw 9 0 0 9 216.8358 587.1401 Tm ( )Tj /T1_5 1 Tf -0.03 Tc 0.03 Tw 0.344 0 Td [(R)37(UNX1)]TJ /T1_4 1 Tf 0.096 Tw [( missense or)-30( )]TJ 0.018 Tw -18.77 -1.111 Td [(truncation mutations are characteristic in de novo )37(AML.)]TJ 0.03 Tw 5.247 0 0 5.247 256.9586 580.1371 Tm (54,55)Tj 0.018 Tw 9 0 0 9 269.2994 577.1401 Tm [( In SDS)-30( )]TJ 0.069 Tw -24.255 -1.111 Td [(patients,)37( )1(the acquisition of )1(biallelic )1(alterations )1(of the )]TJ /T1_5 1 Tf 0.03 Tw (TP53)Tj /T1_4 1 Tf 0.069 Tw [( )1(locus )1(is)-30( )]TJ 0 Tw T* [(associated with progression to MDS and )37(AML.)]TJ 0.03 Tw 5.247 0 0 5.247 222.5929 560.1371 Tm (93,101)Tj 0 Tc -0.011 Tw 9 0 0 9 61 547.1401 Tm [(In patients with CIN,)37( clonal hematopoiesis involving spliceo)]TJ 0 Tw (-)Tj 0.174 Tw -1.111 -1.111 Td (some gene mutations and comutation patterns involving epi)Tj 0 Tw (-)Tj 0.095 Tw T* [(genetic )1(regulators )1(such )]TJ /T1_5 1 Tf 0 Tw 10.395 0 Td (TET2)Tj /T1_4 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_5 1 Tf 0 Tc 0 Tw 3.17 0 Td (DNMT3A)Tj /T1_4 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_5 1 Tf 0 Tc 0 Tw 5.168 0 Td (ASXL1)Tj /T1_4 1 Tf 0.095 Tw [(,)37( )1(or )]TJ /T1_5 1 Tf 0 Tw 5.154 0 Td (IDH1/2)Tj /T1_4 1 Tf ( )Tj 0.032 Tw -23.888 -1.111 Td (have a positive predictive value for MDS/leukemia transforma)Tj 0 Tw (-)Tj T* (tion.)Tj 5.247 0 0 5.247 69.0089 510.1371 Tm (60,94,95)Tj 0.156 Tw 9 0 0 9 89.4301 507.1401 Tm [( )37(The surrogate markers for MDS/AML transforma)]TJ 0 Tw (-)Tj -4.27 -1.111 Td (tion are summarized in Box 9.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 8 0 0 8 51 468.1401 Tm [(SPECIAL SITUA)74(TIONS)]TJ /T1_3 1 Tf 0 -1.907 TD [(Pr)18(egnancy)]TJ 0 0 0 1 k /GS1 gs /T1_4 1 Tf 0.074 Tw 9 0 0 9 61 442.8881 Tm (Long-term G-CSF treatment has been shown to be safe and )Tj 0.037 Tw -1.111 -1.111 Td (effective in severe CN resulting in prolonged life expectancy of )Tj -0.052 Tw 0 -1.111 TD [(patients.)37( For patients who have reached adulthood the desire for )]TJ 0.103 Tw T* [(parenthood has become an emerging issue.)37( )37(T)86(wo questions are )]TJ 0 Tw T* (asked frequently in this respect.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_6 1 Tf 8 0 0 8 51 380.8881 Tm [(Can I continue using G-CSF for the tr)-6(eatment of neutropenia during )]TJ 0 -1.375 TD [(pr)-6(egnancy?)]TJ 0 0 0 1 k /GS1 gs /T1_4 1 Tf -0.036 Tw 9 0 0 9 61 359.8881 Tm (Data on the use of G-CSF during pregnancy is limited \(see list )Tj 0.044 Tw -1.111 -1.111 Td [(of publications in Suppl.)37( )37(T)86(able S1\).)]TJ 0 Tw 5.247 0 0 5.247 188.5867 352.8851 Tm (102\226111)Tj 0.044 Tw 9 0 0 9 208.7141 349.8881 Tm [( However)111(,)37( in all publi)]TJ 0 Tw (-)Tj -0.021 Tw -17.524 -1.111 Td [(cations,)37( the use of G-CSF throughout pregnancy )1(has been docu)]TJ 0 Tw (-)Tj -0.046 Tw 0 -1.111 TD (mented as safe and well tolerated with no noticeable side effects.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_6 1 Tf 0 Tw 8 0 0 8 51 307.8881 Tm (What is the risk of having an affected child?)Tj 0 0 0 1 k /GS1 gs /T1_4 1 Tf 0.092 Tw 9 0 0 9 61 297.8881 Tm [(W)18(ith an increasing number of adult patients suffering from )]TJ 0.228 Tw -1.111 -1.111 Td [(genetic neutropenia subtypes,)37( genetic counseling before con)]TJ 0 Tw (-)Tj 0.125 Tw T* [(ception )1(and )1(supportive )1(care )1(of )1(mothers )1(during )1(pregnancy )1(are )]TJ 0.204 Tw T* [(crucial.)37( It is important that the patient is informed that the )]TJ 0.111 Tw T* (acceptance of having affected children is reasonable given the )Tj 0 Tw T* [(high quality of life obtained due to the treatment with G-CSF)129(.)]TJ 1.111 -1.111 Td [(The recommendation )1(for the use of G-CSF during pregnancy )]TJ 0.164 Tw -1.111 -1.111 Td [(is summarized in Box 10.)37( )37(A)74(vailable data support the contin)]TJ 0 Tw (-)Tj 0.154 Tw T* (uation of G-CSF treatment in women with different types of )Tj -0.007 Tw T* [(SCN )1(throughout the pregnancy )1(to prevent )1(major )1(infections and )]TJ 0.121 Tw T* [(newborn complications.)37( )37(The recommendation is based on the )]TJ 0.135 Tw T* (reported high risk for bacterial infections and septic death in )Tj 0.108 Tw T* [(severe )1(CN.)37( )38(The )1(risk )1(may )1(be )1(lower )1(for )1(patients )1(suffering )1(from )]TJ -0.069 Tw T* [(CyN or IN.)37( However)111(,)37( because there is no better predictor for this )]TJ 0.128 Tw T* [(risk than the )37(ANC,)37( we recommend offering G-CSF treatment )]TJ 0.229 Tw 29 63.121 Td [(to all patients with )37(ANC below 0.5)]TJ ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 61 297.8881 Tm 44.451 47.567 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 462.193 725.9911 Tm (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 61 297.8881 Tm 45.133 47.567 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 468.322 725.9911 Tm (10)Tj 0 Tw 5.247 0 0 5.247 478.3265 728.9731 Tm (9)Tj 0.229 Tw 9 0 0 9 481.2438 725.9761 Tm (/L if they were on )Tj 0.069 Tw -18.805 -1.111 Td (G-CSF treatment before pregnancy; for patients who were not )Tj -0.005 Tw T* [(on treatment,)37( G-CSF treatment might be also considered.)37( Based )]TJ 0.116 Tw T* [(on experts\222 experience,)37( we recommend frequent evaluation of )]TJ 0.291 Tw T* [(ANCs during pregnancy)92(,)37( particularly in patients with )37(AIN,)37( )]TJ 0 Tw T* [(because an )37(ANC increase can be seen during pregnancy)92(.)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_3 1 Tf 8 0 0 8 312 653.984 Tm [(Neonatal neutr)18(openia)]TJ 0 0 0 1 k /GS1 gs /T1_4 1 Tf -0.01 Tc 0.022 Tw 9 0 0 9 322 643.984 Tm [(As already mentioned in De\037nition and Diagnosis section,)37( the)-10( )]TJ 0.058 Tw -1.111 -1.111 Td [(lower normal limit of )37(ANC in Caucasian children up to the age)-10( )]TJ 0.139 Tw T* (of 1 year is 1.0)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 322 643.984 Tm 5.732 -2.222 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 374.623 623.986 Tm (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 322 643.984 Tm 6.393 -2.222 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 380.572 623.986 Tm (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 390.396 626.981 Tm (9)Tj -0.01 Tc 0.139 Tw 9 0 0 9 393.2609 623.984 Tm [(/L.)37( However)111(,)37( this limit is different in neo)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.056 Tw -9.029 -1.111 Td [(nates <14 days of life where there is a great variability)92(,)37( with the)-10( )]TJ 0.066 Tw T* [(gestational age being the principal variable affecting the normal)-10( )]TJ 0.01 Tw T* (range.)Tj 5.247 0 0 5.247 335.4628 596.981 Tm (16)Tj 0.223 Tw 9 0 0 9 341.1925 593.984 Tm [( In healthy and at term newborns between 6 and 24)-10( )]TJ 0.006 Tw -3.244 -1.111 Td [(hours of age,)37( neutropenia is de\037ned as an )37(ANC <6.0\2267.0)]TJ ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 341.1925 593.984 Tm 20.759 -1.111 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 529.0315 583.985 Tm (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 341.1925 593.984 Tm 21.417 -1.111 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 534.9805 583.985 Tm (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 544.8123 586.981 Tm (9)Tj -0.01 Tc 0.01 Tw 9 0 0 9 547.6771 583.984 Tm [(/L;)-10( )]TJ 0.088 Tw -26.186 -1.111 Td [(after that,)37( there is a slow decrease and the limit is <3)]TJ ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 547.6771 583.984 Tm -3.091 -1.111 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 520.9291 573.985 Tm (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 547.6771 583.984 Tm -2.426 -1.111 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 526.8781 573.985 Tm (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 536.7001 576.981 Tm (9)Tj -0.01 Tc 0.088 Tw 9 0 0 9 539.5649 573.984 Tm [(/L at)-10( )]TJ 0.131 Tw -25.285 -1.111 Td [(about 72 hours of life.)37( However)111(,)37( the situation is very different)-10( )]TJ 0.077 Tw T* [(in preterm newborns.)37( For nonextreme preterms,)37( the lower limit)-10( )]TJ -0.153 Tw T* [(of )-148(ANC )-185(is )-185(<3.0)]TJ ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 539.5649 573.984 Tm -18.753 -3.333 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 539.5649 573.984 Tm -18.638 -3.333 Td (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 539.5649 573.984 Tm -18.092 -3.333 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 539.5649 573.984 Tm -17.977 -3.333 Td (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 387.6015 546.981 Tm (9)Tj -0.01 Tc 0.032 Tw 9 0 0 9 390.4663 543.984 Tm (/L at 24 hours of age and <1.0)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 507.8366 543.984 Tm ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 508.8973 543.984 Tm (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 390.4663 543.984 Tm 13.705 0 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 514.8463 543.984 Tm (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 524.6721 546.981 Tm (9)Tj -0.01 Tc 0.032 Tw 9 0 0 9 527.5369 543.984 Tm [(/L at 72)-10( )]TJ 0.136 Tw -23.949 -1.111 Td [(hours )1(of )1(life )1(\(less )1(than )1(half )1(of )1(the )1(at term newborn )1(cutoff\); in)-10( )]TJ 0.015 Tw T* [(extremely preterm newborns,)37( the \037fth percentile of normal )37(ANC)-10( )]TJ -0.153 Tw T* [(is )-134(about )-134(1.0)]TJ ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 527.5369 543.984 Tm -18.993 -3.333 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 527.5369 543.984 Tm -18.878 -3.333 Td (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 527.5369 543.984 Tm -18.332 -3.333 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 527.5369 543.984 Tm -18.217 -3.333 Td (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 373.4173 516.981 Tm (9)Tj -0.01 Tc -0.019 Tw 9 0 0 9 376.2821 513.984 Tm (/L immediately after birth.)Tj 0.01 Tw 5.247 0 0 5.247 475.8231 516.981 Tm (16)Tj -0.019 Tw 9 0 0 9 481.5527 513.984 Tm [( Moreover)111(,)37( there are)-10( )]TJ 0.115 Tw -18.839 -1.111 Td [(many other variables and diseases,)37( related or not to pregnancy)-10( )]TJ 0.163 Tw T* [(or delivery)92(,)37( capable of interfering with the )37(ANC.)37( Examples of)-10( )]TJ 0.058 Tw T* [(variables not related to pregnancy or delivery are the following:)-10( )]TJ 0.045 Tw T* [(\(a\) )1(females )1(have )38(ANC )1(counts )1(on )1(average )1(2.0)]TJ ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 481.5527 513.984 Tm 0.236 -4.444 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 484.7117 473.988 Tm (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 481.5527 513.984 Tm 0.897 -4.444 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 490.6607 473.988 Tm (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 500.488 476.981 Tm (9)Tj -0.01 Tc 0.045 Tw 9 0 0 9 503.3529 473.984 Tm [(/L )1(higher )1(than)-10( )]TJ 0.01 Tw -21.261 -1.111 Td (males;)Tj 5.247 0 0 5.247 335.9487 466.981 Tm (16)Tj 0.011 Tw 9 0 0 9 341.6783 463.984 Tm [( \(b\) )37(ANC in capillary blood is on average 1.5\2262.0)]TJ ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 530.3875 463.984 Tm ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 531.4433 463.984 Tm (\327)Tj ET BT /Span <>BDC /T1_4 1 Tf 9 0 0 9 341.6783 463.984 Tm 21.631 0 Td ( )Tj EMC ET BT /T1_4 1 Tf 9 0 0 9 537.3923 463.984 Tm (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 547.2242 466.981 Tm (9)Tj -0.01 Tc 0.01 Tw 9 0 0 9 550.0891 463.984 Tm [(/L)-10( )]TJ 0.054 Tw -26.454 -1.111 Td (higher than in cord blood;)Tj 0.01 Tw 5.247 0 0 5.247 413.6459 456.981 Tm (112,113)Tj 0.054 Tw 9 0 0 9 432.2411 453.984 Tm [( \(c\) )37(ANC is on average higher at)-10( )]TJ 0.009 Tw -13.36 -1.111 Td (altitude than at sea level;)Tj 0.01 Tw 5.247 0 0 5.247 406.4069 446.981 Tm (114)Tj 0.009 Tw 9 0 0 9 415.0014 443.984 Tm ( and \(d\) severe necrotizing enterocoli)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.05 Tw -11.445 -1.111 Td [(tis in the newborn,)37( especially if preterm,)37( is frequently associated)-10( )]TJ 0.124 Tw T* [(with transiently low )37(ANCs.)]TJ 0.01 Tw 5.247 0 0 5.247 419.6897 426.981 Tm (115)Tj 0.124 Tw 9 0 0 9 428.2842 423.984 Tm [( Examples of variables related to)-10( )]TJ -0.031 Tw -12.92 -1.111 Td [(pregnancy )1(or )1(delivery )1(include )1(the )1(following: )1(\(a\) )1(maternal )1(tobacco)-10( )]TJ 0.108 Tw T* [(smoking is associated with lower )37(ANC;)]TJ 0.01 Tw 5.247 0 0 5.247 466.718 406.981 Tm (116)Tj 0.108 Tw 9 0 0 9 475.3125 403.984 Tm ( \(b\) maternal chemo)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.117 Tw -18.146 -1.111 Td (therapy results in neutropenia in 5%\22633% of the newborns;)Tj 0.01 Tw 5.247 0 0 5.247 549.353 396.981 Tm (117)Tj 0 Tc 0 Tw 9 0 0 9 557.9476 393.984 Tm ( )Tj -0.01 Tc -0.036 Tw -27.327 -1.111 Td [(\(c\) maternal antiretroviral therapy results in neutropenia in about)-10( )]TJ 0.014 Tw T* (20%\22650% of the newborns;)Tj 0.01 Tw 5.247 0 0 5.247 420.7577 376.981 Tm (118)Tj 0.014 Tw 9 0 0 9 429.3522 373.984 Tm [( \(d\) maternal hypertension during)-10( )]TJ -0.007 Tw -13.039 -1.111 Td (pregnancy results is neutropenia in about half of newborns;)Tj 0.01 Tw 5.247 0 0 5.247 537.2482 366.981 Tm (119)Tj -0.007 Tw 9 0 0 9 545.8427 363.984 Tm [( \(e\))-10( )]TJ -0.04 Tw -25.983 -1.111 Td (prenatal growth retardation is an independent risk factor for neu)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.01 Tw T* (tropenia;)Tj 5.247 0 0 5.247 346.1998 346.981 Tm (120)Tj 0.061 Tw 9 0 0 9 354.7943 343.984 Tm [( \(f\) labor before delivery results in higher )37(ANC;)]TJ 0.01 Tw 5.247 0 0 5.247 538.9915 346.981 Tm (16)Tj 0.062 Tw 9 0 0 9 544.7212 343.984 Tm [( )1(\(g\))-10( )]TJ 0.083 Tw -25.858 -1.111 Td (Rh-hemolytic disease of the newborn is associated with neutro)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.018 Tw T* [(penia in about 50% of newborns whether or not combined with)-10( )]TJ 0.149 Tw T* (severe anemia and thrombocytopenia;)Tj 0.01 Tw 5.247 0 0 5.247 460.3619 316.981 Tm (121)Tj 0.149 Tw 9 0 0 9 468.9565 313.984 Tm ( \(h\) twin-twin transfu)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.031 Tw -17.44 -1.111 Td (sion syndrome is a rare condition with neutropenia always pres)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.054 Tw T* (ent in the donor twin \(the anemic one\);)Tj 0.01 Tw 5.247 0 0 5.247 463.9131 296.981 Tm (122)Tj 0.054 Tw 9 0 0 9 472.5077 293.984 Tm [( and \(i\) neutropenia is)-10( )]TJ 0 Tw -17.834 -1.111 Td (present in 67% of infants with asphyxia.)Tj 0.01 Tw 5.247 0 0 5.247 466.9521 286.981 Tm (123)Tj 0 Tc 0.194 Tw 9 0 0 9 322.0001 273.984 Tm (The most common types of neonatal neutropenia are dis)Tj 0 Tw (-)Tj -1.111 -1.111 Td [(cussed below)92(.)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_6 1 Tf 8 0 0 8 312.0001 242.9919 Tm (Infection-induced neutropenia)Tj 0 0 0 1 k /GS1 gs /T1_4 1 Tf -0.005 Tc 0.056 Tw 9 0 0 9 322.0001 232.9919 Tm [(Infection-induced neutropenia is probably the most common)-5( )]TJ 0.154 Tw -1.111 -1.111 Td (neutropenia in newborns and infants.)Tj 0.005 Tw 5.247 0 0 5.247 461.4883 225.9889 Tm (124)Tj 0.154 Tw 9 0 0 9 470.1615 222.9919 Tm [( )37(The duration of neu)]TJ 0 Tc 0 Tw (-)Tj -0.005 Tc 0.129 Tw -17.573 -1.111 Td [(tropenia is frequently short,)37( typically <10 days,)37( and therefore,)32( )]TJ 0.138 Tw T* [(a diagnosis of infection-related neutropenia can be considered)-5( )]TJ 0 0 0 0 k /GS0 gs 0 Tc 0 Tw 28.297 12.568 Td [(A)37(Q14)]TJ 0 0 0 1 k /GS1 gs /T1_7 1 Tf -56.574 -21.29 Td [(Box 9: Pr)18(ognostic Indicators of T)92(ransformation into )]TJ T* (MDS/Leukemia)Tj /T1_4 1 Tf 0.202 Tw 0 -1.778 TD [(T)86(ypical )1(morphology for MDS )1(in peripheral )1(blood and/or )]TJ 0.203 Tw 0 -1.111 TD [(bone marrow)92(,)37( cytogenetic abnormalities \(trisomy 21,)37( and )]TJ 0.049 Tw T* [(monosomy 7\),)37( somatic leukemia-associated )1(mutations \(e.g.,)37( )]TJ -0.01 Tw T* [(CSF3R,)37( R)30(UNX1,)37( and )37(ASXL1\),)37( and biallelic )37(TP53 mutations )]TJ 0.199 Tw T* (in Shwachman-Diamond syndrome are prognostic indica)Tj 0 Tw (-)Tj T* (tors of development into MDS/leukemia.)Tj ET 0 0 0 1 K 0.5 w 4 M 51.25 42.25 245.5 94.926 re S BT /T1_7 1 Tf 9 0 0 9 318.5 178.4999 Tm [(Box 10: Pr)18(egnancy)]TJ /T1_4 1 Tf -0.007 Tw 0 -1.778 TD (The panel recommends G-CSF treatment to all patients who )Tj 0.028 Tw 0 -1.111 TD [(were )1(on )1(G-CSF )1(treatment )1(before )1(pregnancy )1(and )1(all )1(patients )]TJ 0 Tw T* (with severe congenital neutropenia.)Tj -0.037 Tw 1.111 -1.111 Td [(For patients who were not on treatment,)37( G-CSF treatment )]TJ 0 Tw -1.111 -1.111 Td (might be considered.)Tj -0.015 Tc -0.034 Tw 1.111 -1.111 Td [(It )1(also )1(suggested )1(to )1(frequently )1(evaluate )38(ANCs )1(during )1(G-CSF)-15( )]TJ -0.066 Tw -1.111 -1.111 Td [(therapy in pregnancy)92(,)37( particularly in patients with autoimmune)-15( )]TJ 0 Tw T* [(neutropenia,)37( because a physiological increase can be seen.)]TJ 0 Tc -0.054 Tw 1.111 -1.111 Td [(After delivery)92(,)37( the neutrophil count of the newborn should )]TJ 0 Tw -1.111 -1.111 Td (be checked.)Tj 0.044 Tw 8 0 0 8 318.5 57.4999 Tm (CBC = complete blood counts; G-CSF = granulocyte colony stimu)Tj 0 Tw (-)Tj 0 -1.125 TD [(lating factor)111(.)]TJ ET 312.25 42.25 245.5 148.926 re S q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 1 w 10 M 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 793 0 obj <> endobj 794 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 285.052 24.0881 Tm (10)Tj ET q 0 g /GS0 gs /Fm1 Do Q BT /T1_1 1 Tf -0.005 Tc -0.079 Tw 9 0 0 9 36 725.8231 Tm [(frequency )-37(of TCR)37(-)]TJ /T1_2 1 Tf 0 Tc 0 Tw (\037)Tj /T1_1 1 Tf 8.477 0 Td (/)Tj /T1_2 1 Tf 0.273 0 Td (\036)Tj /T1_1 1 Tf -0.005 Tc -0.042 Tw 0.555 0 Td (-positive double-negative \(CD4)Tj 0 Tc 0 Tw 5.247 0 0 5.247 238.6578 728.8201 Tm (-)Tj -0.005 Tc -0.042 Tw 9 0 0 9 240.3788 725.8231 Tm ( and CD8)Tj 0 Tc 0 Tw 5.247 0 0 5.247 277.2821 728.8201 Tm (-)Tj 9 0 0 9 279.0031 725.8231 Tm (\) )Tj -0.005 Tc 0.095 Tw -27 -1.111 Td [(T cells; \(b\) common variable immunode\037ciency)92(,)37( which is char)]TJ 0 Tc 0 Tw 27 0 Td (-)Tj -0.005 Tc 0.049 Tw -27 -1.111 Td (acterized by the low frequency of CD19)Tj 0 Tc 0 Tw 5.247 0 0 5.247 191.9431 708.8201 Tm (+)Tj -0.005 Tc 0.049 Tw 9 0 0 9 194.8342 705.8231 Tm [( B cells due to the low)-5( )]TJ 0.123 Tw -17.648 -1.111 Td (number of the switched memory \(CD27)Tj 0 Tc 0 Tw 5.247 0 0 5.247 194.9468 698.8201 Tm (+)Tj -0.005 Tc 0.005 Tw 9 0 0 9 197.8379 695.8231 Tm (IgD)Tj 0 Tc 0 Tw 5.247 0 0 5.247 212.1928 698.8201 Tm (\034)Tj -0.005 Tc 0.005 Tw 9 0 0 9 215.0839 695.8231 Tm (IgM)Tj 0 Tc 0 Tw 5.247 0 0 5.247 231.4367 698.8201 Tm (\034)Tj -0.005 Tc 0.123 Tw 9 0 0 9 234.3278 695.8231 Tm (\) B-cell sub)Tj 0 Tc 0 Tw (-)Tj -0.005 Tc 0.136 Tw -22.036 -1.111 Td [(population,)37( low expression of B-cell activating factor receptor)-5( )]TJ 0.033 Tw 0 -1.111 TD [(\(BAFFR\) )1(on )1(B )1(cells )1(in )1(patients )1(with )1(BAFFR )1(mutations,)37( )1(and )1(low)-5( )]TJ 0.071 Tw T* [(expression )1(of )1(the )1(inducible )1(costimulator )1(\(ICOS\) )1(on )1(activated )38(T)-5( )]TJ T* [(cells )1(in )1(patients )1(with )1(ICOS )1(de\037ciency; )1(\(c\) )1(hyper )1(IgM )1(syndrome)-5( )]TJ 0.174 Tw T* [(\(HIGM\) characterized by the absence of expression of CD40)-5( )]TJ 0.001 Tw T* (ligand \(CD40L; CD154\) on activated CD4)Tj 0 Tc 0 Tw 5.247 0 0 5.247 200.3583 638.8201 Tm (+)Tj -0.005 Tc 0.001 Tw 9 0 0 9 203.2494 635.8231 Tm [( )37(T cells in the major)]TJ 0 Tc 0 Tw 8.417 0 Td (-)Tj -0.005 Tc 0.079 Tw -27 -1.111 Td [(ity )1(of )1(patients )1(with )1(X-linked )1(HIGM )1(and )1(lack )1(of )1(CD40 )1(expres)]TJ 0 Tc 0 Tw (-)Tj -0.005 Tc -0.006 Tw T* (sion on B cells in patients with the autosomal recessive HIGM.)Tj 0.005 Tw 5.247 0 0 5.247 276.1916 618.8201 Tm (92)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_3 1 Tf 0 Tc 0 Tw 8 0 0 8 36 595.2278 Tm [(T)92(elomer)-6(e biology disorders)]TJ 0 0 0 1 k /GS1 gs /T1_1 1 Tf 0.253 Tw 9 0 0 9 46 585.2278 Tm (Flow FISH \(or other clinically validated telomere lengths )Tj 0.192 Tw -1.111 -1.111 Td [(measurement technique\) is recommended where available,)37( to )]TJ 0.103 Tw T* [(rule out a telomere biology disorder)111(.)37( Given that this group of )]TJ -0.016 Tw T* [(diseases cannot be entirely excluded by genetic testing,)37( telomere )]TJ 0 Tw T* (length measurement may help to reduce the diagnostic gap.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_4 1 Tf 8 0 0 8 36 517.5038 Tm [(NA)74(TURAL HISTOR)37(Y)80(: FOLLOW-UP)]TJ /T1_5 1 Tf 0 -1.906 TD [(Which gr)18(oups of patients need follow-up \(CBC, BM, cytogenetics, )]TJ 0 -1.375 TD (and somatic gene NGS\) and how often?)Tj 0 0 0 1 k /GS1 gs /T1_1 1 Tf 0.174 Tw 9 0 0 9 46 481.2518 Tm (The importance of baseline BM evaluation including mor)Tj 0 Tw 25.889 0 Td (-)Tj 0.407 Tw -27 -1.111 Td [(phology)92(,)37( cytogenetics,)37( and NGS-based analysis of somatic )]TJ 0.416 Tw 0 -1.111 TD (leukemia-associated gene mutations has been discussed in )Tj 0.139 Tw T* [(the previous section and is summarized in Box 8.)37( Exceptions )]TJ 0.229 Tw T* (for baseline BM evaluations are summarized as follows: \(a\) )Tj -0.046 Tw 29 31.636 Td (newborns with a family history of CN with a known gene muta)Tj 0 Tw (-)Tj -0.037 Tw T* [(tion,)37( where the genetic analysis may be performed \037rst,)37( but does )]TJ -0.001 Tw T* (not replace subsequent BM evaluation; \(b\) infants with positive )Tj 0.004 Tw T* [(antineutrophil antibodies and no history of bacterial infections,)37( )]TJ 0.072 Tw T* (where a BM evaluation may be omitted but should be consid)Tj 0 Tw (-)Tj 0.08 Tw T* (ered if the patient develops severe or recurrent bacterial infec)Tj 0 Tw (-)Tj -0.044 Tw T* (tions or additional abnormalities in CBCs; and \(c\) adult patients )Tj -0.039 Tw T* [(with unexplained,)37( long-standing,)37( mild,)37( and isolated neutropenia )]TJ 0 Tw T* (that remain stable over time.)Tj -0.005 Tc 0.031 Tw 1.111 -1.111 Td [(Recommendations for follow-up are also summarized in Box)-5( )]TJ -0.063 Tw -1.111 -1.111 Td [(8.)37( )37(Annual BM evaluation is highly recommended in children with)-5( )]TJ 0.222 Tw T* [(CN to recognize cytogenetic abnormalities,)37( high-risk somatic)-5( )]TJ 0.087 Tw T* [(mutations,)37( or MDS before the development of frank leukemia.)32( )]TJ 0.117 Tw T* [(Morphological assessment of BM smears,)37( cytogenetic analysis,)32( )]TJ -0.006 Tw T* [(and somatic NGS-based sequencing of a leukemia gene panel or)111(,)32( )]TJ 0.047 Tw T* [(at least,)37( deep sequencing of )]TJ /T1_6 1 Tf 0.005 Tw (CSF3R)Tj /T1_1 1 Tf -0.042 Tc 0.042 Tw (, )Tj /T1_6 1 Tf -0.005 Tc 0.005 Tw 15.699 0 Td [(R)37(UNX1)]TJ /T1_1 1 Tf 0.047 Tw [(,)37( and )]TJ /T1_6 1 Tf 0.005 Tw (TP53)Tj /T1_1 1 Tf 0.047 Tw [( should)-5( )]TJ 0.106 Tw -15.699 -1.111 Td (be performed.)Tj 0.005 Tw 5.247 0 0 5.247 351.8633 568.9731 Tm (54\22658)Tj 0.106 Tw 9 0 0 9 366.0248 565.9761 Tm [( )37(Although a high sensitivity of )]TJ /T1_6 1 Tf 0.005 Tw (CSF3R)Tj /T1_1 1 Tf 0.106 Tw ( muta)Tj 0 Tc 0 Tw (-)Tj -0.005 Tc 0.214 Tw -7.669 -1.111 Td [(tion detection has been demonstrated using NGS-based deep)-5( )]TJ -0.049 Tw T* [(sequencing of PB neutrophils,)37( evaluation of BM morphology and)-5( )]TJ 0.014 Tw T* [(cytogenetics are essential for the diagnosis of MDS or leukemia.)32( )]TJ 0.187 Tw T* (The sensitivity of detection of other somatic leukemia-associ)Tj 0 Tc 0 Tw (-)Tj -0.005 Tc -0.005 Tw T* [(ated mutations in PB compared with BM is still being evaluated.)32( )]TJ 0.182 Tw T* [(Annual NGS analysis )1(allows )1(assessment )1(of )1(the acquisition of)-5( )]TJ 0.229 Tw T* (new HSC clones carrying somatic mutations and the associ)Tj 0 Tc 0 Tw (-)Tj -0.005 Tc 0.037 Tw T* [(ated variant allele frequencies \(V)105(AF\).)37( It also enables monitoring)-5( )]TJ 0.069 Tw T* [(the temporal behavior of HSC clones with acquired mutations.)32( )]TJ -0.035 Tw T* [(Notably)92(,)37( some CN patients with a very high frequency of )]TJ /T1_6 1 Tf 0.005 Tw (CSF3R)Tj /T1_1 1 Tf 0 Tc 0 Tw 27.333 0 Td ( )Tj -0.005 Tc 0.237 Tw -27.333 -1.111 Td [(HSC clones do not develop leukemia for years.)37( In addition,)32( )]TJ 0.047 Tw T* [(recent evidence )1(suggests that CN patients with different genetic)-5( )]TJ 0.15 Tw T* [(backgrounds,)37( independent )1(of )1(inherited )1(CN-causing )1(mutations,)32( )]TJ 0.051 Tw T* [(may acquire somatic leukemia-associated mutations at a higher)-5( )]TJ 0.04 Tw T* (frequency compared with healthy individuals of the same age.)Tj 0.005 Tw 5.247 0 0 5.247 537.1916 418.9731 Tm (59)Tj 0 Tc 0 Tw 9 0 0 9 542.9738 415.9761 Tm ( )Tj -0.005 Tc 0.089 Tw -27.33 -1.111 Td [(The same study has shown that acquisition of multiple genetic)-5( )]TJ -0.017 Tw T* [(lesions,)37( especially in )]TJ /T1_6 1 Tf 0.005 Tw [(R)37(UNX1)]TJ /T1_1 1 Tf -0.042 Tc 0.042 Tw (, )Tj /T1_6 1 Tf -0.005 Tc 0.005 Tw 12.842 0 Td (SETBP1)Tj /T1_1 1 Tf -0.042 Tc 0.042 Tw (, )Tj /T1_6 1 Tf -0.005 Tc 0.005 Tw 4.13 0 Td (ASXL1)Tj /T1_1 1 Tf -0.042 Tc 0.042 Tw (, )Tj /T1_6 1 Tf -0.005 Tc 0.005 Tw 3.69 0 Td (TP53)Tj /T1_1 1 Tf -0.042 Tc 0.042 Tw (, )Tj /T1_6 1 Tf -0.005 Tc 0.005 Tw 2.862 0 Td (PTPN11)Tj /T1_1 1 Tf 0 Tc 0 Tw 3.809 0 Td ( )Tj -0.005 Tc -0.004 Tw -27.333 -1.111 Td [(in association with CSF3R mutation might be a strong indicator)-5( )]TJ 0.047 Tw T* [(of a preleukemia stage in CN patients at neutropenia stage and)-5( )]TJ 0 Tw T* (requires closer patient follow-up.)Tj 0.005 Tw 5.247 0 0 5.247 423.9977 368.9731 Tm (59)Tj 0 Tc -0.061 Tw 9 0 0 9 307 355.9761 Tm (A small group of CN/AML patients do not have either )Tj /T1_6 1 Tf 0 Tw (CSF3R)Tj /T1_1 1 Tf ( )Tj 0.084 Tw -1.111 -1.111 Td (or R)Tj /T1_6 1 Tf 0 Tw (UNX1)Tj /T1_1 1 Tf 0.084 Tw [( mutations but develop other leukemogenic events.)37( )]TJ -0.028 Tw T* (SDS patients have an increased frequency of clonal hematopoie)Tj 0 Tw (-)Tj -0.017 Tw T* [(sis from )1(a young age,)37( with the )1(acquisition of mutations )1(in )]TJ /T1_6 1 Tf 0 Tw (TP53)Tj /T1_1 1 Tf ( )Tj T* (and )Tj /T1_6 1 Tf 1.835 0 Td (EIF6)Tj /T1_1 1 Tf -0.055 Tw [(,)37( in particular)111(.)]TJ 0 Tw 5.247 0 0 5.247 386.2359 318.9731 Tm (7,93)Tj -0.055 Tw 9 0 0 9 396.4465 315.9761 Tm ( Patients with overt leukemia acquired )Tj -0.048 Tw -11.05 -1.111 Td (biallelic alterations of the )Tj /T1_6 1 Tf 0 Tw (TP53)Tj /T1_1 1 Tf -0.048 Tw [( locus due to deletion,)37( CN-LOH,)37( )]TJ 0.14 Tw T* (or point mutation.)Tj 0 Tw 5.247 0 0 5.247 371.5331 298.9731 Tm (93)Tj 0.14 Tw 9 0 0 9 377.3677 295.9761 Tm [( )37(Therefore,)37( annual NGS leukemia predis)]TJ 0 Tw (-)Tj 0.092 Tw -8.93 -1.111 Td (position myeloid panel analysis and SNP array should be per)Tj 0 Tw 27 0 Td (-)Tj -0.003 Tw -27 -1.111 Td [(formed in the BM,)37( or in PB myeloid cells if BM is not available.)]TJ 0.005 Tc 0.333 Tw 1.111 -1.111 Td [(Regarding adults with CIN,)37( the importance of baseline)5( )]TJ 0.033 Tw -1.111 -1.111 Td [(NGS analysis of BM or PB cells to identify mutations in genes)5( )]TJ 0.116 Tw T* [(related to myeloid malignancies has already been highlighted)5( )]TJ 0.138 Tw T* [(\(Box 6\).)37( CIN patients with clonal disease,)37( also characterized)5( )]TJ 0.156 Tw T* [(as patients with clonal cytopenia of undermined signi\037cance)5( )]TJ -0.005 Tw T* (\(CCUS\),)Tj 5.247 0 0 5.247 329.8044 218.9731 Tm (20)Tj 0.192 Tw 9 0 0 9 335.6916 215.9761 Tm ( display increased risk of transformation to MDS/)Tj 0.011 Tw -4.299 -1.111 Td [(AML )1(depending on )1(the )1(type )1(and number )1(of mutations )1(and the)5( )]TJ 0.048 Tw T* (size of clone\(s\).)Tj -0.005 Tw 5.247 0 0 5.247 358.1346 198.9731 Tm (53,94)Tj 0.048 Tw 9 0 0 9 371.3937 195.9761 Tm [( )37(Although studies with CCUS patients with)5( )]TJ 0.114 Tw -8.266 -1.111 Td [(isolated neutropenia are limited,)37( reports from CCUS patients)5( )]TJ 0.02 Tw T* [(with any type of cytopenia have shown that gene mutations in)5( )]TJ 0.044 Tw T* [(splicing factors,)37( )]TJ /T1_6 1 Tf -0.005 Tw (TP53)Tj /T1_1 1 Tf -0.032 Tc 0.032 Tw (, )Tj /T1_6 1 Tf 0.005 Tc -0.005 Tw 10.18 0 Td (IDH1/2)Tj /T1_1 1 Tf 0.044 Tw [(,)37( or )1(in D)55(T)74(A \()]TJ /T1_6 1 Tf 0.007 Tw [(DNMT3A,)37( TET2,)42( )]TJ -0.005 Tw -10.18 -1.111 Td (ASXL1)Tj /T1_1 1 Tf 0.351 Tw [(\) in combination with mutations in other myeloid)5( )]TJ 0.131 Tw T* [(genes,)37( have an increased risk of progression to myeloid neo)]TJ 0 Tc 0 Tw (-)Tj 0.005 Tc -0.005 Tw T* (plasms.)Tj 5.247 0 0 5.247 326.3127 138.9731 Tm (60,94,95)Tj 0.144 Tw 9 0 0 9 346.9438 135.9761 Tm [( )37(W)74(e recommend that patients with mutations in)5( )]TJ 0.162 Tw -5.549 -1.111 Td [(1 or more MDS/leukemia-associated genes,)37( particularly with)5( )]TJ 0.045 Tw T* [(a high )37(V)105(AF \(>10%\) and especially younger patients where the)5( )]TJ -0.033 Tw T* [(frequency of clonal hematopoiesis with indeterminate potential)5( )]TJ 0.13 Tw T* [(is low)92(,)]TJ -0.005 Tw 5.247 0 0 5.247 323.1702 98.9731 Tm (96\22698)Tj 0.13 Tw 9 0 0 9 337.5941 95.9761 Tm [( need to have a closer follow-up \(>4 times a year\))5( )]TJ 0.074 Tw -4.51 -1.111 Td [(with CBC,)37( differential count,)37( and morphological examination)5( )]TJ 0.176 Tw T* [(of )1(PB )1(smear)111(.)37( )1(BM )1(examination )1(including )1(aspiration,)37( )1(trephine)5( )]TJ 0.109 Tw T* [(biopsy)92(,)37( karyotype,)37( and NGS analysis should be performed as)5( )]TJ 0.056 Tw T* [(indicated,)37( )1(that )1(is,)37( )1(worsening )1(of )1(cytopenias,)37( )1(macrocytosis,)37( )1(and/)]TJ 0 Tw T* (or morphological abnormalities.)Tj 0 0 0 0 k /GS0 gs 0 Tc 28.297 6.903 Td [(A)37(Q13)]TJ 0 0 0 1 k /GS1 gs /T1_7 1 Tf -56.574 33.489 Td [(Box 8: Which Gr)18(oups of Patients Need Follow-up )]TJ T* (\(CBC, BM, Cytogenetics, Somatic Genes NGS\) and )Tj T* (How Often?)Tj /T1_1 1 Tf -0.047 Tw 0 -1.778 TD [(As )1(stated )1(in )1(Box )1(4,)37( )1(annual )1(BM )1(with )1(cytogenetics )1(and )1(NGS )1(of )]TJ 0.055 Tw 0 -1.111 TD (genes related to myeloid malignancies should be performed )Tj 0.074 Tw T* [(in )1(all )1(patients )1(with )1(congenital )1(BM )1(failure )1(syndromes,)37( )1(inde)]TJ 0 Tw (-)Tj 0.01 Tw T* [(pendent of )37(ANC and treatment with G-CSF)129(,)37( to assess clonal )]TJ 0 Tw T* (hematopoiesis and for early diagnosis of MDS or leukemia.)Tj 0.016 Tw 1.111 -1.111 Td [(In chronic neutropenia patients,)37( we recommend perform)]TJ 0 Tw (-)Tj 0.055 Tw -1.111 -1.111 Td (ing CBC with differential white blood cell counts and mor)Tj 0 Tw 25.556 0 Td (-)Tj -25.556 -1.111 Td (phological evaluation every 3\2264 months.)Tj 0.273 Tw 1.111 -1.111 Td [(When approaching adulthood,)37( CN patients should be )]TJ 0 Tw -1.111 -1.111 Td (transferred to a dedicated hematology specialist.)Tj 1.111 -1.111 Td (Particularly for adults:)Tj 0.131 Tw T* [(As already stated in Box 4,)37( a diagnostic BM with mor)]TJ 0 Tw 24.445 0 Td (-)Tj 0.103 Tw -25.556 -1.111 Td (phology and cytogenetics should be performed in all adult )Tj 0.323 Tw T* (patients with unexplained chronic neutropenia with the )Tj -0.022 Tw T* [(exception of those with long-standing,)37( mild,)37( isolated neutro)]TJ 0 Tw (-)Tj T* (penia that remains stable over time.)Tj -0.048 Tw 1.111 -1.111 Td [(As already stated in Box 6,)37( NGS analysis of BM or periph)]TJ 0 Tw (-)Tj -0.028 Tw -1.111 -1.111 Td (eral blood for acquired somatic variants is recommended for )Tj 0 Tw T* (patients with chronic unexplained neutropenia.)Tj 0.087 Tw 1.111 -1.111 Td (Patients with mutations in 1 or more MDS/leukemia-as)Tj 0 Tw (-)Tj 0.318 Tw -1.111 -1.111 Td [(sociated genes,)37( particularly with high )37(V)105(AF \(>10%\) and )]TJ 0.062 Tw T* (especially younger patients where the frequency of CHIP is )Tj 0.057 Tw T* [(low)92(,)37( need to have a closer follow-up \(>4 times a year\) with )]TJ 0.002 Tw T* [(CBC,)37( differential white blood cell count,)37( and morphological )]TJ -0.053 Tw T* [(examination.)37( BM examination including aspiration,)37( trephine )]TJ 0.126 Tw T* [(biopsy)92(,)37( karyotype,)37( and NGS analysis should be performed )]TJ -0.032 Tw T* [(when indicated,)37( that is,)37( worsening of cytopenias,)37( macrocyto)]TJ 0 Tw (-)Tj T* [(sis,)37( and/or morphological abnormalities.)]TJ -0.034 Tw 8 0 0 8 42.5 88.4999 Tm [(ANC )1(= absolute )1(neutrophil count; )1(BM = )1(bone marrow; )1(CBC )1(= com)]TJ 0 Tw (-)Tj 0.085 Tw 0 -1.125 TD (plete blood counts; CHIP = clonal hematopoiesis of indeterminate )Tj 0.084 Tw T* (potential; CN = congenital neutropenia; G-CSF = granulocyte col)Tj 0 Tw (-)Tj 0.064 Tw T* (ony stimulating factor; MDS = myelodysplastic neoplasms; NGS = )Tj 0 Tw T* [(next generation sequencing; )37(V)105(AF = variant allele frequency)92(.)]TJ ET 0 0 0 1 K 0.5 w 4 M 36.25 46.25 245.5 375.926 re S q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 1 w 10 M 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 795 0 obj <> endobj 796 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 302.276 24.0881 Tm (9)Tj ET /PlacedGraphic /MC0 BDC q 1 0 0 1 55.0115967 759.9024048 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 0 -2.901 l -2.529 -2.901 l -2.529 0 l -4.011 0 l -4.011 -7.304 l -2.529 -7.304 l -2.529 -4.151 l 0 -4.151 l 0 -7.304 l 1.481 -7.304 l 1.481 0 l h f Q q 51 750.589 56.165 9.41 re W n q 1 0 0 1 58.9167023 755.8701019 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.307 0.974 0.053 0.604 0 0 c 2.942 -2.466 m 2.571 -3.112 1.958 -3.366 1.005 -3.366 c -0.582 -3.366 -1.344 -2.339 -1.344 -0.974 c -1.344 -0.254 l -1.344 1.344 -0.54 2.116 0.835 2.116 c 2.33 2.116 3.016 1.248 3.016 -0.36 c 3.016 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 67.2454071 752.5995941 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -1.344 0 l -1.344 3.101 l -1.344 3.947 -1.672 4.223 -2.148 4.223 c -2.625 4.223 -2.984 3.863 -2.984 3.111 c -2.984 0 l -4.339 0 l -4.339 5.291 l -3.016 5.291 l -3.016 4.848 l -2.815 5.122 -2.435 5.387 -1.842 5.387 c -1.207 5.387 -0.688 5.144 -0.36 4.678 c 0.013 5.135 0.574 5.396 1.164 5.387 c 2.317 5.387 2.995 4.687 2.995 3.312 c 2.995 -0.001 l 1.64 -0.001 l 1.64 3.101 l 1.64 3.895 1.366 4.223 0.825 4.223 c 0.339 4.223 0 3.863 0 3.111 c h f Q q 1 0 0 1 74.0608063 754.7783051 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -0.889 0 l -1.439 0 -1.683 -0.18 -1.683 -0.593 c -1.683 -1.005 -1.375 -1.186 -0.91 -1.186 c -0.296 -1.186 0.003 -0.921 0.003 -0.201 c h -1.047 0.996 m 0 0.996 l 0 1.304 l 0 1.896 -0.179 2.086 -0.941 2.086 c -1.46 2.086 -1.714 2.012 -1.937 1.663 c -2.889 2.326 l -2.499 2.972 -1.906 3.205 -0.814 3.205 c 0.55 3.205 1.323 2.802 1.323 1.289 c 1.323 -2.182 l 0 -2.182 l 0 -1.717 l -0.212 -2.076 -0.529 -2.277 -1.143 -2.277 c -2.244 -2.277 -3.005 -1.696 -3.005 -0.617 c -3.005 0.51 -2.159 0.996 -1.047 0.996 c f Q q 1 0 0 1 80.4425964 758.0068054 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.317 0.498 -0.698 0.741 -1.439 0.741 c -2.103 0.741 -2.466 0.435 -2.466 -0.062 c -2.466 -0.635 -2 -0.889 -1.026 -1.132 c 0.497 -1.513 1.186 -2.084 1.186 -3.373 c 1.186 -4.568 0.381 -5.5 -1.333 -5.5 c -2.614 -5.5 -3.502 -5.15 -4.148 -4.304 c -3.016 -3.521 l -2.625 -4.008 -2.18 -4.251 -1.429 -4.251 c -0.582 -4.251 -0.296 -3.881 -0.296 -3.436 c -0.296 -2.928 -0.603 -2.643 -1.791 -2.335 c -3.229 -1.954 -3.948 -1.268 -3.948 -0.061 c -3.948 1.094 -3.187 1.993 -1.451 1.993 c -0.289 1.993 0.592 1.602 1.11 0.797 c h f Q q 1 0 0 1 85.7776031 754.9795074 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 0 0.55 l 0 1.396 -0.265 1.862 -0.931 1.862 c -1.577 1.862 -1.873 1.439 -1.873 0.666 c -1.873 0.002 l -1.873 -0.76 -1.693 -1.331 -0.931 -1.331 c -0.202 -1.337 -0.001 -0.761 -0.001 0.002 c h 1.354 -0.083 m 1.354 -1.459 0.656 -2.476 -0.709 -2.476 c -1.26 -2.476 -1.63 -2.369 -1.871 -2.168 c -1.871 -4.39 l -3.228 -4.39 l -3.228 2.914 l -1.874 2.914 l -1.874 2.564 l -1.62 2.85 -1.239 3.009 -0.699 3.009 c 0.524 3.007 1.354 2.149 1.354 0.637 c h f Q q 1 0 0 1 88.0207977 759.902298 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.352 0 l 1.352 -2.424 l 1.554 -2.159 1.925 -1.916 2.538 -1.916 c 3.606 -1.916 4.475 -2.424 4.475 -3.991 c 4.475 -7.304 l 3.132 -7.304 l 3.132 -4.202 l 3.132 -3.377 2.836 -3.08 2.285 -3.08 c 1.661 -3.08 1.355 -3.495 1.355 -4.191 c 1.355 -7.303 l 0 -7.303 l h f Q q 1 0 0 1 94.7415009 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.659 0 l 1.628 0.687 1.354 0.974 0.846 0.974 c 0.306 0.974 0.052 0.604 0 0 c 2.941 -2.466 m 2.571 -3.112 1.957 -3.366 1.005 -3.366 c -0.583 -3.366 -1.345 -2.339 -1.345 -0.974 c -1.345 -0.254 l -1.345 1.344 -0.541 2.116 0.835 2.116 c 2.329 2.116 3.015 1.248 3.015 -0.36 c 3.015 -0.963 l 0 -0.963 l 0.01 -1.693 0.243 -2.223 0.995 -2.223 c 1.557 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 101.5989075 756.4199066 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.139 0.201 -0.328 0.402 -0.664 0.402 c -1.173 0.402 -1.511 0.032 -1.511 -0.709 c -1.511 -3.82 l -2.868 -3.82 l -2.868 1.471 l -1.545 1.471 l -1.545 1.027 l -1.366 1.292 -1.017 1.566 -0.393 1.566 c 0.232 1.566 0.723 1.29 1.037 0.74 c h f Q q 1 0 0 1 104.1477051 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.309 0.974 0.055 0.604 0 0 c 2.943 -2.466 m 2.572 -3.112 1.959 -3.366 1.007 -3.366 c -0.58 -3.366 -1.343 -2.339 -1.343 -0.974 c -1.343 -0.254 l -1.343 1.344 -0.538 2.116 0.837 2.116 c 2.331 2.116 3.018 1.248 3.018 -0.36 c 3.018 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.936 -1.768 c h f Q EMC Q BT /T1_1 1 Tf 8 0 0 8 107.1653 750.5894 Tm ( )Tj /T1_2 1 Tf 0.278 0.25 Td ( \(2023\) 7:4)Tj ET BT /Span <>BDC /T1_2 1 Tf 38.328 Tw 8 0 0 8 107.1653 750.5894 Tm 4.93 0.25 Td ( )Tj EMC ET BT /T1_2 1 Tf 8 0 0 8 455.4453 752.5894 Tm (www)Tj 8 0 0 8 107.1653 750.5894 Tm 45.703 0.25 Td [(.hemaspher)18(ejour)-18(nal.com)]TJ /T1_3 1 Tf -0.01 Tc 0.019 Tw 9 0 0 9 51 725.9761 Tm [(are identi\037ed in targeted genes,)37( extending the analysis to all cod)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.037 Tw 0 -1.111 TD [(ing regions in the genome.)37( In all NGS applications,)37( the bioinfor)]TJ 0 Tc 0 Tw 27 0 Td (-)Tj -0.01 Tc 0.122 Tw -27 -1.111 Td [(matics interpretation )1(of the )1(pathogenicity of )1(genetic variants )1(is)-10( )]TJ 0.022 Tw T* (challenging and should be based on consensus guidelines.)Tj 0.01 Tw 5.247 0 0 5.247 269.9114 698.9731 Tm (2,81)Tj -0.015 Tw 9 0 0 9 279.9121 695.9761 Tm [( The)-10( )]TJ 0.174 Tw -25.435 -1.111 Td [(pathogenicity of variants of unknown signi\037cance should rely)92(,)27( )]TJ 0.071 Tw T* [(as much as possible,)37( on family segregation studies and on func)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc -0.04 Tw T* [(tional studies if relevant.)37( If suspicion of CN is high and both NGS)-10( )]TJ 0.014 Tw T* [(panels and )37(WES analysis are negative,)37( whole genome sequencing)-10( )]TJ 0.102 Tw T* [(and RNA-sequencing should be considered.)37( DNA for detection)-10( )]TJ 0.116 Tw T* [(of )1(potential )1(germline mutations is extracted from )1(PB; however)111(,)27( )]TJ 0.068 Tw T* [(in the presence of leukemic blasts in PB,)37( nonhematopoietic cells)-10( )]TJ 0.151 Tw T* [(should be used,)37( preferably skin \037broblasts,)37( hair follicles kerat)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.122 Tw T* [(inocytes,)37( or cells from a buccal swab \(although the last carries)-10( )]TJ 0.134 Tw T* [(the risk of blood contamination\).)37( Leukemia-associated somatic)-10( )]TJ 0.104 Tw T* [(mutations that are acquired over time and possibly involved in)-10( )]TJ 0.135 Tw T* [(leukemic transformation can be detected by a designated NGS)-10( )]TJ 0.123 Tw T* (somatic panel.)Tj 0.01 Tw 5.247 0 0 5.247 106.8459 568.9731 Tm (42,53)Tj 0.123 Tw 9 0 0 9 119.7114 565.9761 Tm ( Except in cases of severe neutropenia/mono)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.053 Tw -7.635 -1.111 Td [(cytopenia,)37( PB and BM are considered equivalent sources for the)-10( )]TJ 0.327 Tw T* [(detection )1(of somatic )1(mutations in )1(myeloid-speci\037c genes.)]TJ 0.01 Tw 5.247 0 0 5.247 284.082 548.9731 Tm (82,83)Tj 0 Tc 0 Tw 9 0 0 9 296.9475 545.9761 Tm ( )Tj -0.01 Tc 0.035 Tw -27.327 -1.111 Td [(For RNA-sequencing,)37( RNA should be extracted from PB or BM)-10( )]TJ 0 Tw T* [(myeloid cells,)37( preferably BM promyelocytes or PB neutrophils.)]TJ 0.01 Tc 0.38 Tw 1.111 -1.111 Td [(Genetic testing can be also used for the con\037rmation)10( )]TJ 0.271 Tw -1.111 -1.111 Td [(of )37(AD)60(AN in patients of Middle Eastern,)37( )37(African,)37( )37(W)74(estern)10( )]TJ 0.22 Tw T* [(India,)37( and )37(Y)86(emenite and Ethiopian Jewish descent present)]TJ 0 Tc 0 Tw (-)Tj 0.01 Tc 0.106 Tw T* [(ing with mild-to-moderate neutropenia \(less frequently )37(ANC)10( )]TJ -0.153 Tw T* (<0.5)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 296.9475 545.9761 Tm -25.341 -7.777 Td ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 296.9475 545.9761 Tm -25.206 -7.777 Td (\327)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 296.9475 545.9761 Tm -24.64 -7.777 Td ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 296.9475 545.9761 Tm -24.505 -7.777 Td (10)Tj 0 Tc 0 Tw 5.247 0 0 5.247 86.586 478.9731 Tm (9)Tj 0.01 Tc 0.158 Tw 9 0 0 9 89.5558 475.9761 Tm [(/L\) without infection propensity)92(.)]TJ -0.01 Tw 5.247 0 0 5.247 222.5015 478.9731 Tm (23\22625,84)Tj 0.121 Tw 9 0 0 9 244.5073 475.9761 Tm [( An )-37(accurate)10( )]TJ 0.03 Tw -21.501 -1.111 Td [(genetic diagnosis will save an extensive unnecessary work-up.)47( )]TJ -0.037 Tw T* [(The )1(investigation )1(can identify )1(the )1(rs2814778 )1(polymorphism )1(in)10( )]TJ -0.01 Tw T* (the )Tj /T1_4 1 Tf 1.674 0 Td [(A)37(CKR1/D)45(ARC)]TJ /T1_3 1 Tf 0.023 Tw [( gene as described in the De\037nition section)10( )]TJ 0.14 Tw -1.674 -1.111 Td [(of this text.)37( Notably)92(,)37( the same polymorphism has also been)10( )]TJ 0.171 Tw T* [(identi\037ed in a cohort of European patients \(mostly Greeks\))10( )]TJ 0.193 Tw T* (with chronic idiopathic neutropenia \(CIN\).)Tj -0.01 Tw 5.247 0 0 5.247 229.2598 418.9731 Tm (85)Tj 0.193 Tw 9 0 0 9 235.1993 415.9761 Tm ( It is thus rea)Tj 0 Tc 0 Tw (-)Tj 0.01 Tc 0.181 Tw -20.467 -1.111 Td [(sonable to include the investigation for the presence of the)10( )]TJ -0.01 Tw T* (rs2814778 )Tj /T1_4 1 Tf 5.13 0 Td [(A)37(CKRI/D)45(ARC)]TJ /T1_3 1 Tf 0.082 Tw [( polymorphism in all patients with)10( )]TJ -0.025 Tw -5.13 -1.111 Td [(chronic and mild neutropenia.)37( )37(All above recommendations are)10( )]TJ 0 Tw T* (summarized in Box 6.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_5 1 Tf 0 Tc 8 0 0 8 312 727.1401 Tm [(The r)18(ole of FC for the diagnosis of chr)18(onic neutr)18(openias)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf -0.01 Tc 0.063 Tw 9 0 0 9 322 717.1401 Tm [(FC of PB and/or BM cell populations is a supportive tool for)-10( )]TJ -0.02 Tw -1.111 -1.111 Td [(the diagnosis of speci\037c types of chronic neutropenia as shown in)-10( )]TJ 0.017 Tw T* [(Box 7.)37( Further to the quanti\037cation of cell populations from dif)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc -0.062 Tw T* [(ferent lineages,)37( it may evaluate cell surface,)37( intracellular and intra)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.037 Tw T* [(nuclear )1(proteins,)37( as )1(well )1(as )1(the )1(biological )1(functions )1(and )1(immune)-10( )]TJ -0.006 Tw T* [(characteristics of neutrophils and lymphocytes.)37( FC is particularly)-10( )]TJ 0 Tw T* (useful in the following neutropenia-associated diseases.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_6 1 Tf 0 Tc 8 0 0 8 312 636.5449 Tm (Large granular lymphocyte-leukemia)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.08 Tw 9 0 0 9 322 626.5449 Tm (FC analysis of PB lymphocytes is important for the diagno)Tj 0 Tw (-)Tj 0.15 Tw -1.111 -1.111 Td [(sis of large granular lymphocyte \(LGL\)-leukemia.)37( )37(The )37(T)104(-LGL )]TJ 0.365 Tw T* (subtype is characterized by the CD3)Tj 0 Tw 5.247 0 0 5.247 468.4451 609.5419 Tm (+)Tj 9 0 0 9 471.3624 606.5449 Tm (/CD8)Tj 5.247 0 0 5.247 492.3683 609.5419 Tm (+)Tj 9 0 0 9 495.2856 606.5449 Tm (/CD57)Tj 5.247 0 0 5.247 521.2954 609.5419 Tm (+)Tj 0.365 Tw 9 0 0 9 524.2128 606.5449 Tm ( expres)Tj 0 Tw (-)Tj 0.056 Tw -23.579 -1.111 Td [(sion,)37( whereas the NK-LGL subtype by the CD3)]TJ 0 Tw 5.247 0 0 5.247 499.7304 599.5419 Tm (\034)Tj 9 0 0 9 502.6477 596.5449 Tm (/CD8)Tj 5.247 0 0 5.247 523.6536 599.5419 Tm (+)Tj 9 0 0 9 526.5709 596.5449 Tm (/CD16)Tj 5.247 0 0 5.247 552.5808 599.5419 Tm (+)Tj 9 0 0 9 555.4981 596.5449 Tm (/)Tj -27.055 -1.111 Td (CD56)Tj 5.247 0 0 5.247 335.508 589.5419 Tm (+)Tj 0.122 Tw 9 0 0 9 338.4253 586.5449 Tm ( phenotype.)Tj 0 Tw 5.247 0 0 5.247 385.0349 589.5419 Tm (86)Tj 0.122 Tw 9 0 0 9 390.8695 586.5449 Tm [( For )37(T)104(-LGL,)37( diagnosis of clonality is con)]TJ 0 Tw (-)Tj 0.003 Tw -8.763 -1.111 Td [(\037rmed )1(by )1(FC-based )38(T)104(-cell )1(receptor )38(V)]TJ /T1_7 1 Tf 0 Tw (\036)Tj /T1_3 1 Tf 0.003 Tw [( )1(\(TCR)74(V)]TJ /T1_7 1 Tf 0 Tw (\036)Tj /T1_3 1 Tf 0.003 Tw [(\) )1(repertoire )1(and/)]TJ 0.296 Tw T* [(or polymerase chain reaction-based )37(TRB and/or )37(TRG gene )]TJ 0.293 Tw T* (rearrangement analysis assays.)Tj 0 Tw 5.247 0 0 5.247 435.7707 559.5419 Tm (86)Tj 0.293 Tw 9 0 0 9 441.6053 556.5449 Tm [( Recently)92(,)37( a single antibody )]TJ 0.129 Tw -14.401 -1.111 Td [(\(TRBC1-binding )1(monoclonal )1(antibody)92(,)37( )1(clone )1(JO)74(VI\0341\) )1(against )]TJ 0.12 Tw T* [(1 of the 2 mutually exclusive )37(TCR )]TJ /T1_7 1 Tf 0 Tw (\036)Tj /T1_3 1 Tf 0.12 Tw ( chain constant domains )Tj 0.043 Tw T* [(\(TRBC1 and )37(TRBC2\) randomly selected during rearrangement )]TJ 0.099 Tw T* [(of the )37(TRB gene has been proposed as a potential FC marker )]TJ 0.043 Tw T* [(for the assessment of )37(T)]TJ /T1_7 1 Tf 0 Tw (\037\036)Tj /T1_3 1 Tf 0.043 Tw [(-cell clonality)92(.)]TJ 0 Tw 5.247 0 0 5.247 467.329 509.5419 Tm (87)Tj 0.043 Tw 9 0 0 9 473.1636 506.5449 Tm [( For NK-LGL,)37( assess)]TJ 0 Tw (-)Tj -0.006 Tw -17.907 -1.111 Td [(ment of clonality is dif\037cult to perform; restricted )1(expression of )]TJ -0.016 Tw T* (activating isoforms of killer immunoglobulin-like receptors has )Tj 0 Tw T* (been used as a surrogate marker for a monoclonal expansion.)Tj 5.247 0 0 5.247 551.0471 479.5419 Tm (86)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_6 1 Tf 8 0 0 8 312.0001 455.9496 Tm (Myelodysplastic neoplasms)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf -0.015 Tc 0.122 Tw 9 0 0 9 322.0001 445.9496 Tm [(FC can be helpful for the identi\037cation of myeloid precursor)-15( )]TJ 0.111 Tw -1.111 -1.111 Td [(lesions or MDS cases in patients with unexplained neutropenia,)22( )]TJ -0.044 Tw T* (with a high speci\037city \(up to 95%\) and sensitivity \(up to 75%\).)Tj 0.015 Tw 5.247 0 0 5.247 545.187 428.9467 Tm (62,63)Tj 0 Tc 0 Tw 9 0 0 9 557.9214 425.9496 Tm ( )Tj -0.015 Tc 0.172 Tw -27.325 -1.111 Td [(FC evaluation of the BM myeloid lineage using speci\037c panels)-15( )]TJ 0.001 Tw T* [(proposed by International FC Scienti\037c Societies can help exclude)-15( )]TJ 0.015 Tw T* (MDS.)Tj 5.247 0 0 5.247 334.4641 398.9467 Tm (88,89)Tj 0.053 Tw 9 0 0 9 347.1985 395.9496 Tm [( )37(Abnormalities of the myeloid series suggestive of MDS)-15( )]TJ 0.107 Tw -3.911 -1.111 Td [(include the following: quantitative and qualitative alterations of)-15( )]TJ 0.05 Tw T* [(cells )1(in )1(the )1(CD34)]TJ 0 Tc 0 Tw 5.247 0 0 5.247 378.0539 378.9467 Tm (+)Tj -0.015 Tc 0.05 Tw 9 0 0 9 380.8925 375.9496 Tm [( )1(blast )1(gate; )1(abnormal )1(distribution )1(of )1(immature)-15( )]TJ 0.208 Tw -7.655 -1.111 Td [(and )1(mature )1(granulocytic )1(cells; )1(abnormal )1(pattern )1(of )1(expression)-15( )]TJ 0.119 Tw T* [(of CD11b,)37( CD13,)37( CD33,)37( CD16,)37( CD10,)37( CD5,)37( CD7,)37( and CD56)-15( )]TJ 0.038 Tw T* [(granulocytic cells; and low granulocytic cell granularity based on)-15( )]TJ -0.035 Tw T* (their side scatter characteristics.)Tj 0.015 Tw 5.247 0 0 5.247 429.8065 338.9467 Tm (62,63,88,89)Tj -0.035 Tw 9 0 0 9 456.6552 335.9496 Tm [( FC is also indicated for the)-15( )]TJ -0.028 Tw -16.073 -1.111 Td (identi\037cation of paroxysmal nocturnal hemoglobinuria clones.)Tj 0.015 Tw 5.247 0 0 5.247 545.187 328.9467 Tm (90,91)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_6 1 Tf 0 Tc 0 Tw 8 0 0 8 312.0001 305.3544 Tm [(Primar)-18(y immunode\037ciencies)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf -0.005 Tc -0.008 Tw 9 0 0 9 322.0001 295.3544 Tm [(Although the de\037nitive )1(diagnosis )1(of primary immunode\037cien)]TJ 0 Tc 0 Tw (-)Tj -0.005 Tc -0.045 Tw -1.111 -1.111 Td [(cies is generally ascertained by genetic analysis,)37( FC is particularly)-5( )]TJ -0.033 Tw T* (helpful in the diagnosis of the following: \(a\) autoimmune lymph)Tj 0 Tc 0 Tw (-)Tj -0.005 Tc 0.268 Tw T* [(oproliferative syndrome,)37( which is characterized by increased)-5( )]TJ 0 0 0 0 k /GS0 gs 0 Tc 0 Tw 28.297 24.813 Td [(A)37(Q11)]TJ 0 -23.466 TD [(A)37(Q12)]TJ 0 0 0 1 k /GS1 gs /T1_8 1 Tf -56.574 5.336 Td [(Box 6: What Is the Role of Genetic T)111(esting: Which )]TJ 0 -1.111 TD [(Genes, Methods, and Cell Sour)18(ce? What Is Its )]TJ T* (Position in the Diagnostic Algorithm?)Tj /T1_3 1 Tf 0.301 Tw 0 -1.778 TD (Genetic diagnosis is important to con\037rm the diagnosis )Tj 0.113 Tw 0 -1.111 TD [(of CN,)37( estimate the risk for MDS/AML,)37( support stem cell )]TJ 0 Tw T* [(donor selection for patients,)37( and family counseling.)]TJ 0.161 Tw 1.111 -1.111 Td [(When the clinical picture,)37( inheritance,)37( or bone marrow )]TJ 0.005 Tw -1.111 -1.111 Td [(features \(i.e.,)37( block at the promyelocyte stage\) are indicative )]TJ 0.122 Tw T* [(of a speci\037c gene mutation,)37( single-gene analysis by Sanger )]TJ 0 Tw T* (sequencing technique could be applied.)Tj 0.022 Tw 1.111 -1.111 Td (For CN where the clinical picture does not suggest a spe)Tj 0 Tw (-)Tj -0.051 Tw -1.111 -1.111 Td [(ci\037c genetic cause,)37( we recommend the use of NGS techniques )]TJ 0 Tw T* [(such as multigene panels or targeted )37(WES.)37( )]TJ 0.16 Tw 1.111 -1.111 Td (For patients for whom a genetic cause is not identi\037ed )Tj 0.1 Tw -1.111 -1.111 Td [(by )1(the )1(above )1(methods,)37( )37(WGS )1(and )1(RNA-sequencing )1(may )1(be )]TJ 0 Tw T* (powerful diagnostic tools.)Tj 0.187 Tw 1.111 -1.111 Td (NGS analysis of bone marrow or peripheral blood for )Tj 0.016 Tw -1.111 -1.111 Td (acquired somatic variants is recommended for patients with )Tj 0 Tw T* (chronic unexplained neutropenia.)Tj -0.024 Tw 1.111 -1.111 Td (Screening for known mutations is recommended in family )Tj 0 Tw -1.111 -1.111 Td (members.)Tj 0.097 Tw 1.111 -1.111 Td (It is important to validate germline mutations mainly in )Tj 0.103 Tw -1.111 -1.111 Td (\037broblasts or hair follicles keratinocytes \(cells from buccal )Tj -0.031 Tw T* [(swab are less indicated for possible blood contamination\),)37( in )]TJ 0 Tw T* (the presence of leukemic blasts in PB.)Tj -0.048 Tw 8 0 0 8 57.5 64.4999 Tm (AML = acute myeloid leukemia; CN = congenital neutropenia; MDS )Tj 0.129 Tw 0 -1.125 TD [(= )1(myelodysplastic )1(neoplasms; )1(NGS )1(= )1(next )1(generation )1(sequencing; )]TJ -0.048 Tw T* [(WES = whole exome sequencing; )37(WGS,)37( = whole genome sequencing.)]TJ ET 0 0 0 1 K 0.5 w 4 M 51.25 40.25 245.5 297.926 re S BT /T1_8 1 Tf 0 Tw 9 0 0 9 318.5 232.4999 Tm (Box 7: The Role of Flow Cytometry for the )Tj 0 -1.111 TD [(Diagnosis of Chr)18(onic Neutr)18(openias)]TJ /T1_3 1 Tf 0.043 Tw 0 -1.778 TD [(FC )1(of PB lymphocytes )1(and )1(BM granulocytic )1(cells should )1(be )]TJ 0.097 Tw 0 -1.111 TD [(included )1(in )1(the )1(diagnostic )1(algorithm )1(of )1(adult )1(patients )1(with )]TJ 0.166 Tw T* (chronic neutropenias to support LGL leukemia and MDS )Tj 0 Tw T* [(diagnosis,)37( respectively)92(.)]TJ 0.11 Tw 1.111 -1.111 Td (FC is an important tool in the diagnosis of neutropenia )Tj 0.159 Tw -1.111 -1.111 Td [(associated with PID syndromes such as )37(ALPS,)37( CVID)55(,)37( and )]TJ 0 Tw T* (HIGM syndrome.)Tj 0.438 Tw 1.111 -1.111 Td (Assessment of a PNH clone by FC testing is also )Tj 0 Tw -1.111 -1.111 Td (recommended.)Tj 0.014 Tw 1.111 -1.111 Td [(Flow )1(FISH )1(is recommended )1(when )1(a )1(telomere )1(biology )1(dis)]TJ 0 Tw (-)Tj -1.111 -1.111 Td (order is suspected.)Tj 0.208 Tw 8 0 0 8 318.5 91.4999 Tm (ALPS = autoimmune lymphoproliferative syndrome; BM = bone )Tj 0.126 Tw 0 -1.125 TD (marrow; CVID = common variable immunode\037ciency; FC = \036ow )Tj 0.292 Tw T* [(cytometry; )1(HIGM = )1(hyper IgM; )1(LG = large )1(granular )1(lympho)]TJ 0 Tw (-)Tj 0.147 Tw T* (cytes; MDS = myelodysplastic neoplasms; PB = peripheral blood; )Tj 0.2 Tw T* (PID = primary immunode\037ciency; PNH = paroxysmal nocturnal )Tj 0 Tw T* (hemoglobinuria.)Tj ET 312.25 40.25 245.5 204.926 re S q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 1 w 10 M 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 797 0 obj <> endobj 798 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 287.276 24.0881 Tm (8)Tj ET q 0 g /GS0 gs /Fm1 Do Q BT /T1_1 1 Tf 0.15 Tw 9 0 0 9 36 725.9761 Tm [(Megakaryocytes are normal in number and morphology)92(.)37( )37(The )]TJ 0.095 Tw 0 -1.111 TD (in vitro growth of granulocyte colonies in granulocyte-macro)Tj 0 Tw (-)Tj 0.009 Tw T* [(phage colony-forming unit assays,)37( if performed,)37( may also show )]TJ 0 Tw T* (a maturation arrest that mimics the disease.)Tj -0.01 Tc 0.03 Tw 1.111 -1.111 Td (BM aspiration and trephine biopsy in combination with cyto)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc -0.059 Tw -1.111 -1.111 Td [(genetics and \036ow cytometry \(FC\) should be considered in all adult)-10( )]TJ 0.032 Tw T* [(patients with unexplained neutropenia to exclude MDS or other)-10( )]TJ 0.05 Tw T* [(hematologic diseases with BM involvement \(e.g.,)37( leukemia,)37( lym)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.046 Tw T* [(phoma,)37( )1(myeloma,)37( and )1(myelo\037brosis\),)37( )1(or even in\037ltration )1(of BM)-10( )]TJ 0.094 Tw T* [(by nonhematologic malignancy)92(.)]TJ 0.01 Tw 5.247 0 0 5.247 158.2613 638.9731 Tm (62,63)Tj 0.094 Tw 9 0 0 9 171.1268 635.9761 Tm ( In patients with long-stand)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc -0.01 Tw -15.014 -1.111 Td [(ing,)37( isolated,)37( mild neutropenia that remains longitudinally stable,)27( )]TJ 0.02 Tw T* [(the BM examination might be omitted and if performed,)37( there is)-10( )]TJ 0.077 Tw T* [(no need to repeat it if the initial evaluation does not reveal any)-10( )]TJ -0.043 Tw T* [(underlying disease,)37( unless there is a signi\037cant change in CBCs.)]TJ 0.01 Tw 5.247 0 0 5.247 271.9468 598.9731 Tm (1,12)Tj 0 Tc 0.221 Tw 9 0 0 9 46 585.9761 Tm [(Annual BM examination \(aspiration,)37( trephine biopsy)92(,)37( and )]TJ 0.049 Tw -1.111 -1.111 Td (cytogenetic evaluation\) is recommended for CN and other BM )Tj 0.267 Tw T* [(failure syndromes independent of )37(ANC and treatment with )]TJ 0.187 Tw T* [(G-CSF)129(.)37( It may be also considered for idiopathic neutropenia )]TJ -0.06 Tw T* [(\(IN\) that is not clearly congenital,)37( but requires G-CSF treatment.)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_2 1 Tf 0 Tw 8 0 0 8 36 524.9761 Tm [(What is the r)18(ole of antineutr)18(ophil antibody testing? What ar)18(e the )]TJ 0 -1.375 TD [(r)18(ecommended tests? How should we interpr)18(et positive r)18(esults?)]TJ 0 0 0 1 k /GS1 gs /T1_1 1 Tf 0.055 Tw 9 0 0 9 46 503.9761 Tm (Evidence on the role and signi\037cance of antineutrophil anti)Tj 0 Tw (-)Tj -0.05 Tw -1.111 -1.111 Td (bodies in the diagnosis of neutropenias comes mainly from pedi)Tj 0 Tw (-)Tj 0.129 Tw 0 -1.111 TD (atric data.)Tj 0 Tw 5.247 0 0 5.247 76.6654 486.9731 Tm (40,41)Tj 0.129 Tw 9 0 0 9 89.7933 483.9761 Tm [( )37(The identi\037cation of autoantibodies in children )]TJ -0.026 Tw -5.977 -1.111 Td [(veri\037es the diagnosis of )37(AIN,)37( an entity with typically early onset )]TJ -0.01 Tw T* [(and benign clinical course with few infections,)37( spontaneous res)]TJ 0 Tw (-)Tj 0.103 Tw T* [(olution within a few years,)37( and no risk for leukemic develop)]TJ 0 Tw (-)Tj T* (ment.)Tj 5.247 0 0 5.247 57.9867 446.9731 Tm (64\22671)Tj 0.103 Tw 9 0 0 9 72.2794 443.9761 Tm [( )37(The speci\037city of autoantibodies is against Fc)]TJ /T1_3 1 Tf 0 Tw (\035)Tj /T1_1 1 Tf (RIIIb )Tj 0.164 Tw -4.031 -1.111 Td [(\(CD16b\) in the majority of patients.)37( Studies on the presence )]TJ 0.142 Tw T* (of antineutrophil antibodies in neutropenic adult patients are )Tj 0.002 Tw T* [(far fewer compared with those in children.)37( )37(The main target still )]TJ 0.042 Tw T* (appears to be Fc)Tj /T1_3 1 Tf 0 Tw (\035)Tj /T1_1 1 Tf 0.042 Tw (RIIIb \(CD16b\) but a broader antibody speci)Tj 0 Tw (-)Tj T* (\037city has been described compared with children.)Tj 5.247 0 0 5.247 227.527 396.9731 Tm (72\22674)Tj -0.015 Tc 0.229 Tw 9 0 0 9 46 383.9761 Tm [(The most widely used and validated assay for detection of)-15( )]TJ 0.099 Tw -1.111 -1.111 Td [(antineutrophil )1(antibodies is the )1(indirect granulocyte )1(immuno\036u)]TJ 0 Tc 0 Tw (-)Tj -0.015 Tc 0.127 Tw T* [(orescence test \(GIFT\),)37( which relies on incubation of test granu)]TJ 0 Tc 0 Tw (-)Tj -0.015 Tc 0.161 Tw T* [(locytes with patient serum followed by the detection of bound)-15( )]TJ 0.007 Tw T* [(antibody using a \036uorescent antihuman immunoglobulin reagent.)22( )]TJ 0.071 Tw T* [(Other available assays such as the granulocyte agglutination test)-15( )]TJ 0.057 Tw T* [(and monoclonal antibody immobilization of granulocyte antigen)-15( )]TJ 0.143 Tw T* [(\(MAIGA\) )1(have )1(been found )1(to be inferior to )1(GIFT as )1(screening)-15( )]TJ -0.047 Tw T* [(assays )1(in the )1(diagnostic )1(of autoantibodies.)]TJ 0.015 Tw 5.247 0 0 5.247 191.6069 306.9731 Tm (40,65,75)Tj -0.047 Tw 9 0 0 9 211.3985 303.9761 Tm [( However)111(,)37( they )1(can)-15( )]TJ 0.097 Tw -19.489 -1.111 Td (be used to determine antibody speci\037city or as additional meth)Tj 0 Tc 0 Tw (-)Tj -0.015 Tc -0.028 Tw T* [(ods in selected cases.)37( Recently)92(,)37( high-throughput bead-based assays)-15( )]TJ 0.22 Tw T* [(such )1(as )1(the LabScreen )1(Multi )1(have )1(been )1(used )1(for )1(alloantibody)-15( )]TJ 0.123 Tw T* [(detection,)37( but it is yet to be evaluated in a larger series of )37(AIN)-15( )]TJ 0.106 Tw T* (patients as a screening test.)Tj 0.015 Tw 5.247 0 0 5.247 140.8882 256.9731 Tm (76)Tj 0.106 Tw 9 0 0 9 146.5654 253.9761 Tm [( Notably)92(,)37( most clinical laboratories)-15( )]TJ 0.006 Tw -12.285 -1.111 Td [(use only one of these methods,)37( which may have a higher or lower)-15( )]TJ 0.078 Tw T* [(false-positive or false-negative rate depending on the technology)92(,)22( )]TJ 0.162 Tw T* [(so antineutrophil antibody testing should not be used alone to)-15( )]TJ 0 Tw T* [(make a diagnosis,)37( and should be interpreted with caution.)]TJ 0.015 Tw 5.247 0 0 5.247 253.0335 216.9731 Tm (77)Tj 0.214 Tw 9 0 0 9 46 203.9761 Tm [(Positive antibody identi\037cation makes the diagnosis of )37(AIN)-15( )]TJ 0.178 Tw -1.111 -1.111 Td [(likely)92(,)37( especially in children of the right age group and with a)-15( )]TJ 0.205 Tw T* [(typical )1(medical )1(history)92(.)37( )38(Although )1(less )1(emphasis )1(can )1(be )1(put )1(on)-15( )]TJ 0.079 Tw T* [(considering alternative diagnoses in such cases,)37( the possibility of)-15( )]TJ -0.05 Tw T* [(false-positive and false-negative results must always be considered.)22( )]TJ 0.08 Tw T* [(However)111(,)37( positive antibody testing has been reported in patients)-15( )]TJ 0.156 Tw T* [(with genetically proven severe CN,)37( so the result should not be)-15( )]TJ 0.2 Tw T* (used to exclude that diagnosis.)Tj 0.015 Tw 5.247 0 0 5.247 158.0508 136.9731 Tm (78,79)Tj 0.2 Tw 9 0 0 9 170.7852 133.9761 Tm [( Several studies have shown)-15( )]TJ 0.057 Tw -14.976 -1.111 Td (that small children without detectable antibodies but with a typ)Tj 0 Tc 0 Tw (-)Tj -0.015 Tc 0.038 Tw T* [(ical medical history have a very similar disease course as patients)-15( )]TJ 0.091 Tw T* (with AIN.)Tj 0.015 Tw 5.247 0 0 5.247 75.0865 106.9731 Tm (41)Tj 0.128 Tw 9 0 0 9 80.7637 103.9761 Tm [( Following thorough investigations to exclude other)-15( )]TJ -0.033 Tw -4.974 -1.111 Td [(disease entities,)37( a diagnosis of IN can be given in these patients.)37( IN)-15( )]TJ 0.084 Tw T* [(and )37(AIN have overlapping clinical features,)37( although the former)-15( )]TJ -0.008 Tw T* [(may )1(present )1(at )1(older )1(age )1(with )1(longer )1(disease )1(duration )1(and )1(distinct)-15( )]TJ 0.04 Tw T* [(immunologic )1(pro\037le )1(as )1(mentioned )1(in )1(the )1(Classi\037cation )1(section )1(of)-15( )]TJ 0.018 Tw T* [(the )1(text.)]TJ 0.015 Tw 5.247 0 0 5.247 66.9368 56.9731 Tm (41,42)Tj 0.018 Tw 9 0 0 9 79.6711 53.9761 Tm [( )1(Repeated )1(antibody )1(testing )1(in )1(reference )1(laboratories )1(is)-15( )]TJ 0 Tw -4.852 -1.111 Td [(recommended in cases of suspected )37(AIN with negative tests.)]TJ 0 Tc 0.038 Tw 30.111 75.778 Td [(In adults,)37( antineutrophil antibodies can be found in primary )]TJ -0.005 Tw -1.111 -1.111 Td [(and )-37(secondary AIN.)]TJ 0 Tw 5.247 0 0 5.247 375.2425 718.9731 Tm (1,12,35)Tj 0.032 Tw 9 0 0 9 392.7463 715.9761 Tm ( It is particularly important to exclude )Tj 0.208 Tw -10.638 -1.111 Td [(the )1(presence )1(of )1(alloantibodies )1(again )1(HLA )1(class )1(I,)37( )1(which )1(are )]TJ -0.016 Tw T* (common in transfused patients and previously pregnant women )Tj -0.007 Tw T* (and can give false-positive GIFT results.)Tj 0 Tw 5.247 0 0 5.247 451.6841 688.9731 Tm (19)Tj -0.007 Tw 9 0 0 9 457.5187 685.9761 Tm [( )37(An independent anal)]TJ 0 Tw (-)Tj 0.015 Tw -17.835 -1.111 Td [(ysis )1(of )1(HLA )1(class )1(I )1(antibodies,)37( )1(and/or )1(con\037rmation )1(of )1(the )1(spec)]TJ 0 Tw (-)Tj 0.012 Tw T* (i\037city of the granulocyte antibodies using MAIGA test or GIFT )Tj 0.136 Tw T* [(with genotyped neutrophils,)37( is therefore recommended )1(before )]TJ 0 Tw T* (positive antibody results are conclusively interpreted.)Tj 0.352 Tw 1.111 -1.111 Td (The summary of recommendations on the autoantibody )Tj 0 Tw -1.111 -1.111 Td [(screening for the diagnosis of )37(AIN is presented in Box 5.)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_2 1 Tf 8 0 0 8 297 602.8359 Tm [(What is the r)18(ole of genetic testing: which genes, methods, and cell )]TJ 0 -1.375 TD [(sour)18(ce? What is its position in the diagnostic algorithm?)]TJ 0 0 0 1 k /GS1 gs /T1_1 1 Tf 0.099 Tw 9 0 0 9 307 581.8359 Tm [(Genetic )1(testing )1(and )1(analysis )1(of )1(CN )1(patients )1(is )1(important )1(to )]TJ 0.109 Tw -1.111 -1.111 Td [(con\037rm diagnosis,)37( to estimate the relative risk of late compli)]TJ 0 Tw (-)Tj 0.09 Tw 0 -1.111 TD [(cations such as MDS/AML,)37( and to offer genetic counseling to )]TJ 0.082 Tw T* [(affected )1(patients )1(and )1(family )1(members.)37( )1(Because )1(of )1(the )1(variabil)]TJ 0 Tw (-)Tj 0.133 Tw T* [(ity of the clinical picture,)37( unaffected related donors for those )]TJ 0.049 Tw T* (patients who are candidates for hematopoietic stem cell \(HSC\) )Tj 0 Tw T* (transplantation should always undergo genetic screening.)Tj 0.259 Tw 1.111 -1.111 Td [(Following negative )1(results )1(of \037rst-level )1(investigations )1(\(see )]TJ 0.213 Tw -1.111 -1.111 Td [(Box 3\),)37( all patients with SCN and recurrent infections and/)]TJ 0.118 Tw T* (or family history of severe neutropenia and typical anomalies )Tj 0.158 Tw T* (should undergo genetic work-up either by single-gene Sanger )Tj 0.071 Tw T* (sequencing or by multigene next generation sequencing \(NGS\) )Tj 0.108 Tw T* [(methods.)37( Sanger sequencing of )]TJ /T1_4 1 Tf 0 Tw (ELANE)Tj /T1_1 1 Tf 0.108 Tw ( \(mutated in ~45% of )Tj 0.037 Tw T* (patients with severe CN\) is recommended as the \037rst approach )Tj 0.049 Tw T* (to genetic diagnosis of typical cases.)Tj 0 Tw 5.247 0 0 5.247 438.7114 444.8329 Tm (3,4)Tj 0.049 Tw 9 0 0 9 446.0047 441.8359 Tm [( However)111(,)37( family history )]TJ -0.016 Tw -16.556 -1.111 Td [(or )1(clinical )1(\037ndings )1(may )1(suggest )1(another )1(speci\037c )1(neutropenia-as)]TJ 0 Tw (-)Tj 0.149 Tw T* [(sociated gene to be sequenced \(T)86(able\035)-149(2\).)37( For example,)37( in the )]TJ -0.023 Tw T* [(presence of cardiomyopathy)92(,)37( )]TJ /T1_4 1 Tf -0.067 Tc 0.067 Tw [(TA)-67(Z)]TJ /T1_1 1 Tf 0 Tc -0.023 Tw 14.569 0 Td ( \(Barth syndrome\) sequencing )Tj 0.148 Tw -14.569 -1.111 Td [(may be diagnostic,)37( while in the presence of cardiac and gen)]TJ 0 Tw (-)Tj 0.19 Tw T* (itourinary malformations sequencing of )Tj /T1_4 1 Tf 0 Tw (G6PC3)Tj /T1_1 1 Tf 0.19 Tw ( may lead to )Tj 0.163 Tw T* [(diagnosis.)37( Poor growth,)37( malabsorption,)37( fatty stool,)37( and bone )]TJ 0.083 Tw T* (malformation suggest )Tj /T1_4 1 Tf 0 Tw (SBDS)Tj /T1_1 1 Tf 0.083 Tw ( mutations that are found in most )Tj -0.011 Tw T* (patients with Shwachman-Diamond syndrome \(SDS\).)Tj 0 Tw 5.247 0 0 5.247 503.5988 364.8329 Tm (80)Tj -0.011 Tw 9 0 0 9 509.4333 361.8359 Tm [( Overall,)37( )]TJ 0.055 Tw -23.604 -1.111 Td (Sanger sequencing of the suspected genes is relatively easy and )Tj -0.061 Tw T* [(cost )1(effective.)37( Following )1(identi\037cation )1(of )1(the responsible )1(gene\(s\),)37( )]TJ 0.016 Tw T* (Sanger sequencing is also recommended for mutation screening )Tj 0 Tw T* (of the members of affected families.)Tj 5.247 0 0 5.247 435.454 324.8329 Tm (3)Tj -0.01 Tc 0.225 Tw 9 0 0 9 307 311.8359 Tm [(Multigene NGS or whole exome sequencing \(WES\) ideally)-10( )]TJ 0.101 Tw -1.111 -1.111 Td [(should include patient and parental DNA \(trio analysis\).)37( )37(A tar)]TJ 0 Tc 0 Tw 27 0 Td (-)Tj -0.01 Tc -0.006 Tw -27 -1.111 Td [(geted )1(NGS )1(panel )1(including )1(all )1(genes )1(known )1(to )1(be )1(mutated )1(in )1(CN)-10( )]TJ 0.148 Tw T* [(\(>30\) )1(is )1(a )1(reasonable )1(\037rst )1(step )1(that )1(provides )1(uniform )1(sequenc)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.059 Tw T* (ing coverage for all genes of interest and requires simpler bioin)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.137 Tw T* [(formatic analysis.)37( )37(The choice of genes within the panel should)-10( )]TJ 0.13 Tw T* [(include not only all those that strictly cause neutropenia when)-10( )]TJ -0.016 Tw T* [(mutated but also genes resulting in diseases in which neutropenia)-10( )]TJ 0.005 Tw T* [(is a secondary feature \(immunode\037ciency/immune dysregulation,)27( )]TJ 0.024 Tw T* [(metabolic and nutritional de\037ciency)92(,)37( and other BMF syndromes\))-10( )]TJ 0.01 Tw T* [(\(T)86(able\035)-10(2\).)]TJ 5.247 0 0 5.247 333.4167 214.8329 Tm (3,4,42)Tj 9 0 0 9 347.6884 211.8359 Tm [( )37(WES can also be used in cases where no mutations)-10( )]TJ /T1_5 1 Tf 0 Tc 0 Tw -4.91 -4.148 Td [(Box 5: Recommendations on Antineutr)18(ophil )]TJ T* [(Antibody T)111(esting)]TJ /T1_1 1 Tf 0.08 Tw 0 -1.778 TD [(As shown in Box 3,)37( antineutrophil antibody testing should )]TJ 0.034 Tw 0 -1.111 TD (be performed as \037rst-line investigation in both children and )Tj 0 Tw T* (adults.)Tj 0.201 Tw 1.111 -1.111 Td [(Indirect granulocyte )1(immuno\036uorescence )1(test \(GIFT\) is )]TJ 0 Tw -1.111 -1.111 Td (recommended as a \037rst-line assay in reference laboratories.)Tj -0.014 Tw 1.111 -1.111 Td [(A positive GIFT in combination with laboratory )1(tests and )]TJ 0.118 Tw -1.111 -1.111 Td (clinical picture can support diagnosis of autoimmune neu)Tj 0 Tw (-)Tj 0.068 Tw T* [(tropenia )1(\(AIN\) but does )1(not exclude )1(the diagnosis )1(of other )]TJ 0 Tw T* (types of neutropenia.)Tj 0.049 Tw 1.111 -1.111 Td [(W)18(ith a negative indirect GIFT)111(,)37( if the clinical suspicion of )]TJ 0 Tw -1.111 -1.111 Td [(AIN remains high,)37( GIFT should be repeated several times.)]TJ ET 0 0 0 1 K 0.5 w 4 M 297.25 42.25 245.5 144.926 re S q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 1 w 10 M 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 799 0 obj <> endobj 800 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 302.276 24.0881 Tm (7)Tj ET /PlacedGraphic /MC0 BDC q 1 0 0 1 55.0115967 759.9024048 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 0 -2.901 l -2.529 -2.901 l -2.529 0 l -4.011 0 l -4.011 -7.304 l -2.529 -7.304 l -2.529 -4.151 l 0 -4.151 l 0 -7.304 l 1.481 -7.304 l 1.481 0 l h f Q q 51 750.589 56.165 9.41 re W n q 1 0 0 1 58.9167023 755.8701019 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.307 0.974 0.053 0.604 0 0 c 2.942 -2.466 m 2.571 -3.112 1.958 -3.366 1.005 -3.366 c -0.582 -3.366 -1.344 -2.339 -1.344 -0.974 c -1.344 -0.254 l -1.344 1.344 -0.54 2.116 0.835 2.116 c 2.33 2.116 3.016 1.248 3.016 -0.36 c 3.016 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 67.2454071 752.5995941 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -1.344 0 l -1.344 3.101 l -1.344 3.947 -1.672 4.223 -2.148 4.223 c -2.625 4.223 -2.984 3.863 -2.984 3.111 c -2.984 0 l -4.339 0 l -4.339 5.291 l -3.016 5.291 l -3.016 4.848 l -2.815 5.122 -2.435 5.387 -1.842 5.387 c -1.207 5.387 -0.688 5.144 -0.36 4.678 c 0.013 5.135 0.574 5.396 1.164 5.387 c 2.317 5.387 2.995 4.687 2.995 3.312 c 2.995 -0.001 l 1.64 -0.001 l 1.64 3.101 l 1.64 3.895 1.366 4.223 0.825 4.223 c 0.339 4.223 0 3.863 0 3.111 c h f Q q 1 0 0 1 74.0608063 754.7783051 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -0.889 0 l -1.439 0 -1.683 -0.18 -1.683 -0.593 c -1.683 -1.005 -1.375 -1.186 -0.91 -1.186 c -0.296 -1.186 0.003 -0.921 0.003 -0.201 c h -1.047 0.996 m 0 0.996 l 0 1.304 l 0 1.896 -0.179 2.086 -0.941 2.086 c -1.46 2.086 -1.714 2.012 -1.937 1.663 c -2.889 2.326 l -2.499 2.972 -1.906 3.205 -0.814 3.205 c 0.55 3.205 1.323 2.802 1.323 1.289 c 1.323 -2.182 l 0 -2.182 l 0 -1.717 l -0.212 -2.076 -0.529 -2.277 -1.143 -2.277 c -2.244 -2.277 -3.005 -1.696 -3.005 -0.617 c -3.005 0.51 -2.159 0.996 -1.047 0.996 c f Q q 1 0 0 1 80.4425964 758.0068054 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.317 0.498 -0.698 0.741 -1.439 0.741 c -2.103 0.741 -2.466 0.435 -2.466 -0.062 c -2.466 -0.635 -2 -0.889 -1.026 -1.132 c 0.497 -1.513 1.186 -2.084 1.186 -3.373 c 1.186 -4.568 0.381 -5.5 -1.333 -5.5 c -2.614 -5.5 -3.502 -5.15 -4.148 -4.304 c -3.016 -3.521 l -2.625 -4.008 -2.18 -4.251 -1.429 -4.251 c -0.582 -4.251 -0.296 -3.881 -0.296 -3.436 c -0.296 -2.928 -0.603 -2.643 -1.791 -2.335 c -3.229 -1.954 -3.948 -1.268 -3.948 -0.061 c -3.948 1.094 -3.187 1.993 -1.451 1.993 c -0.289 1.993 0.592 1.602 1.11 0.797 c h f Q q 1 0 0 1 85.7776031 754.9795074 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 0 0.55 l 0 1.396 -0.265 1.862 -0.931 1.862 c -1.577 1.862 -1.873 1.439 -1.873 0.666 c -1.873 0.002 l -1.873 -0.76 -1.693 -1.331 -0.931 -1.331 c -0.202 -1.337 -0.001 -0.761 -0.001 0.002 c h 1.354 -0.083 m 1.354 -1.459 0.656 -2.476 -0.709 -2.476 c -1.26 -2.476 -1.63 -2.369 -1.871 -2.168 c -1.871 -4.39 l -3.228 -4.39 l -3.228 2.914 l -1.874 2.914 l -1.874 2.564 l -1.62 2.85 -1.239 3.009 -0.699 3.009 c 0.524 3.007 1.354 2.149 1.354 0.637 c h f Q q 1 0 0 1 88.0207977 759.902298 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.352 0 l 1.352 -2.424 l 1.554 -2.159 1.925 -1.916 2.538 -1.916 c 3.606 -1.916 4.475 -2.424 4.475 -3.991 c 4.475 -7.304 l 3.132 -7.304 l 3.132 -4.202 l 3.132 -3.377 2.836 -3.08 2.285 -3.08 c 1.661 -3.08 1.355 -3.495 1.355 -4.191 c 1.355 -7.303 l 0 -7.303 l h f Q q 1 0 0 1 94.7415009 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.659 0 l 1.628 0.687 1.354 0.974 0.846 0.974 c 0.306 0.974 0.052 0.604 0 0 c 2.941 -2.466 m 2.571 -3.112 1.957 -3.366 1.005 -3.366 c -0.583 -3.366 -1.345 -2.339 -1.345 -0.974 c -1.345 -0.254 l -1.345 1.344 -0.541 2.116 0.835 2.116 c 2.329 2.116 3.015 1.248 3.015 -0.36 c 3.015 -0.963 l 0 -0.963 l 0.01 -1.693 0.243 -2.223 0.995 -2.223 c 1.557 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 101.5989075 756.4199066 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.139 0.201 -0.328 0.402 -0.664 0.402 c -1.173 0.402 -1.511 0.032 -1.511 -0.709 c -1.511 -3.82 l -2.868 -3.82 l -2.868 1.471 l -1.545 1.471 l -1.545 1.027 l -1.366 1.292 -1.017 1.566 -0.393 1.566 c 0.232 1.566 0.723 1.29 1.037 0.74 c h f Q q 1 0 0 1 104.1477051 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.309 0.974 0.055 0.604 0 0 c 2.943 -2.466 m 2.572 -3.112 1.959 -3.366 1.007 -3.366 c -0.58 -3.366 -1.343 -2.339 -1.343 -0.974 c -1.343 -0.254 l -1.343 1.344 -0.538 2.116 0.837 2.116 c 2.331 2.116 3.018 1.248 3.018 -0.36 c 3.018 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.936 -1.768 c h f Q EMC Q BT /T1_1 1 Tf 8 0 0 8 107.1653 750.5894 Tm ( )Tj /T1_2 1 Tf 0.278 0.25 Td ( \(2023\) 7:4)Tj ET BT /Span <>BDC /T1_2 1 Tf 38.328 Tw 8 0 0 8 107.1653 750.5894 Tm 4.93 0.25 Td ( )Tj EMC ET BT /T1_2 1 Tf 8 0 0 8 455.4453 752.5894 Tm (www)Tj 8 0 0 8 107.1653 750.5894 Tm 45.703 0.25 Td [(.hemaspher)18(ejour)-18(nal.com)]TJ /T1_3 1 Tf 0.084 Tw 9 0 0 9 312 119.6982 Tm [(work-up,)37( BM examination should be initiated before granulo)]TJ 0 Tw (-)Tj 0.241 Tw 0 -1.111 TD (cyte-colony stimulating factor \(G-CSF\) treatment to exclude )Tj 0.016 Tw T* (MDS/AML and as a baseline for monitoring the risk for malig)Tj 0 Tw (-)Tj 0.079 Tw T* [(nant transformation.)37( In )1(many CN patients,)37( the )1(diagnostic BM )]TJ 0.055 Tw T* (shows a maturation arrest of neutrophil precursors at an early )Tj 0.199 Tw T* (stage \(promyelocyte/myelocyte\) with few cells of the neutro)Tj 0 Tw (-)Tj 0.139 Tw T* (philic series beyond the promyelocyte stage.)Tj 0 Tw 5.247 0 0 5.247 488.2536 62.6952 Tm (61)Tj 0.139 Tw 9 0 0 9 494.0883 59.6982 Tm [( )37(The number of )]TJ 0.32 Tw -20.232 -1.111 Td [(promyelocytes is slightly increased.)37( Marrow eosinophilia is )]TJ 0.217 Tw T* [(common.)37( )1(Cellularity )1(is )1(usually )1(normal )1(or )1(slightly )1(decreased.)37( )]TJ ET q 64.56 488.732 479.88 237.119 re W n q /GS0 gs 479.8800049 0 0 237.1199951 64.5599976 488.7319946 cm /Im0 Do Q Q q 1 0 0 1 51 732.7471008 cm 0 0 0 1 K 0.5 w 0 0 m 507 0 l S Q q 1 0 0 1 51 471.1271057 cm 0 0 0 1 K 0.5 w 0 0 m 507 0 l S Q BT /T1_1 1 Tf 0 Tw 7.5 0 0 7.5 51 477.3771 Tm [(Figur)18(e 1.)]TJ ET BT /Span <>BDC /T1_1 1 Tf 7.5 0 0 7.5 81.84 477.3771 Tm ( )Tj EMC ET BT /T1_1 1 Tf 7.5 0 0 7.5 85.59 477.3771 Tm (Flowchart for the basic evaluation of a patient with chr)Tj 7.5 0 0 7.5 51 477.3771 Tm 30.572 0 Td [(onic neutr)18(openia.)]TJ /T1_2 1 Tf ( )Tj /T1_4 1 Tf 9 0 0 9 57.5 449.5741 Tm [(Box 3: What T)111(ests Should the Dif)18(fer)18(ent Lines of )]TJ T* [(Investigation of Chr)18(onic Neutr)18(openia Include After )]TJ T* (Referral to the Specialist?)Tj /T1_5 1 Tf 0 -1.556 TD [(First-line in)18(v)24(estigations)]TJ /T1_3 1 Tf -0.055 Tc 0.047 Tw 0 -1.111 TD [(CBCs,)37( PB smear)111(,)37( biochemistry tests including liver and kidney func)]TJ 0 Tc 0 Tw (-)Tj -0.055 Tc -0.017 Tw T* [(tion,)37( immunoglobulin levels,)37( CRP)129(,)37( vitamin B12 and folate,)37( \036ow cyto)]TJ 0 Tc 0 Tw (-)Tj -0.055 Tc -0.056 Tw T* [(metric analysis of PB lymphocyte subsets,)37( virology antibody screening)-55( )]TJ 0.098 Tw T* [(\(i.e.,)37( HepB,)37( HepC,)37( HIV)129(,)37( EBV)129(,)37( CMV)129(,)37( and Parvovirus\),)37( indirect anti)]TJ 0 Tc 0 Tw (-)Tj -0.055 Tc 0.198 Tw T* [(neutrophil antibodies \(GIFT)111(,)37( GA)74(T)111(,)37( and other\); thyroid hormones)-55( )]TJ 0 Tw T* [(\(FT3,)37( FT4,)37( )37(TSH\),)37( antithyroid antibodies \(anti-TG and anti-TPO\).)]TJ 0 Tc -0.038 Tw 1.111 -1.111 Td (Additional investigation in children: \036ow cytometric anal)Tj 0 Tw (-)Tj 0.029 Tw -1.111 -1.111 Td [(ysis )-37(of TCR)37(-)]TJ /T1_6 1 Tf 0 Tw (\037)Tj /T1_3 1 Tf (/)Tj /T1_6 1 Tf (\036)Tj /T1_3 1 Tf 0.066 Tw (-positive double-negative \(CD4- and CD8-\) )Tj 0 Tw T* (CD3 PB lymphocytes.)Tj 0.042 Tw 1.111 -1.111 Td (Additional investigations in adults: antiphospholipid and )Tj 0.033 Tw -1.111 -1.111 Td [(anticardiolipin antibodies,)37( \036ow cytometric analysis of LGL/)]TJ 0.06 Tw T* [(TCR clonality in PB lymphocytes,)37( serum ferritin,)37( RF)129(,)37( )37(ANA,)37( )]TJ 0 Tw T* [(ENA,)37( ds-DNA,)37( and ESR.)]TJ /T1_5 1 Tf 0 -1.556 TD [(Second-line in)18(v)24(estigations)]TJ /T1_3 1 Tf 0.072 Tw 0 -1.111 TD [(CBCs in family members,)37( serial blood counts twice a week )]TJ -0.052 Tw T* [(over a period of 6 weeks to exclude CyN,)37( copper; ceruloplas)]TJ 0 Tw (-)Tj 0.226 Tw T* [(min,)37( anti-tTG-IgA,)37( deamidated gliadin peptide antibodies )]TJ 0 Tw T* (IgA/IgG and pancreatic isoamylase.\035)Tj 0.031 Tw 1.111 -1.111 Td [(Additional investigation in children: RF)129(,)37( )37(ANA,)37( ENA,)37( and )]TJ 0 Tw -1.111 -1.111 Td (ds-DNA)Tj 0.244 Tw 1.111 -1.111 Td (Additional investigation in adults: serum electrophore)Tj 0 Tw (-)Tj 0.019 Tw -1.111 -1.111 Td [(sis,)37( serum complement )1(levels,)37( next generation sequencing )1(of )]TJ 0 Tw T* (gene panels related to myeloid malignancies to identify idio-)Tj T* (pathic cases at risk to MDS/AML development.)Tj 0.327 Tw 1.111 -1.111 Td [(In children,)37( young adults,)37( and considered for adults: )]TJ 0 Tw -1.111 -1.111 Td (genetic investigations.)Tj 0.222 Tw 8 0 0 8 57.5 136.5741 Tm [(AML = acute myeloid leukemia; )37(ANA = antinuclear antibodies; )]TJ 0.205 Tw 0 -1.125 TD (anti-TG = antithyroglobulin; anti-TPO = antithyroid peroxidase; )Tj 0.174 Tw T* (CBC = complete blood counts; CMV = cytomegalovirus; CyN = )Tj 0.245 Tw T* [(cyclic )1(neutropenia; )1(dsDNA )1(= )1(double-stranded )1(DNA; )1(tTG )1(= tis)]TJ 0 Tw (-)Tj 0.184 Tw T* (sue transglutaminase antibodies; EBV = Epstein-Barr virus; ENA )Tj 0.272 Tw T* (= extractable nuclear antigen; ESR = erythrocyte sedimentation )Tj 0.042 Tw T* [(rate; GA)74(T = granulocyte agglutination test; Hep = hepatitis; HIV = )]TJ 0.113 Tw T* (human immunode\037ciency virus; GIFT = granulocyte immuno\036uo)Tj 0 Tw (-)Tj 0.008 Tw T* (rescence test; LGL = large granular lymphocytes; MDS = myelodys)Tj 0 Tw (-)Tj 0.056 Tw T* (plastic neoplasms; PB = peripheral blood; RF = rheumatoid factor; )Tj 0 Tw T* [(TCR = )37(T)104(-cell receptor)111(.)]TJ ET 0 0 0 1 K 0.5 w 4 M 51.25 40.324 245.5 421.926 re S BT /T1_4 1 Tf 9 0 0 9 318.5 449.5741 Tm (Box 4: What Is the Role of BM Examination? When )Tj 0 -1.111 TD (and How Often?)Tj /T1_3 1 Tf -0.063 Tw 0 -1.778 TD [(A diagnostic BM with morphology)92(,)37( cytogenetics,)37( and NGS of )]TJ 0 Tw 0 -1.111 TD (genes related to myeloid malignancies should be performed:)Tj 0.159 Tw 0 -1.778 TD (1.)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 325.673 397.5721 Tm ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 330.497 397.5721 Tm (In pediatric patients with severe and moderate chronic )Tj 0.317 Tw 0 -1.111 TD (neutropenia with the exception of patients with pri)Tj 0 Tw 9 0 0 9 318.5 449.5741 Tm 25.557 -6.889 Td (-)Tj 0.126 Tw -24.224 -1.111 Td [(mary )37(AIN with positive antigranulocyte antibodies and )]TJ 0 Tw T* (drug-induced neutropenias.)Tj 0.053 Tw -1.333 -1.111 Td (2.)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 325.673 357.5761 Tm ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 330.497 357.5761 Tm (In patients with suggested )Tj 9 0 0 9 318.5 449.5741 Tm 12.953 -10.222 Td (AIN but negative granulocyte )Tj 0 Tw -11.62 -1.111 Td [(antibody test,)37( if patients suffer from recurrent infections.)]TJ -1.333 -1.111 Td (3.)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 325.673 337.5781 Tm ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 330.497 337.5781 Tm (In any patients before G-CSF treatment.)Tj 0.063 Tw -1.333 -1.111 Td (4.)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 325.673 327.5791 Tm ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 330.497 327.5791 Tm (In all adult patients with unexplained chronic neutrope)Tj 0 Tw 9 0 0 9 318.5 449.5741 Tm 25.558 -13.555 Td (-)Tj 0.016 Tw -24.225 -1.111 Td [(nia )1(with )1(the )1(exception )1(of )1(those )1(with )1(long-standing,)37( )1(mild,)37( )]TJ 0 Tw T* (isolated neutropenia that remains stable over time.)Tj 0.206 Tw -0.222 -1.778 Td [(Annual BM )1(and cytogenetics )1(follow-up )1(should be )1(per)]TJ 0 Tw 24.445 0 Td (-)Tj -25.556 -1.111 Td (formed in patients:)Tj 0.188 Tw 0 -1.778 TD (1.)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 325.673 265.5781 Tm ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 330.497 265.5781 Tm (W)Tj 9 0 0 9 318.5 449.5741 Tm 2.315 -20.444 Td [(ith congenital BM failure syndromes independent )1(of )]TJ 0 Tw -0.982 -1.111 Td [(ANC and treatment with G-CSF)129(.)]TJ 0.068 Tw -1.333 -1.111 Td (2.)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 325.673 245.5801 Tm ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 330.497 245.5801 Tm (W)Tj 9 0 0 9 318.5 449.5741 Tm 2.315 -22.666 Td [(ith )1(unde\037ned )1(SCN )1(\(after )1(extensive )1(investigation\) )1(with )]TJ 0 Tw -0.982 -1.111 Td [(G-CSF treatment,)37( may be considered.)]TJ -0.222 -1.778 Td (Repeated BM follow-up should be performed in patients:)Tj 0.301 Tw 0 -1.111 TD [(W)18(ith decreasing )37(ANC or additional changes in other )]TJ 0.163 Tw -1.111 -1.111 Td [(blood cell counts \(e.g.,)37( anemia and thrombocytopenia\) or )]TJ 0 Tw T* (erythrocyte indices.)Tj -0.008 Tw 8 0 0 8 318.5 174.5741 Tm [(AIN = autoimmune neutropenia; )37(ANC = absolute neutrophil count; )]TJ 0.334 Tw 0 -1.125 TD (BM = bone marrow; G-CSF = granulocyte colony stimulating )Tj 0.137 Tw T* (factor; NGS = next generation sequencing; SCN = severe chronic )Tj 0 Tw T* (neutropenia.)Tj ET 312.25 141.324 245.5 320.926 re S q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 1 w 10 M 2 J /GS2 gs 27.5 425.5 849 23 re S Q Q endstream endobj 801 0 obj <> endobj 802 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 287.276 24.0881 Tm (6)Tj ET q 0 g /GS0 gs /Fm1 Do Q BT /T1_1 1 Tf 0.159 Tw 9 0 0 9 36 84.0446 Tm (investigation should be followed if the \037rst-line evaluation is )Tj 0 Tw 0 -1.111 TD [(inconclusive,)37( as also shown in Box 3.)]TJ 0.011 Tw 1.111 -1.111 Td [(Notably)92(,)37( the GL-WG experts highly recommend genetic test)]TJ 0 Tw (-)Tj 0.186 Tw -1.111 -1.111 Td [(ing in children,)37( young adults,)37( and selected adults to exclude )]TJ 0.061 Tw T* [(CN if the second level of investigation is inconclusive.)37( )37(Also,)37( in )]TJ 0.071 Tw 29 25.473 Td [(young children with a family history of severe neutropenia,)37( or )]TJ 0.021 Tw T* [(with typical congenital anomalies or repeated severe infections,)37( )]TJ -0.019 Tw T* (genetic testing should be expedited and performed after the \037rst )Tj 0 Tw T* (level of investigation.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_2 1 Tf 8 0 0 8 297 214.2974 Tm [(What is the r)18(ole of BM examination? When and how often?)]TJ 0 0 0 1 k /GS1 gs /T1_1 1 Tf 0.162 Tw 9 0 0 9 307 204.2974 Tm [(The recommendations on the type,)37( time,)37( and frequency of )]TJ -0.015 Tw -1.111 -1.111 Td [(BM investigations are summarized in Box 4.)37( BM aspiration and )]TJ -0.048 Tw T* [(trephine biopsy can give information on the cellularity)92(,)37( the num)]TJ 0 Tw (-)Tj 0.177 Tw T* [(bers and maturation of erythroid,)37( myeloid precursors,)37( mega)]TJ 0 Tw (-)Tj 0.15 Tw T* [(karyocytes,)37( and on the presence of dysplastic features.)37( It can )]TJ 0.018 Tw T* (also inform on the presence of nonmyeloid cells and contribute )Tj 0 Tw T* [(to the differential diagnosis,)37( particularly in adults.)]TJ -0.045 Tw 1.111 -1.111 Td [(Besides morphology)92(,)37( a cytogenetic evaluation can give further )]TJ -0.047 Tw -1.111 -1.111 Td (information on acquired chromosomal abnormalities typical for )Tj 0.022 Tw T* [(MDS or )37(AML.)37( BM samples can also be used for genetic testing )]TJ 0.042 Tw T* [(of acquired somatic gene mutation,)37( which play a role in leuke)]TJ 0 Tw (-)Tj -0.012 Tw T* [(mogenesis in CN \(e.g.,)37( )]TJ /T1_3 1 Tf 0 Tw [(R)37(UNX-1)]TJ /T1_1 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_3 1 Tf 0 Tc 0 Tw 14.385 0 Td (CSF3R)Tj /T1_1 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_3 1 Tf 0 Tc 0 Tw 3.563 0 Td (TP53)Tj /T1_1 1 Tf (\))Tj 5.247 0 0 5.247 483.0392 97.2944 Tm (3,53\22659)Tj -0.012 Tw 9 0 0 9 501.7079 94.2974 Tm ( or suggest )Tj -0.014 Tw -22.745 -1.111 Td (increased risk of transformation to MDS/AML in acquired neu)Tj 0 Tw (-)Tj T* [(tropenias \(e.g.,)37( )]TJ /T1_3 1 Tf (SRSF2)Tj /T1_1 1 Tf ( and )Tj /T1_3 1 Tf (IDH1)Tj /T1_1 1 Tf (\).)Tj 5.247 0 0 5.247 430.6942 77.2944 Tm (60)Tj 0.109 Tw 9 0 0 9 307 64.2974 Tm [(In patients with severe chronic neutropenia \(SCN\),)37( the BM )]TJ 0.118 Tw -1.111 -1.111 Td [(examination )1(may be )1(helpful for )1(the differential )1(diagnosis and )]TJ -0.017 Tw T* [(exclusion of MDS/AML.)37( If not performed during the diagnostic )]TJ ET q 1 0 0 1 36 726.852005 cm 0.24 0.08 0.08 0.4 K 12 w /GS0 gs 0 0 m 34.896 0 l S Q q 1 0 0 1 36 708.102005 cm 0 0 0 1 K 0.5 w 0 0 m 246 0 l S Q BT 0 0 0 0 k /GS0 gs /T1_4 1 Tf 0 Tw 8 0 0 8 39 723.852 Tm [(T)111(able 3)]TJ 0 0 0 1 k /GS1 gs /T1_5 1 Tf -0.375 -1.5 Td [(Classification of Acquir)18(ed Neutr)18(openias)]TJ ET q 1 0 0 1 36 690.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 83.634 0 l S Q q 1 0 0 1 119.6336975 690.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 162.366 0 l S Q q 1 0 0 1 36 135.4564972 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 83.634 0 l S Q q 1 0 0 1 119.6336975 135.4564972 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 162.366 0 l S Q BT /T1_6 1 Tf 8 0 0 8 36 694.9401 Tm (Acquired )Tj 20.55 0 Td ( )Tj /T1_7 1 Tf -20.55 -1.808 Td [(Primar)-18(y or idiopathic:)37( )]TJ 0 -1.25 TD (neutropenia as )Tj T* [(predominant,)37( often )]TJ T* (isolated feature)Tj 10.829 3.788 Td (Antibody-mediated)Tj ET BT /Span <>BDC /T1_7 1 Tf -0.24 Tw 8 0 0 8 122.632 670.7721 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -3.021 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 36 694.9401 Tm 11.829 -3.021 Td [(Primar)-18(y )-240(autoimmune)]TJ ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 660.7641 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -4.272 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 36 694.9401 Tm 11.829 -4.272 Td [(Primar)-18(y )-240(alloimmune)]TJ 0 Tw -1 -1.251 Td (Nonantibody-mediated)Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 640.7481 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -6.774 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 640.7481 Tm (Idiopathic neutropenia of infancy)Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 630.7321 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -8.026 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 630.7321 Tm (CIN/idiopathic cytopenia of undetermined)Tj ET BT /Span <>BDC /T1_7 1 Tf -0.24 Tw 8 0 0 8 122.632 620.7241 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -9.277 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 36 694.9401 Tm 11.829 -9.277 Td [(significance-neutropenia )-240(\(ICUS-N\))]TJ 0 Tw -11.829 -1.251 Td [(Secondar)-18(y:)37( neutropenia )]TJ T* (associated/due to)Tj 10.829 1.25 Td [(Hypersplenism \(due to congestive,)37( infiltrative,)37( )]TJ T* [(phagocytic,)37( and reactive splenomegaly\))]TJ 0 -1.251 TD (Infections)Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 580.7001 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.792 -14.28 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.336 580.7001 Tm (Viral \(e.g.,)Tj 8 0 0 8 36 694.9401 Tm 15.341 -14.28 Td [( HIV)92(,)37( HCV)92(,)37( HBV)92(,)37( CMV)92(,)37( EBV)92(,)37( HIV)92(,)37( influenza,)37( )]TJ -3.549 -1.25 Td [(par)-18(vovirus B19,)37( measles,)37( and Sars-Cov-2\))]TJ ET BT /Span <>BDC /T1_7 1 Tf -0.24 Tw 8 0 0 8 122.632 560.6921 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -16.781 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 36 694.9401 Tm 11.829 -16.781 Td [(Bacterial )-240(\(e.g.,)37( )]TJ /T1_8 1 Tf 0 Tw 5.327 0 Td (Salmonella)Tj /T1_7 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_8 1 Tf 0 Tc 0 Tw (Brucella)Tj /T1_7 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_8 1 Tf 0 Tc 0 Tw (Rickettsia)Tj /T1_7 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_8 1 Tf 0 Tc 0 Tw -5.327 -1.25 Td (Mycobacterium)Tj /T1_7 1 Tf -0.037 Tc 0.037 Tw (, )Tj /T1_8 1 Tf 0 Tc 0 Tw (Mycoplasma)Tj /T1_7 1 Tf [(,)37( and )]TJ /T1_8 1 Tf [(H.)37( Pylori)]TJ /T1_7 1 Tf (\))Tj ET BT /Span <>BDC /T1_7 1 Tf -0.24 Tw 8 0 0 8 122.632 540.6841 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -19.282 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 36 694.9401 Tm 11.829 -19.282 Td [(Parasitic )-240(\(e.g.,)37( )]TJ /T1_8 1 Tf 0 Tw 5.27 0 Td (Plasmodium spp)Tj /T1_7 1 Tf [(,)37( visceral )]TJ -5.27 -1.25 Td (leismaniasis\))Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 520.6761 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -21.783 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 520.6761 Tm (Fungal \(e.g.,)Tj 8 0 0 8 36 694.9401 Tm 16.212 -21.783 Td ( histoplasmosis\))Tj -5.383 -1.251 Td (Autoimmune diseases)Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 500.6601 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -24.285 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 500.6601 Tm (Organ specific \(e.g.,)Tj 8 0 0 8 36 694.9401 Tm 18.914 -24.285 Td [( thyroid diseases,)37( inflammator)-18(y )]TJ -7.085 -1.25 Td [(bowel disease,)37( and primar)-18(y biliar)-18(y cirrhosis\))]TJ ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 480.6521 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -26.786 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 480.6521 Tm (Systemic \(e.g.,)Tj 8 0 0 8 36 694.9401 Tm 17.027 -26.786 Td [( systemic lupus er)-18(ythematosus,)37( )]TJ -5.198 -1.25 Td [(rheumatoid arthritis including Felty\222)55(s syndrome,)37( )]TJ 0 -1.25 TD [(Sjogren syndrome,)37( systemic sclerosis,)37( and graft-vs-)]TJ T* (host disease\))Tj -1 -1.251 Td (Nutritional deficiencies)Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 430.6361 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -33.038 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 430.6361 Tm (B12,)Tj 8 0 0 8 36 694.9401 Tm 13.492 -33.038 Td [( folic acid,)37( iron,)37( copper)74(,)37( and caloric malnutrition)]TJ -2.663 -1.251 Td [(Immuno-regulator)-18(y disorders)]TJ ET BT /Span <>BDC /T1_7 1 Tf -0.037 Tw 8 0 0 8 122.632 410.6201 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -35.54 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 410.6201 Tm (Common )Tj 8 0 0 8 36 694.9401 Tm 15.256 -35.54 Td [(variable )-37(immunodeficiency)55(,)37( ALPS,)37( ALPS-like )]TJ 0 Tw -3.427 -1.25 Td [(diseases,)37( HLH,)37( and macrophage activation syndrome)]TJ -1 -1.251 Td (Hematologic diseases)Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 380.6041 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -39.292 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 380.6041 Tm (Primar)Tj 8 0 0 8 36 694.9401 Tm 14.179 -39.292 Td (y benign \(aplastic anemia\))Tj ET BT /Span <>BDC /T1_7 1 Tf 8 0 0 8 122.632 370.5961 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -40.543 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 370.5961 Tm (Clonal \(myeloid malignancies/lymphoid malignancies )Tj T* (including LGL\))Tj -1 -1.251 Td (Drug-induced)Tj ET BT /Span <>BDC /T1_7 1 Tf -0.24 Tw 8 0 0 8 122.632 340.5801 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -44.295 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 36 694.9401 Tm 11.829 -44.295 Td (-Chemotherapy)Tj ET BT /Span <>BDC /T1_7 1 Tf 0.015 Tc 0 Tw 8 0 0 8 122.632 330.5721 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.844 -45.546 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.752 330.5721 Tm (-Nonchemotherapeutic drugs:)Tj 8 0 0 8 36 694.9401 Tm 22.781 -45.546 Td [( analgesics and)15( )]TJ -10.937 -1.25 Td [(NSAIDs,)37( antibiotics \(beta-lactams,)37( cefipime,)52( )]TJ T* [(trimethoprim-sulfametoxazole,)37( sulfasalazine,)52( )]TJ T* [(vancomycin,)37( rifampicin,)37( fluconazole,)37( ketoconazole\),)52( )]TJ T* [(antidiuretics \(furosemide,)37( spironolactone\),)52( )]TJ T* [(antiretroviral \(HIV\) therapy)55(,)37( antithyroids \(tiamazofe,)52( )]TJ T* [(metimazole\),)37( clozapine \(olanzapine\),)37( deferiprone,)52( )]TJ T* [(dipyrone \(metamizole\),)37( phenothiazines)15( )]TJ 0 Tc 14.264 0 Td ( )Tj 0.015 Tc -14.264 -1.25 Td [(\(alimemazine\),)37( quinine/quinidine,)37( IVIG,)37( monoclonal)15( )]TJ T* [(antibodies \(Rituximab\),)37( and biological therapies)15( )]TJ T* [(\(Infliximab,)37( etanercept\))15( )]TJ ET BT /Span <>BDC /T1_7 1 Tf 0 Tc 8 0 0 8 122.632 220.5721 Tm ( )Tj 8 0 0 8 36 694.9401 Tm 11.829 -59.296 Td ( )Tj EMC ET BT /T1_7 1 Tf 8 0 0 8 130.632 220.5721 Tm (Extended list of drugs associated with neutropenia )Tj T* (can be found in the following references:)Tj 8 0 0 8 36 694.9401 Tm 26.223 -60.546 Td ( )Tj 4.664 0 0 4.664 247.703 213.1444 Tm (35\22638)Tj 8 0 0 8 258.9898 210.4804 Tm (.)Tj -27.874 -1.251 Td (Likely acquired)Tj 0 -1.251 TD [(In children/adolescents when neutropenia,)37( in the presence or absence of specific )]TJ 0 -1.25 TD [(antibodies against neutrophils arises or persists beyond the age of 5 ye\ ars,)38( the defi-)]TJ T* [(nition of late-onset and long-lasting neutropenia may be appropriate.)38( Recent articles )]TJ T* (identified this atypical neutropenia as an epiphenomenon of immune dysre\ gulation )Tj T* (with typical biochemical/immunological features and the presence of vari\ ants in )Tj T* [(genes regulating immunity)55(.)]TJ 7 0 0 7 36 125.4565 Tm (ALPS = autoimmune lymphoproliferative syndrome; CIN = Chronic idiopathic\ neutropenia; CMV )Tj 0 -1.286 TD (= cytomegalovirus; EBV = Epstein-Barr virus; HCV = Hepatitis C virus; HL\ H = hemophagocytic )Tj T* (lymphohistiocystosis; ICUS-N = idiopathic cytopenia of undetermined sign\ ificance-neutropenia.)Tj 0 0 0 0 k /GS0 gs /T1_1 1 Tf -0.037 Tc 0.037 Tw 9 0 0 9 6.1715 713.9761 Tm [(AQ)-37(9)]TJ 0 0 0 1 k /GS1 gs /T1_4 1 Tf 0 Tc 0 Tw 33.036 0.661 Td [(Box 1: What is Important to Know Fr)18(om Patient/)]TJ 0 -1.111 TD [(Family History When W)37(e Investigate Neutr)18(openia?)]TJ /T1_1 1 Tf 0.11 Tw 0 -1.778 TD (Patient history should include inquiry about occurrence of )Tj 0.141 Tw 0 -1.111 TD [(infections and their frequency)92(,)37( type,)37( severity)92(,)37( and need for )]TJ 0.024 Tw T* [(hospitalization.)37( Speci\037cally)92(,)37( history of omphalitis,)37( gingivitis,)37( )]TJ 0.064 Tw T* [(periodontitis,)37( skin infections,)37( abscesses,)37( and pneumonias as )]TJ 0.073 Tw T* (well as duration and response to antibiotics should be also )Tj 0 Tw T* (investigated.)Tj 0.198 Tw 1.111 -1.111 Td (Presence of congenital malformations in the patient or )Tj 0 Tw -1.111 -1.111 Td (family is important.)Tj 0.125 Tw 1.111 -1.111 Td [(For adult patients,)37( drug history is important,)37( as well as )]TJ 0.104 Tw -1.111 -1.111 Td (work-up for autoimmune and other disorders that may be )Tj 0 Tw T* (associated with neutropenias.)Tj 0.028 Tw 1.111 -1.111 Td [(Detailed family history should include ethnic origin,)37( con)]TJ 0 Tw (-)Tj -0.01 Tw -1.111 -1.111 Td [(sanguinity)92(,)37( occurrence of recurrent infections,)37( and neutrope)]TJ 0 Tw (-)Tj 0.035 Tw T* [(nias in other family members,)37( as well as unexplained infant )]TJ 0 Tw T* (death or miscarriages.)Tj ET 0 0 0 1 K 0.5 w 4 M 297.25 547.676 245.5 184.926 re S BT /T1_4 1 Tf 9 0 0 9 303.5 512.6732 Tm (Box 2: What Should a Detailed Clinical Examination )Tj T* [(Comprise When W)37(e Investigate Neutr)18(openia?)]TJ /T1_1 1 Tf 0.317 Tw 0 -1.778 TD (Careful clinical examination of skin and mucous mem)Tj 0 Tw (-)Tj 0.101 Tw 0 -1.111 TD [(branes,)37( upper and lower respiratory tract and abdomen to )]TJ -0.013 Tw T* [(exclude underlying infection,)37( lymphadenopathy)92(,)37( and/or hep)]TJ 0 Tw (-)Tj 0.03 Tw T* [(atosplenomegaly)92(.)37( Clinicians should be aware that neutrope)]TJ 0 Tw (-)Tj 0.125 Tw T* (nic patients might have only subtle symptoms of infection )Tj 0 Tw T* (due to reduced in\036ammatory response.)Tj -0.015 Tc 0.208 Tw 1.111 -1.111 Td [(In children and adults,)37( clinical examination is crucial to)-15( )]TJ -0.068 Tw -1.111 -1.111 Td [(detect congenital disorders.)37( It should focus on growth,)37( evidence)-15( )]TJ 0.157 Tw T* [(of cognitive impairment,)37( developmental delay)92(,)37( dysmorphism)-15( )]TJ 0.258 Tw T* [(\(mainly skeletal\),)37( nail,)37( hair or skin abnormalities,)37( signs of)-15( )]TJ 0.01 Tw T* [(bronchiectasis due to recurrent chest infections,)37( hepatomegaly)-15( )]TJ 0.089 Tw T* [(or splenomegaly)92(,)37( organ malformation,)37( evidence of super\037cial)-15( )]TJ 0 Tw T* [(veins,)37( and \037nally signs of photophobia,)37( nystagmus,)37( oculocuta)]TJ 0 Tc (-)Tj -0.015 Tc 0.005 Tw T* [(neous albinism,)37( and neuropathy)92(.)37( )37(The absence of obvious clini)]TJ 0 Tc 0 Tw (-)Tj -0.015 Tc -0.045 Tw T* [(cal signs does not exclude the presence of a congenital disorder)111(.)]TJ 0 Tc -0.014 Tw 1.111 -1.111 Td [(Cardiac function,)37( presence of enlarged lymph nodes,)37( joint )]TJ 0.293 Tw -1.111 -1.111 Td [(symptoms,)37( and symptoms compatible with autoimmune,)37( )]TJ 0.269 Tw T* [(metabolic,)37( gastrointestinal,)37( or nutritional diseases should )]TJ 0 Tw T* [(also be considered.)37( )]TJ ET 297.25 300.423 245.5 224.926 re S q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 1 w 10 M 2 J /GS3 gs 27.5 425.5 849 23 re S Q Q endstream endobj 803 0 obj <> endobj 804 0 obj <> endobj 805 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 302.276 24.0881 Tm (5)Tj ET /PlacedGraphic /MC0 BDC q 1 0 0 1 55.0115967 759.9024048 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 0 -2.901 l -2.529 -2.901 l -2.529 0 l -4.011 0 l -4.011 -7.304 l -2.529 -7.304 l -2.529 -4.151 l 0 -4.151 l 0 -7.304 l 1.481 -7.304 l 1.481 0 l h f Q q 51 750.589 56.165 9.41 re W n q 1 0 0 1 58.9167023 755.8701019 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.307 0.974 0.053 0.604 0 0 c 2.942 -2.466 m 2.571 -3.112 1.958 -3.366 1.005 -3.366 c -0.582 -3.366 -1.344 -2.339 -1.344 -0.974 c -1.344 -0.254 l -1.344 1.344 -0.54 2.116 0.835 2.116 c 2.33 2.116 3.016 1.248 3.016 -0.36 c 3.016 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 67.2454071 752.5995941 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -1.344 0 l -1.344 3.101 l -1.344 3.947 -1.672 4.223 -2.148 4.223 c -2.625 4.223 -2.984 3.863 -2.984 3.111 c -2.984 0 l -4.339 0 l -4.339 5.291 l -3.016 5.291 l -3.016 4.848 l -2.815 5.122 -2.435 5.387 -1.842 5.387 c -1.207 5.387 -0.688 5.144 -0.36 4.678 c 0.013 5.135 0.574 5.396 1.164 5.387 c 2.317 5.387 2.995 4.687 2.995 3.312 c 2.995 -0.001 l 1.64 -0.001 l 1.64 3.101 l 1.64 3.895 1.366 4.223 0.825 4.223 c 0.339 4.223 0 3.863 0 3.111 c h f Q q 1 0 0 1 74.0608063 754.7783051 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -0.889 0 l -1.439 0 -1.683 -0.18 -1.683 -0.593 c -1.683 -1.005 -1.375 -1.186 -0.91 -1.186 c -0.296 -1.186 0.003 -0.921 0.003 -0.201 c h -1.047 0.996 m 0 0.996 l 0 1.304 l 0 1.896 -0.179 2.086 -0.941 2.086 c -1.46 2.086 -1.714 2.012 -1.937 1.663 c -2.889 2.326 l -2.499 2.972 -1.906 3.205 -0.814 3.205 c 0.55 3.205 1.323 2.802 1.323 1.289 c 1.323 -2.182 l 0 -2.182 l 0 -1.717 l -0.212 -2.076 -0.529 -2.277 -1.143 -2.277 c -2.244 -2.277 -3.005 -1.696 -3.005 -0.617 c -3.005 0.51 -2.159 0.996 -1.047 0.996 c f Q q 1 0 0 1 80.4425964 758.0068054 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.317 0.498 -0.698 0.741 -1.439 0.741 c -2.103 0.741 -2.466 0.435 -2.466 -0.062 c -2.466 -0.635 -2 -0.889 -1.026 -1.132 c 0.497 -1.513 1.186 -2.084 1.186 -3.373 c 1.186 -4.568 0.381 -5.5 -1.333 -5.5 c -2.614 -5.5 -3.502 -5.15 -4.148 -4.304 c -3.016 -3.521 l -2.625 -4.008 -2.18 -4.251 -1.429 -4.251 c -0.582 -4.251 -0.296 -3.881 -0.296 -3.436 c -0.296 -2.928 -0.603 -2.643 -1.791 -2.335 c -3.229 -1.954 -3.948 -1.268 -3.948 -0.061 c -3.948 1.094 -3.187 1.993 -1.451 1.993 c -0.289 1.993 0.592 1.602 1.11 0.797 c h f Q q 1 0 0 1 85.7776031 754.9795074 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 0 0.55 l 0 1.396 -0.265 1.862 -0.931 1.862 c -1.577 1.862 -1.873 1.439 -1.873 0.666 c -1.873 0.002 l -1.873 -0.76 -1.693 -1.331 -0.931 -1.331 c -0.202 -1.337 -0.001 -0.761 -0.001 0.002 c h 1.354 -0.083 m 1.354 -1.459 0.656 -2.476 -0.709 -2.476 c -1.26 -2.476 -1.63 -2.369 -1.871 -2.168 c -1.871 -4.39 l -3.228 -4.39 l -3.228 2.914 l -1.874 2.914 l -1.874 2.564 l -1.62 2.85 -1.239 3.009 -0.699 3.009 c 0.524 3.007 1.354 2.149 1.354 0.637 c h f Q q 1 0 0 1 88.0207977 759.902298 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.352 0 l 1.352 -2.424 l 1.554 -2.159 1.925 -1.916 2.538 -1.916 c 3.606 -1.916 4.475 -2.424 4.475 -3.991 c 4.475 -7.304 l 3.132 -7.304 l 3.132 -4.202 l 3.132 -3.377 2.836 -3.08 2.285 -3.08 c 1.661 -3.08 1.355 -3.495 1.355 -4.191 c 1.355 -7.303 l 0 -7.303 l h f Q q 1 0 0 1 94.7415009 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.659 0 l 1.628 0.687 1.354 0.974 0.846 0.974 c 0.306 0.974 0.052 0.604 0 0 c 2.941 -2.466 m 2.571 -3.112 1.957 -3.366 1.005 -3.366 c -0.583 -3.366 -1.345 -2.339 -1.345 -0.974 c -1.345 -0.254 l -1.345 1.344 -0.541 2.116 0.835 2.116 c 2.329 2.116 3.015 1.248 3.015 -0.36 c 3.015 -0.963 l 0 -0.963 l 0.01 -1.693 0.243 -2.223 0.995 -2.223 c 1.557 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 101.5989075 756.4199066 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.139 0.201 -0.328 0.402 -0.664 0.402 c -1.173 0.402 -1.511 0.032 -1.511 -0.709 c -1.511 -3.82 l -2.868 -3.82 l -2.868 1.471 l -1.545 1.471 l -1.545 1.027 l -1.366 1.292 -1.017 1.566 -0.393 1.566 c 0.232 1.566 0.723 1.29 1.037 0.74 c h f Q q 1 0 0 1 104.1477051 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.309 0.974 0.055 0.604 0 0 c 2.943 -2.466 m 2.572 -3.112 1.959 -3.366 1.007 -3.366 c -0.58 -3.366 -1.343 -2.339 -1.343 -0.974 c -1.343 -0.254 l -1.343 1.344 -0.538 2.116 0.837 2.116 c 2.331 2.116 3.018 1.248 3.018 -0.36 c 3.018 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.936 -1.768 c h f Q EMC Q BT /T1_1 1 Tf 8 0 0 8 107.1653 750.5894 Tm ( )Tj /T1_2 1 Tf 0.278 0.25 Td ( \(2023\) 7:4)Tj ET BT /Span <>BDC /T1_2 1 Tf 38.328 Tw 8 0 0 8 107.1653 750.5894 Tm 4.93 0.25 Td ( )Tj EMC ET BT /T1_2 1 Tf 8 0 0 8 455.4453 752.5894 Tm (www)Tj 8 0 0 8 107.1653 750.5894 Tm 45.703 0.25 Td [(.hemaspher)18(ejour)-18(nal.com)]TJ /T1_3 1 Tf -0.04 Tw 9 0 0 9 51 127.2045 Tm [(diseases )1(such )1(as )1(skin )1(rashes,)37( )1(arthritis,)37( )1(vitiligo,)37( )1(hepatosplenomeg)]TJ 0 Tw (-)Tj 0.161 Tw 0 -1.111 TD [(aly)92(,)37( dryness of eyes or mouth,)37( and lymphadenopathy)92(,)37( among )]TJ 0 Tw T* (others.)Tj 5.247 0 0 5.247 77.5047 110.2015 Tm (10\22612)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_4 1 Tf 8 0 0 8 51 78.2045 Tm (What tests should be included in the initial and further levels of )Tj 0 -1.375 TD (investigation?)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.283 Tw 9 0 0 9 61 57.2045 Tm [(Patients )1(with )1(acute )1(neutropenia,)37( )1(particularly )1(in )1(the )1(pres)]TJ 0 Tw (-)Tj 0.22 Tw -1.111 -1.111 Td [(ence of symptoms/signs of infection,)37( may require immediate )]TJ -0.033 Tw 29 8.889 Td (investigation and even hospitalization depending on the severity )Tj 0.12 Tw 0 -1.111 TD [(of neutropenia )1(and )1(symptoms.)37( For )1(patients with )1(chronic,)37( iso)]TJ 0 Tw (-)Tj -0.015 Tw T* (lated neutropenia without a phenotype suggestive of any under)Tj 0 Tw 27 0 Td (-)Tj -0.015 Tw -27 -1.111 Td [(lying CN syndrome,)37( a \036owchart of basic investigation shown in )]TJ 0 Tw T* (Figure\0351 is recommended.)Tj 5.247 0 0 5.247 412.0068 90.2015 Tm (10\22612,15,19)Tj 0.058 Tw 9 0 0 9 322 77.2045 Tm [(If the initial evaluation does not suggest )37(AD)60(AN,)37( nor postin)]TJ 0 Tw (-)Tj 0.046 Tw -1.111 -1.111 Td [(fectious or drug-induced neutropenias,)37( the \037rst level of investi)]TJ 0 Tw (-)Tj -0.031 Tw T* [(gation,)37( possibly adjusted to the availability of the recommended )]TJ 0.087 Tw T* [(tests,)37( should be followed as shown in Box 3.)37( )37(A second line of )]TJ 0 0 0 0 k /GS0 gs 0 Tw 29.055 4.68 Td (F1)Tj ET q 1 0 0 1 51 691.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 109 0 l S Q q 1 0 0 1 160 691.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 78.5 0 l S Q q 1 0 0 1 238.5 691.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 79 0 l S Q q 1 0 0 1 317.5 691.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 240.239 0 l S Q q 1 0 0 1 51 186.080307 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 109 0 l S Q q 1 0 0 1 160 186.080307 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 78.5 0 l S Q q 1 0 0 1 238.5 186.080307 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 79 0 l S Q q 1 0 0 1 317.5 186.080307 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 240.239 0 l S Q q 1 0 0 1 51 705.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 109 0 l S Q q 1 0 0 1 160 705.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 78.5 0 l S Q q 1 0 0 1 238.5 705.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 79 0 l S Q q 1 0 0 1 317.5 705.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 240.239 0 l S Q BT 0 0 0 1 k /GS1 gs /T1_5 1 Tf 8 0 0 8 263.8661 709.9401 Tm (Congenital Neutropenias)Tj -26.608 -1.764 Td ( )Tj 15.534 0 Td [(Genes Involved )-2814(T)55(ype of Inheritance )]TJ 28.875 0 Td [(Main F)20(eatures/Notes )]TJ ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 51.0021 681.3641 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.645 -3.572 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.645 -3.572 Td [(WHIM )-240(syndrome)]TJ /T1_7 1 Tf 0 Tw 16.328 0 Td (CXCR4)Tj /T1_6 1 Tf 10.565 0 Td [(AD)-4794(No arrest of maturation,)37( myelokathexis,)37( and lymphopenia,)37( cardiopathy \(T)74(etralogy of )]TJ 5.831 -1.25 Td (Fallot\))Tj ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.9941 661.3481 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.646 -6.074 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.646 -6.074 Td [(Wiskott-Aldrich )-240(syndrome)]TJ /T1_7 1 Tf -0.018 Tc 0.018 Tw 13.868 0 Td [(WA)-18(S)]TJ /T1_6 1 Tf 0 Tc 0 Tw 1.684 0 Td [( gain of function)-4702(X-linked)-3870(Eczema,)37( thrombocytopenia,)37( severe infections,)37( and bloody diarrhea)]TJ ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.9861 651.3401 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.61 -7.325 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.61 -7.325 Td (CVID)Tj 0 Tw 13.342 0 Td [(V)18(arious genes including )]TJ /T1_7 1 Tf -0.01 Tw -0.342 -1.25 Td [(TNFSRF13,)37( BAFFR,)37( CTL4,)37( )]TJ 0 Tw 2.535 -1.25 Td [(LRBA,)37( PI3K)]TJ /T1_6 1 Tf 10.702 2.5 Td [(AD,AR)-4174(Infection recurrence,)37( hypogamma globulinemia,)37( and autoimmune cytopenias )]TJ 6.451 -1.25 Td (including neutropenia.)Tj -33.688 -2.501 Td (Associated with metabolic disorders )Tj 0 -1.25 TD (and nutritional deficiency)Tj 18.291 1.25 Td ( )Tj 9.844 0 Td ( )Tj 5.552 0 Td ( )Tj ET BT /Span <>BDC /T1_6 1 Tf 8 0 0 8 50.9781 601.3241 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.611 -13.577 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 58.9781 601.3241 Tm (Gaucher disease type I)Tj /T1_7 1 Tf 16.763 0 Td (GBA)Tj /T1_6 1 Tf 10.112 0 Td [(AR)-4812(HSM,)]TJ 8 0 0 8 263.8661 709.9401 Tm 8.964 -13.577 Td [( thrombocytopenia,)37( and osteolytic lesions)]TJ ET BT /Span <>BDC /T1_6 1 Tf 8 0 0 8 50.9701 591.3161 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.612 -14.828 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 58.9701 591.3161 Tm (Glycogen storage disease Ib)Tj /T1_7 1 Tf 14.499 0 Td (SLC37A4/G6PT1)Tj /T1_6 1 Tf 12.376 0 Td [(AR)-4812(Hepatomegaly)]TJ 8 0 0 8 263.8661 709.9401 Tm 12.038 -14.828 Td [(,)37( IBD,)37( and fasting hypoglycemia)]TJ ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.9621 581.3001 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.613 -16.08 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.613 -16.08 Td [(Isovaleric )-240(acidemia)]TJ /T1_7 1 Tf 0 Tw 16.94 0 Td (IVD)Tj /T1_6 1 Tf 9.935 0 Td [(AR)-4812(Neonatal ketoacidosis,)37( developmental delay)55(,)37( lethargy)55(,)37( and feeding refusal)]TJ ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.9541 571.2921 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.614 -17.331 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.614 -17.331 Td [(Methylmalonic )-240(acidemia)]TJ /T1_7 1 Tf 0 Tw 16.373 0 Td (MMUT)Tj /T1_6 1 Tf 10.502 0 Td [(AR)-4812(Lethargy)55(,)37( failure to thrive,)37( recurrent vomiting,)37( hypotonia,)37( hepatomegaly)55(,)37( and )]TJ 5.812 -1.25 Td (developmental delay)Tj ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.9461 551.2841 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.615 -19.832 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.615 -19.832 Td [(Propionic )-240(acidemia)]TJ /T1_7 1 Tf 0 Tw 15.292 0 Td [(PCCB,)37( PCCA)]TJ /T1_6 1 Tf 11.583 0 Td [(AR)-4812(Lethargy)55(,)37( cardiomyopathy)55(,)37( feeding difficulties,)37( and acute encephalopathy)]TJ ET BT /Span <>BDC /T1_6 1 Tf 8 0 0 8 50.9381 541.2761 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.653 -21.083 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 58.6421 541.2761 Tm (T)Tj 8 0 0 8 263.8661 709.9401 Tm -25.283 -21.083 Td (ranscobalamin II deficiency)Tj /T1_7 1 Tf 16.208 0 Td (TCN2)Tj /T1_6 1 Tf 10.334 0 Td [(AR)-4812(Developmental delay)55(,)37( diarrhea,)37( vomit,)37( lethargy)55(,)37( and mucosal ulceration)]TJ -27.876 -1.251 Td (Associated with bone marrow failure)Tj 18.291 0 Td ( )Tj 9.844 0 Td ( )Tj 5.552 0 Td ( )Tj ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.9221 521.2601 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.618 -23.585 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.618 -23.585 Td [(Fanconi )-240(anemia)]TJ /T1_7 1 Tf 0 Tw 13.393 0 Td [(F)37(ANC)]TJ /T1_6 1 Tf ( complementation )Tj 3.12 -1.25 Td (group)Tj 7.235 1.25 Td [(AR X-linked \(F)37(ANCB\))-1686(Congenital malformations and cancer predisposition)]TJ ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.9141 501.2521 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.619 -26.086 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.619 -26.086 Td (Ribosomopathies)Tj 0 Tw 17.291 0 Td ( )Tj 9.844 0 Td ( )Tj 5.552 0 Td ( )Tj ET BT /Span <>BDC /T1_6 1 Tf 0.76 Tw 8 0 0 8 50.9061 491.2441 Tm ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 66.9061 491.2441 Tm (Diamond-Blackfan )Tj 8 0 0 8 263.8661 709.9401 Tm -17.902 -27.337 Td (Anemia)Tj /T1_7 1 Tf 0 Tw 5.879 0 Td [(RPS7,)37( RPS10,)37( RPS15,)37( )]TJ -0.24 -1.25 Td [(RPS17,)37( RPS19,)37( RPS24,)37( )]TJ -0.213 -1.25 Td [(RPS26,)37( RPS27,)37( RPS27a,)37( )]TJ 1.746 -1.25 Td [(RPS28,)37( RPS29)]TJ -0.972 -1.25 Td [(RPL5,)37( RPL9,)37( RPL11,)37( )]TJ -0.48 -1.25 Td [(RPL15,)37( RPL18,)37( RPL26,)37( )]TJ -0.111 -1.25 Td [(RPL27,)37( RPL31,)37( RPL35a)]TJ /T1_6 1 Tf 13.53 7.5 Td [(AD)-4794(Er)-18(ythroid hypoplasia,)37( congenital malformations,)37( growth retardation,)37( osteosarcoma,)37( )]TJ -0.037 Tw 5.831 -1.25 Td [(MDS,)37( )-37(and AML)]TJ /T1_7 1 Tf -0.055 Tc 0.055 Tw -16.332 -7.501 Td [(G)-55(ATA)-55(1)]TJ /T1_6 1 Tf 0 Tc 0 Tw 9.577 0 Td [(X-linked)-3870(Early-onset anemia,)37( thrombocytopenia,)37( and bone marrow er)-18(ythroid hypoplasia)]TJ /T1_7 1 Tf -9.142 -1.251 Td (EPO)Tj /T1_6 1 Tf 10.084 0 Td [(AR)-4812(Er)-18(ythroid hypoplasia)]TJ /T1_7 1 Tf -11.934 -1.251 Td [(TSR2,)37( HEA)55(TR3)]TJ /T1_6 1 Tf -0.037 Tw 10.39 0 Td (X-linked AR)Tj 0 Tw 7.356 0 Td [(Er)-18(ythroid hypoplasia,)37( craniofacial defects,)37( short stature,)37( facial,)37( and acromelic )]TJ T* [(dysmorphic features,)37( and intellectual disability)]TJ ET BT /Span <>BDC /T1_6 1 Tf 0.76 Tw 8 0 0 8 50.8981 381.2041 Tm ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 66.8981 381.2041 Tm (Cartilage-hair )Tj 8 0 0 8 263.8661 709.9401 Tm -19.588 -41.092 Td (hypoplasia)Tj /T1_7 1 Tf 0 Tw 10.415 0 Td (RMRP)Tj /T1_6 1 Tf 10.427 0 Td [(AR)-4812(Short stature \(dwarfism\) with other skeletal abnormalities; metaphysea\ l )1( )]TJ -0.003 Tw 5.812 -1.25 Td [(chondrodysplasia,)37( ligamentous laxity; fine,)37( sparse hair \(hypotrichosis\); and abnormal )]TJ 0 Tw T* [(immune system function \(immune deficiency\),)37( recurrent infections.)]TJ ET BT /Span <>BDC /T1_6 1 Tf 0.76 Tw 8 0 0 8 50.8901 351.1961 Tm ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 66.8901 351.1961 Tm (Shwachman-Diamond )Tj 0 Tw T* (syndrome)Tj /T1_7 1 Tf 12.472 1.25 Td (SBDS,)Tj 8 0 0 8 263.8661 709.9401 Tm -9.95 -44.843 Td [( EFL1,)37( DNAJC21)]TJ /T1_6 1 Tf 11.203 0 Td [(AR)-4812(Mild neutropenia,)37( dysgranulopoiesis,)37( mild dysmegakar)-18(yopoiesis,)37( dyser)-18(ythropoie-)]TJ 5.812 -1.25 Td [(sis,)37( exocrine pancreas deficiency)55(,)37( metaphyseal dysplasia,)37( cognitive impairment,)37( )]TJ T* [(cardiomyopathy)55(,)37( metaphyseal dysplasia,)37( failure to thrive,)37( and hair/skin/teeth )]TJ T* (abnormalities.)Tj ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.8821 311.1881 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.623 -49.844 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.623 -49.844 Td [(SAMD9/SAMD9L )-240(syndromes)]TJ /T1_7 1 Tf 0 Tw 14.496 0 Td (SAMD9/SAMD9L)Tj /T1_6 1 Tf 12.36 0 Td [(AD)-4794(Adrenal insufficiency)55(,)37( congenital malformations,)37( cerebellar ataxia,)37( severe invasive )]TJ 5.831 -1.25 Td [(infections,)37( and MDS predisposition)]TJ ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.8741 291.1801 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.624 -52.345 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.624 -52.345 Td [(SRP54 )-240(mutation)]TJ /T1_7 1 Tf 0 Tw 16.321 0 Td (SRP54)Tj /T1_6 1 Tf 10.535 0 Td [(AD)-4794(Maturation arrest,)37( severe neurodevelopmental delay)55(,)37( and exocrine pancreatic )]TJ 5.831 -1.25 Td (dysfunction)Tj ET BT /Span <>BDC /T1_6 1 Tf -0.24 Tw 8 0 0 8 50.8661 271.1721 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.662 -54.846 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -25.662 -54.846 Td [(T)74(elomere )-240(diseases)]TJ /T1_7 1 Tf 0 Tw 16.56 0 Td (DKC1)Tj /T1_6 1 Tf 9.41 0 Td [(X-linked)-3870(Mucocutaneous features,)37( liver fibrosis,)37( idiopathic pulmonar)-18(y fibrosis,)37( and cancer )]TJ 6.754 -1.25 Td (predisposition)Tj /T1_7 1 Tf -0.037 Tw -19.484 -0.001 Td [(hTR,)37( TER)18(T)92(,)37( TINF2,)37( )-37(DKC1,)37( )]TJ 0 Tw 3.549 -1.25 Td (ACD)Tj /T1_6 1 Tf 10.103 1.25 Td (AD)Tj /T1_7 1 Tf -13.005 -2.501 Td [(TER)18(T)92(,)37( NHP2,)37( NOP10,)37( )]TJ -0.565 -1.25 Td [(WRAP53,)37( NOLA3,TCB1,)37( )]TJ 0.693 -1.25 Td [(R)18(TEL1,)37( CTC1,)37( P)37(ARN)]TJ /T1_6 1 Tf 12.896 2.5 Td (AR)Tj ET BT /Span <>BDC /T1_6 1 Tf 8 0 0 8 50.8581 211.1481 Tm ( )Tj 8 0 0 8 263.8661 709.9401 Tm -25.626 -62.349 Td ( )Tj EMC ET BT /T1_6 1 Tf 8 0 0 8 58.8581 211.1481 Tm (U6 small nuclear RNA biogenesis)Tj /T1_7 1 Tf 14.618 0 Td (USB1)Tj /T1_6 1 Tf 8 0 0 8 263.8661 709.9401 Tm -9.048 -62.349 Td ( \(Clericuzio )Tj -3.257 -1.25 Td [(syndrome,)37( poikiloderma )]TJ 1.157 -1.25 Td (with neutropenia\))Tj 12.397 2.5 Td [(AR)-4812(Retinopathy)55(,)37( developmental delay)55(,)37( facial dysmorphisms,)37( and poikiloderma)]TJ 7 0 0 7 51 176.0804 Tm [(This is based on the following references:)37( )]TJ 4.081 0 0 4.081 155.2486 178.4114 Tm (3,4,13,15,31\22634)Tj 7 0 0 7 180.7951 176.0804 Tm (.)Tj -18.542 -1.286 Td [(AD = autosomal dominant; )37(AR = autosomal recessive; )37(ALPS = autoimmune lymphoproliferative syndrome; MDS = myelodysplastic sy\ ndrome; )37(AML = acute myeloid leukemia; FHLH = familial hemophago-)]TJ 0 -1.286 TD [(cytic lymphohistiocytosis; HPV = human papilloma virus; IBD = chronic in\ flammator)-17(y bowel disease; HSM = hepatosplenomegaly; BMF = bone marrow failure.)]TJ 0 0 0 0 k /GS0 gs /T1_3 1 Tf -0.037 Tc 0.037 Tw 9 0 0 9 21.1715 178.2044 Tm [(AQ)-37(7)]TJ 0 -1.667 TD [(AQ)-37(8)]TJ ET q 1 0 0 1 51 726.852005 cm 0.24 0.08 0.08 0.4 K 12 w 0 0 m 89.119 0 l S Q q 1 0 0 1 51 720.602005 cm 0 0 0 1 K 0.5 w /GS1 gs 0 0 m 507.119 0 l S Q BT /T1_8 1 Tf 0 Tc 0 Tw 8 0 0 8 54 723.852 Tm [(T)111(able 2)]TJ ET BT /Span <>BDC /T1_8 1 Tf 8 0 0 8 82.896 723.852 Tm ( )Tj EMC ET BT /T1_8 1 Tf 8 0 0 8 90.896 723.852 Tm (\(Continued\))Tj ET q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 2 J /GS3 gs 27.5 425.5 849 23 re S Q Q endstream endobj 806 0 obj <> endobj 807 0 obj <> endobj 808 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 287.276 24.0881 Tm (4)Tj ET q 0 g /GS0 gs /Fm1 Do Q q 1 0 0 1 36 726.852005 cm 0.24 0.08 0.08 0.4 K 12 w /GS0 gs 0 0 m 34.896 0 l S Q q 1 0 0 1 36 708.102005 cm 0 0 0 1 K 0.5 w 0 0 m 507 0 l S Q BT 0 0 0 0 k /GS0 gs /T1_1 1 Tf 8 0 0 8 39 723.852 Tm [(T)111(able 2)]TJ 0 0 0 1 k /GS1 gs /T1_2 1 Tf -0.375 -1.5 Td [(Classification of Congenital Neutr)18(openias )]TJ ET q 1 0 0 1 36 676.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 109 0 l S Q q 1 0 0 1 145 676.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 78.5 0 l S Q q 1 0 0 1 223.5 676.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 79 0 l S Q q 1 0 0 1 302.5 676.6282043 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 240.239 0 l S Q q 1 0 0 1 36 690.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 109 0 l S Q q 1 0 0 1 145 690.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 78.5 0 l S Q q 1 0 0 1 223.5 690.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 79 0 l S Q q 1 0 0 1 302.5 690.740097 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 240.239 0 l S Q BT /T1_3 1 Tf 8 0 0 8 248.8661 694.94 Tm (Congenital Neutropenias)Tj -26.608 -1.764 Td ( )Tj 15.534 0 Td [(Genes Involved )-2814(T)55(ype of Inheritance )]TJ 28.875 0 Td [(Main F)20(eatures/Notes )]TJ /T1_4 1 Tf -44.409 -1.77 Td (Isolated)Tj 18.291 0 Td ( )Tj 9.844 0 Td ( )Tj 5.552 0 Td ( )Tj ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9941 656.66 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.609 -4.785 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.609 -4.785 Td [(Severe )-240(congenital )]TJ 0 Tw 6.512 0 Td ( )Tj -6.512 -1.25 Td (neutropenia)Tj /T1_5 1 Tf 16.356 1.25 Td (ELANE)Tj /T1_4 1 Tf 10.501 0 Td [(AD)-4794(Arrest of neutrophil maturation in bone marrow)]TJ /T1_5 1 Tf -10.528 -1.252 Td (CSF3R)Tj /T1_4 1 Tf 10.528 0 Td [(AD)-4794(Arrest of neutrophil maturation in bone marrow)37(,)37( unresponsive to G-CSF)]TJ /T1_5 1 Tf -10.565 -1.251 Td (CXCR2)Tj /T1_4 1 Tf 10.584 0 Td [(AR)-4812(No arrest of maturation and myelokathexis)]TJ /T1_5 1 Tf -0.018 Tc 0.018 Tw -10.186 -1.251 Td [(WA)-18(S)]TJ /T1_4 1 Tf 0 Tc 0 Tw 9.244 0 Td [(X-linked)-3870(Maturation arrest,)37( monocytopenia,)37( and lymphopenia)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9941 616.62 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.609 -9.79 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.609 -9.79 Td [(Cyclic )-240(neutropenia)]TJ /T1_5 1 Tf 0 Tw 16.356 0 Td (ELANE)Tj /T1_4 1 Tf 10.501 0 Td [(AD)-4794(Intermittent/cyclic impaired differentiation)]TJ -27.857 -1.251 Td (Associated with various )Tj 0 -1.25 TD (extrahematological manifestations )Tj 18.291 1.25 Td ( )Tj 9.844 0 Td ( )Tj 5.552 0 Td ( )Tj -33.688 -2.501 Td ( )Tj 18.291 0 Td ( )Tj 9.844 0 Td ( )Tj 5.552 0 Td ( )Tj ET BT /Span <>BDC /T1_4 1 Tf 8 0 0 8 35.9781 576.596 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.611 -14.793 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 43.9781 576.596 Tm (Barth Syndrome \(3-methylglu)Tj 8 0 0 8 248.8661 694.94 Tm -15.23 -14.793 Td (-)Tj -10.381 -1.25 Td (taconic aciduria type II\))Tj /T1_5 1 Tf -0.055 Tc 0.055 Tw 16.856 1.25 Td [(TA)-55(Z)]TJ /T1_4 1 Tf 0 Tc 0 Tw 9.077 0 Td [(X-linked)-3870(No maturation arrest,)37( hypertrophic cardiomyopathy)55(,)37( and myopathic syndrome)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9701 556.588 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.612 -17.294 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.612 -17.294 Td [(Charcot-Marie-T)74(ooth )]TJ 0 Tw 7.554 0 Td ( )Tj -7.554 -1.25 Td (neuropathy type B)Tj /T1_5 1 Tf 16.411 1.25 Td (DNM2)Tj /T1_4 1 Tf 10.445 0 Td [(AD)-4794(Distal limb muscle weakness and atrophy due to peripheral neuropathy)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9621 536.58 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.613 -19.795 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.613 -19.795 Td [(Cohen )-240(syndrome)]TJ /T1_5 1 Tf 0 Tw 16.09 0 Td (VPS13B)Tj /T1_4 1 Tf 10.785 0 Td [(AR)-4812(No maturation arrest,)37( psychomotor retardation,)37( microcephaly)55(,)37( facial features,)37( )]TJ 5.812 -1.25 Td [(hypotonia,)37( joint laxity)55(,)37( progressive,)37( retino-choroidal dystrophy)55(,)37( and myopia)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9541 516.572 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.614 -22.296 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.614 -22.296 Td [(G6PC3 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 16.283 0 Td (G6PC3)Tj /T1_4 1 Tf 10.592 0 Td [(AR)-4812(Skin hyperelasticity and prominent superficial venous network,)38( congenital heart )]TJ 5.812 -1.25 Td [(disease,)37( arrhythmias,)37( uropathy)55(,)37( cr)-18(yptorchidism,)37( and exocrine pancreatic dysfunction)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9461 496.564 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.615 -24.797 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.615 -24.797 Td [(GFI1 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 16.718 0 Td (GFI1)Tj /T1_4 1 Tf 10.139 0 Td [(AD)-4794(Sometimes maturation arrest,)37( lymphopenia,)37( increased numbers of immature )]TJ 5.831 -1.25 Td (myeloid cells in the peripheral blood and inner ear defect)Tj ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9461 476.556 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.615 -27.298 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.615 -27.298 Td [(HYOU1 )-240(deficiency)]TJ /T1_5 1 Tf 0 Tw 16.282 0 Td (HYOU1)Tj /T1_4 1 Tf 10.593 0 Td [(AR)-4812(Hypoglycemia and inflammator)-18(y complications)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9381 466.548 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.616 -28.549 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.616 -28.549 Td [(JAGN1 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 16.301 0 Td (JAGN1)Tj /T1_4 1 Tf 10.574 0 Td [(AR)-4812(Sometimes maturation arrest,)37( bone and teeth abnormalities,)37( and exocrine )]TJ 5.812 -1.25 Td (pancreatic dysfunction)Tj ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9301 446.54 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.617 -31.05 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.617 -31.05 Td [(Kostmann )-240(disease)]TJ /T1_5 1 Tf 0 Tw 16.551 0 Td (HAX1)Tj /T1_4 1 Tf 10.324 0 Td [(AR)-4812(Maturation arrest,)37( mental retardation,)37( seizures,)37( and susceptibility to MDS/AML)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9221 436.524 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.618 -32.302 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.618 -32.302 Td [(P14/LAMTOR2 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 15.735 0 Td (LAMTOR2)Tj /T1_4 1 Tf 11.14 0 Td [(AR)-4812(Chronic neutropenia,)37( hypogammaglobulinemia,)37( no maturation arrest,)37( )]TJ 5.812 -1.25 Td [(oculocutaneous albinism,)37( and failure to thrive)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9141 416.516 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.619 -34.803 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.619 -34.803 Td [(Pearson )-240(syndrome)]TJ 0 Tw 15.144 0 Td (Mitochondrial )Tj -0.102 -1.25 Td (DNA deletions)Tj 9.946 1.25 Td [(Mitochondrial)-2925(Refractor)-18(y sideroblastic anemia,)37( vacuolization of bone marrow precursors,)37( and )]TJ 7.699 -1.25 Td (exocrine pancreatic dysfunction)Tj ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.9061 396.5 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.62 -37.305 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.62 -37.305 Td [(Schimke )-240(immuno-osseus )]TJ 0 Tw 0 -1.25 Td (dysplasia)Tj /T1_5 1 Tf 15.486 1.25 Td (SMARCAL1)Tj /T1_4 1 Tf 11.389 0 Td [(AR)-4812(Spondylo-epiphyseal dysplasia,)37( slowly progressive immune defect,)37( and )]TJ 5.812 -1.25 Td (immune-complex nephritis)Tj ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8981 376.492 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.621 -39.806 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.621 -39.806 Td [(SEC61A1 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 15.84 0 Td (SEC61A1)Tj /T1_4 1 Tf 11.017 0 Td [(AD)-4794(Maturation arrest and tubulointerstitial kidney disease)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8981 366.484 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.621 -41.057 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.621 -41.057 Td [(SMARCD2 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 15.68 0 Td (SMARCD2)Tj /T1_4 1 Tf 11.195 0 Td [(AR)-4812(Dysplastic syndrome,)37( no granules in neutrophils,)37( chronic diarrhea,)37( bone )]TJ 5.812 -1.25 Td [(abnormalities,)37( and low set ears)]TJ ET BT /Span <>BDC /T1_4 1 Tf 8 0 0 8 35.8901 346.476 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.622 -43.558 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 43.8901 346.476 Tm (Specific granule deficiency)Tj 16.338 0 Td (CEBPE)Tj 10.537 0 Td [(AR)-4812(Neutrophils with bilobed nuclei)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8821 336.468 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.66 -44.809 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.66 -44.809 Td [(TCIRG1 )-240(neutropenia)]TJ /T1_5 1 Tf 0 Tw 16.236 0 Td (TCIRG1)Tj /T1_4 1 Tf 10.657 0 Td [(AD)-4794(V)18(ariable/no maturation arrest and skin angiomatosis)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8741 326.46 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.661 -46.06 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.661 -46.06 Td [(VPS45 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 16.377 0 Td (VPS45)Tj /T1_4 1 Tf 10.535 0 Td [(AR)-4812(Myeloid hyperplasia,)37( myelofibrosis,)37( nephromegaly)55(,)37( HSM,)37( mental retardation,)37( )]TJ 5.812 -1.25 Td [(epilepsy)55(,)37( and osteosclerosis)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8661 306.452 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.662 -48.561 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.662 -48.561 Td [(W)18(olcott-Rallison )-240(syndrome)]TJ /T1_5 1 Tf 0 Tw 16.311 0 Td (EIF2AK)Tj /T1_4 1 Tf 10.601 0 Td [(AR)-4812(Maturation arrest,)37( insulin-dependent neonatal diabetes,)37( epiphyseal dysplasia,)37( )]TJ 5.812 -1.25 Td [(growth retardation,)37( hepatic and renal dysfunction,)37( developmental delay)55(,)37( and )]TJ T* (exocrine pancreatic deficiency)Tj -33.688 -1.251 Td (Associated with immunodeficiency/)Tj T* (immune dysregulation)Tj 18.291 1.25 Td ( )Tj 9.844 0 Td ( )Tj 5.552 0 Td ( )Tj ET BT /Span <>BDC /T1_4 1 Tf 8 0 0 8 35.8501 256.436 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.664 -54.813 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 43.5541 256.436 Tm (Adenosine deaminase 2 deficiency)Tj /T1_5 1 Tf 16.56 0 Td (ADA2)Tj /T1_4 1 Tf 10.352 0 Td [(AR)-4812(Severe combined immunodeficiency)]TJ 8 0 0 8 248.8661 694.94 Tm 19.755 -54.813 Td [(,)37( vasculitis,)37( cerebrovascular disease,)37( pure red )]TJ -12.695 -1.25 Td [(cell aplasia,)37( and BMF)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8421 236.428 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.665 -57.314 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.665 -57.314 Td (ALPS)Tj /T1_5 1 Tf 0 Tw 13.805 0 Td [(F)37(AS,)37( F)37(ASLG,)37( CASP10)]TJ /T1_4 1 Tf 13.088 0 Td [(AD)-4794(L)37(ymphoproliferation and autoimmune cytopenias)]TJ ET BT /Span <>BDC /T1_4 1 Tf 8 0 0 8 35.8341 226.42 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.629 -58.565 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 43.8341 226.42 Tm (CD40L/hyper IgM syndrome,)Tj 8 0 0 8 248.8661 694.94 Tm -15.487 -58.565 Td ( )Tj -10.142 -1.25 Td (type I)Tj /T1_5 1 Tf 16.31 1.25 Td (CD40L)Tj /T1_4 1 Tf 9.623 0 Td [(X-linked)-3870(Severe infections,)37( autoimmune disease,)37( and cancer predisposition)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8261 206.412 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.63 -61.066 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.63 -61.066 Td [(Ch\351diak-Higashi )-240(syndrome)]TJ /T1_5 1 Tf 0 Tw 16.68 0 Td [(L)92(YST)]TJ /T1_4 1 Tf 10.195 0 Td [(AR)-4812(Decreased pigmentation of hair and eyes,)37( peroxidase-positive inclusion bodies )]TJ 5.812 -1.25 Td [(in the myeloblasts and promyelocytes of the bone marrow)37(,)37( peculiar malignant )]TJ T* (lymphoma)Tj ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8181 176.404 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.631 -64.817 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.631 -64.817 Td [(CLPB )-240(syndrome)]TJ /T1_5 1 Tf 0 Tw 16.569 0 Td (CLPB)Tj /T1_4 1 Tf 10.306 0 Td [(AR)-4812(Cataracts and neurologic involvement)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8101 166.396 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.632 -66.068 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.632 -66.068 Td (FHLH)Tj /T1_5 1 Tf 0 Tw 14.988 0 Td (PRF1)Tj /T1_4 1 Tf [(,)37( Perforin )]TJ -0.491 -1.25 Td (deficiency \()Tj /T1_5 1 Tf (FHL2)Tj /T1_4 1 Tf (\))Tj 12.378 1.25 Td [(AR)-4812(Fever)74(,)37( HSM,)37( and cytopenias)]TJ /T1_5 1 Tf -12.619 -2.502 Td [(UNC13D,)37( UNC13D)]TJ /T1_4 1 Tf ( )Tj 0.241 -1.25 Td (deficiency \()Tj /T1_5 1 Tf (FHL3)Tj /T1_4 1 Tf (\))Tj 12.378 1.25 Td [(AR)-4812(Fever)74(,)37( HSM,)37( and cytopenias)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.8021 126.372 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.633 -71.071 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.633 -71.071 Td [(GA)55(T)55(A2 )-240(syndrome)]TJ /T1_5 1 Tf -0.055 Tc 0.055 Tw 16.356 0 Td [(G)-55(ATA)-55(2)]TJ /T1_4 1 Tf 0 Tc 0 Tw 10.501 0 Td [(AD)-4794(Monocytopenia,)37( deafness,)37( and HPV infections)]TJ ET BT /Span <>BDC /T1_4 1 Tf 8 0 0 8 35.8021 116.364 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.633 -72.322 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 43.8021 116.364 Tm (Griscelli syndrome,)Tj 8 0 0 8 248.8661 694.94 Tm -18.954 -72.322 Td ( type II)Tj /T1_5 1 Tf 9.372 0 Td (RAB27A)Tj /T1_4 1 Tf 10.824 0 Td [(AR)-4812(Hypomelanosis and neurologic impairment)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.7941 106.356 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.634 -73.573 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.634 -73.573 Td [(Hermansky-Pudlak )-240(syndrome )]TJ 0 Tw 0 -1.25 Td (type2)Tj /T1_5 1 Tf 16.311 1.25 Td (AP3B1)Tj /T1_4 1 Tf 10.564 0 Td [(AR)-4812(Albinism)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.7861 86.348 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.635 -76.074 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.635 -76.074 Td [(Reticular )-240(dysgenesis)]TJ /T1_5 1 Tf 0 Tw 16.801 0 Td (AK2)Tj /T1_4 1 Tf 10.074 0 Td [(AR)-4812(Severe combined immunodeficiency and sensorineural deafness)]TJ ET BT /Span <>BDC /T1_4 1 Tf -0.24 Tw 8 0 0 8 35.7781 76.34 Tm ( )Tj 8 0 0 8 248.8661 694.94 Tm -25.636 -77.325 Td ( )Tj EMC ET BT /T1_4 1 Tf 8 0 0 8 248.8661 694.94 Tm -25.636 -77.325 Td [(STK4 )-240(mutation)]TJ /T1_5 1 Tf 0 Tw 16.589 0 Td (STK4)Tj /T1_4 1 Tf 10.286 0 Td [(AR)-4812(Intermittent neutropenia,)37( monocytopenia,)37( )37(T)55(- and B-lymphopenia,)37( atrial defect,)37( and )]TJ 5.812 -1.25 Td (HPV infections)Tj ET q 1 0 0 1 36 61.4140015 cm 0 0 0 1 K 0.5 w 0 0 m 507 0 l S Q BT /T1_4 1 Tf 8 0 0 8 510.8729 53.164 Tm (\(Continued\))Tj ET q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 2 J /GS3 gs 27.5 425.5 849 23 re S Q Q endstream endobj 809 0 obj <> endobj 810 0 obj <> endobj 811 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 302.276 24.0881 Tm (3)Tj ET /PlacedGraphic /MC0 BDC EMC q 1 0 0 1 55.0115967 759.9024048 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 0 -2.901 l -2.529 -2.901 l -2.529 0 l -4.011 0 l -4.011 -7.304 l -2.529 -7.304 l -2.529 -4.151 l 0 -4.151 l 0 -7.304 l 1.481 -7.304 l 1.481 0 l h f Q q 51 750.589 56.165 9.41 re W n q 1 0 0 1 58.9167023 755.8701019 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.307 0.974 0.053 0.604 0 0 c 2.942 -2.466 m 2.571 -3.112 1.958 -3.366 1.005 -3.366 c -0.582 -3.366 -1.344 -2.339 -1.344 -0.974 c -1.344 -0.254 l -1.344 1.344 -0.54 2.116 0.835 2.116 c 2.33 2.116 3.016 1.248 3.016 -0.36 c 3.016 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 67.2454071 752.5995941 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -1.344 0 l -1.344 3.101 l -1.344 3.947 -1.672 4.223 -2.148 4.223 c -2.625 4.223 -2.984 3.863 -2.984 3.111 c -2.984 0 l -4.339 0 l -4.339 5.291 l -3.016 5.291 l -3.016 4.848 l -2.815 5.122 -2.435 5.387 -1.842 5.387 c -1.207 5.387 -0.688 5.144 -0.36 4.678 c 0.013 5.135 0.574 5.396 1.164 5.387 c 2.317 5.387 2.995 4.687 2.995 3.312 c 2.995 -0.001 l 1.64 -0.001 l 1.64 3.101 l 1.64 3.895 1.366 4.223 0.825 4.223 c 0.339 4.223 0 3.863 0 3.111 c h f Q q 1 0 0 1 74.0608063 754.7783051 cm 0.992 0.75 0.141 0.02 k /GS0 gs 0 0 m -0.889 0 l -1.439 0 -1.683 -0.18 -1.683 -0.593 c -1.683 -1.005 -1.375 -1.186 -0.91 -1.186 c -0.296 -1.186 0.003 -0.921 0.003 -0.201 c h -1.047 0.996 m 0 0.996 l 0 1.304 l 0 1.896 -0.179 2.086 -0.941 2.086 c -1.46 2.086 -1.714 2.012 -1.937 1.663 c -2.889 2.326 l -2.499 2.972 -1.906 3.205 -0.814 3.205 c 0.55 3.205 1.323 2.802 1.323 1.289 c 1.323 -2.182 l 0 -2.182 l 0 -1.717 l -0.212 -2.076 -0.529 -2.277 -1.143 -2.277 c -2.244 -2.277 -3.005 -1.696 -3.005 -0.617 c -3.005 0.51 -2.159 0.996 -1.047 0.996 c f Q q 1 0 0 1 80.4425964 758.0068054 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.317 0.498 -0.698 0.741 -1.439 0.741 c -2.103 0.741 -2.466 0.435 -2.466 -0.062 c -2.466 -0.635 -2 -0.889 -1.026 -1.132 c 0.497 -1.513 1.186 -2.084 1.186 -3.373 c 1.186 -4.568 0.381 -5.5 -1.333 -5.5 c -2.614 -5.5 -3.502 -5.15 -4.148 -4.304 c -3.016 -3.521 l -2.625 -4.008 -2.18 -4.251 -1.429 -4.251 c -0.582 -4.251 -0.296 -3.881 -0.296 -3.436 c -0.296 -2.928 -0.603 -2.643 -1.791 -2.335 c -3.229 -1.954 -3.948 -1.268 -3.948 -0.061 c -3.948 1.094 -3.187 1.993 -1.451 1.993 c -0.289 1.993 0.592 1.602 1.11 0.797 c h f Q q 1 0 0 1 85.7776031 754.9795074 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 0 0.55 l 0 1.396 -0.265 1.862 -0.931 1.862 c -1.577 1.862 -1.873 1.439 -1.873 0.666 c -1.873 0.002 l -1.873 -0.76 -1.693 -1.331 -0.931 -1.331 c -0.202 -1.337 -0.001 -0.761 -0.001 0.002 c h 1.354 -0.083 m 1.354 -1.459 0.656 -2.476 -0.709 -2.476 c -1.26 -2.476 -1.63 -2.369 -1.871 -2.168 c -1.871 -4.39 l -3.228 -4.39 l -3.228 2.914 l -1.874 2.914 l -1.874 2.564 l -1.62 2.85 -1.239 3.009 -0.699 3.009 c 0.524 3.007 1.354 2.149 1.354 0.637 c h f Q q 1 0 0 1 88.0207977 759.902298 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.352 0 l 1.352 -2.424 l 1.554 -2.159 1.925 -1.916 2.538 -1.916 c 3.606 -1.916 4.475 -2.424 4.475 -3.991 c 4.475 -7.304 l 3.132 -7.304 l 3.132 -4.202 l 3.132 -3.377 2.836 -3.08 2.285 -3.08 c 1.661 -3.08 1.355 -3.495 1.355 -4.191 c 1.355 -7.303 l 0 -7.303 l h f Q q 1 0 0 1 94.7415009 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.659 0 l 1.628 0.687 1.354 0.974 0.846 0.974 c 0.306 0.974 0.052 0.604 0 0 c 2.941 -2.466 m 2.571 -3.112 1.957 -3.366 1.005 -3.366 c -0.583 -3.366 -1.345 -2.339 -1.345 -0.974 c -1.345 -0.254 l -1.345 1.344 -0.541 2.116 0.835 2.116 c 2.329 2.116 3.015 1.248 3.015 -0.36 c 3.015 -0.963 l 0 -0.963 l 0.01 -1.693 0.243 -2.223 0.995 -2.223 c 1.557 -2.223 1.736 -2.057 1.937 -1.768 c h f Q q 1 0 0 1 101.5989075 756.4199066 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m -0.139 0.201 -0.328 0.402 -0.664 0.402 c -1.173 0.402 -1.511 0.032 -1.511 -0.709 c -1.511 -3.82 l -2.868 -3.82 l -2.868 1.471 l -1.545 1.471 l -1.545 1.027 l -1.366 1.292 -1.017 1.566 -0.393 1.566 c 0.232 1.566 0.723 1.29 1.037 0.74 c h f Q q 1 0 0 1 104.1477051 755.8701019 cm 0.113 0.98 0.902 0.023 k /GS0 gs 0 0 m 1.66 0 l 1.628 0.687 1.353 0.974 0.845 0.974 c 0.309 0.974 0.055 0.604 0 0 c 2.943 -2.466 m 2.572 -3.112 1.959 -3.366 1.007 -3.366 c -0.58 -3.366 -1.343 -2.339 -1.343 -0.974 c -1.343 -0.254 l -1.343 1.344 -0.538 2.116 0.837 2.116 c 2.331 2.116 3.018 1.248 3.018 -0.36 c 3.018 -0.963 l 0 -0.963 l 0.011 -1.693 0.243 -2.223 0.996 -2.223 c 1.556 -2.223 1.736 -2.057 1.936 -1.768 c h f Q Q BT /T1_1 1 Tf 8 0 0 8 107.1653 750.5894 Tm ( )Tj /T1_2 1 Tf 0.278 0.25 Td ( \(2023\) 7:4)Tj ET BT /Span <>BDC /T1_2 1 Tf 38.328 Tw 8 0 0 8 107.1653 750.5894 Tm 4.93 0.25 Td ( )Tj EMC ET BT /T1_2 1 Tf 8 0 0 8 455.4453 752.5894 Tm (www)Tj 8 0 0 8 107.1653 750.5894 Tm 45.703 0.25 Td [(.hemaspher)18(ejour)-18(nal.com)]TJ /T1_3 1 Tf 0.022 Tw 9 0 0 9 51 725.9761 Tm [(counts are not clinically available; thus,)37( we still extrapolate the )]TJ 0.238 Tw 0 -1.111 TD [(quantitative )1(correlation between )1(circulating )37(ANC )1(and infec)]TJ 0 Tw (-)Tj 0.126 Tw T* (tions in patients undergoing chemotherapy to classify neutro)Tj 0 Tw (-)Tj 0.109 Tw T* [(penias as mild when )37(ANC is between 1.0 and 1.5 \(or 1.8 for )]TJ 0.054 Tw T* (adults\) \327 10)Tj 0 Tw 5.247 0 0 5.247 98.4913 688.9731 Tm (9)Tj 0.054 Tw 9 0 0 9 101.4086 685.9761 Tm [(/L,)37( moderate when )37(ANC is 0.5 to 1.0)]TJ ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 249.1608 685.9761 Tm ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 250.2776 685.9761 Tm (\327)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 101.4086 685.9761 Tm 17.097 0 Td ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 256.4066 685.9761 Tm (10)Tj 0 Tw 5.247 0 0 5.247 266.4174 688.9731 Tm (9)Tj 0.054 Tw 9 0 0 9 269.3347 685.9761 Tm [(/L,)37( and )]TJ 0.157 Tw -24.259 -1.111 Td [(severe )1(when )38(ANC )1(is )1(<0.5)]TJ ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 269.3347 685.9761 Tm -12.725 -1.111 Td ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 155.9347 675.9771 Tm (\327)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 269.3347 685.9761 Tm -12.044 -1.111 Td ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 162.0637 675.9771 Tm (10)Tj 0 Tw 5.247 0 0 5.247 172.0683 678.9731 Tm (9)Tj 9 0 0 9 174.9856 675.9761 Tm (/L.)Tj 5.247 0 0 5.247 185.4886 678.9731 Tm (19,30)Tj 0.157 Tw 9 0 0 9 198.6165 675.9761 Tm [( )37(The )1(term )1(agranulocyto)]TJ 0 Tw (-)Tj 0.094 Tw -16.402 -1.111 Td [(sis is used for severe neutropenias with )37(ANC <0.2)]TJ ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 198.6165 675.9761 Tm 5.817 -1.111 Td ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 252.0855 665.9771 Tm (\327)Tj ET BT /Span <>BDC /T1_3 1 Tf 9 0 0 9 198.6165 675.9761 Tm 6.497 -1.111 Td ( )Tj EMC ET BT /T1_3 1 Tf 9 0 0 9 258.2145 665.9771 Tm (10)Tj 0 Tw 5.247 0 0 5.247 268.2264 668.9731 Tm (9)Tj 0.094 Tw 9 0 0 9 271.1437 665.9761 Tm (/L and )Tj 0.164 Tw -24.46 -1.111 Td [(is usually associated with a high risk of severe,)37( life-threaten)]TJ 0 Tw (-)Tj 0.127 Tw T* (ing infections.)Tj 0 Tw 5.247 0 0 5.247 106.6547 648.9731 Tm (19)Tj 0.127 Tw 9 0 0 9 112.4894 645.9761 Tm ( Neutropenia is also characterized as acute or )Tj -0.008 Tw -6.832 -1.111 Td [(chronic depending on whether the duration is <3 or >3 months,)37( )]TJ 0 Tw T* [(respectively)92(.)]TJ 5.247 0 0 5.247 97.6643 628.9731 Tm (19)Tj 0.108 Tw 9 0 0 9 61 615.9761 Tm [(Further to the above traditional classi\037cations,)37( the GL-WG )]TJ 0.172 Tw -1.111 -1.111 Td [(agreed on an extended,)37( pathogenesis-based classi\037cation that )]TJ -0.022 Tw T* [(categorizes )1(neutropenias )1(as )1(congenital )1(\()37(T)86(able\035)23(2\) )1(versus )1(acquired )]TJ 0.284 Tw T* [(and likely acquired \()36(T)86(able\035)-284(3\) with respective subcategories.)37( )]TJ 0.027 Tw T* (Congenital neutropenia \(CN\) comprises a group of genetic dis)Tj 0 Tw (-)Tj 0.015 Tw T* [(eases characterized by impaired production,)37( differentiation and )]TJ 0.011 Tw T* [(survival of neutrophils in the bone marrow \(BM\),)37( susceptibility )]TJ 0.06 Tw T* [(to infections,)37( and increased propensity to MDS/AML transfor)]TJ 0 Tw 27 0 Td (-)Tj -27 -1.111 Td (mation.)Tj 5.247 0 0 5.247 80.9968 538.9731 Tm (3\2265,15,31\22633)Tj 0.071 Tw 9 0 0 9 112.4996 535.9761 Tm ( CN can be further subclassi\037ed into disorders )Tj 0.208 Tw -6.833 -1.111 Td (where neutropenia is the only abnormality and those where )Tj 0.2 Tw T* (neutropenia is associated with extrahematological manifesta)Tj 0 Tw (-)Tj 0.102 Tw T* [(tions,)37( immunode\037ciency/immune dysregulation,)37( metabolic dis)]TJ 0 Tw (-)Tj 0.047 Tw T* [(orders and nutritional de\037ciencies,)37( or as part of more complex )]TJ 0.148 Tw T* [(BM failure syndromes.)37( )37(The classi\037cation also takes into con)]TJ 0 Tw (-)Tj 0.018 Tw T* (sideration the genes that have been identi\037ed as responsible for )Tj 0 Tw T* (each CN subtype.)Tj 0.134 Tw 1.111 -1.111 Td (Consensus was reached to classify acquired neutropenia as )Tj 0.046 Tw -1.111 -1.111 Td [(primary or idiopathic,)37( associated with the presence of antineu)]TJ 0 Tw (-)Tj 0.039 Tw T* (trophil antibodies or other unknown mechanisms; and second)Tj 0 Tw (-)Tj 0.048 Tw T* [(ary due to infections,)37( autoimmune diseases,)37( exposure to drugs,)37( )]TJ 0.414 Tw T* [(nutritional de\037ciencies,)37( hypersplenism,)37( or hematologic dis)]TJ 0 Tw (-)Tj T* (eases.)Tj 5.247 0 0 5.247 72.9956 408.9731 Tm (9\22612,35\22639)Tj 0.043 Tw 9 0 0 9 100.1224 405.9761 Tm ( Likely acquired neutropenia includes mostly idio)Tj 0 Tw (-)Tj 0.076 Tw -5.458 -1.111 Td [(pathic or autoimmune neutropenia \(AIN\) of childhood,)37( which )]TJ 0.092 Tw T* (usually seems to have a benign and uncomplicated course but )Tj -0.001 Tw T* (does not resolve after 24\22636 months \(long lasting\) or neutrope)Tj 0 Tw (-)Tj 0.068 Tw T* [(nia,)37( with and without antibodies,)37( which arises after the age of )]TJ -0.003 Tw T* [(3 )1(years )1(\(late )1(onset\).)]TJ 0 Tw 5.247 0 0 5.247 126.4044 358.9731 Tm (18,40\22642)Tj -0.003 Tw 9 0 0 9 147.9904 355.9761 Tm [( )38(A )1(proportion )1(of )1(these )1(patients )1(display )]TJ 0.154 Tw -10.777 -1.111 Td (lymphopenia due to low B cells and natural killer \(NK\)-cells )Tj 0.109 Tw T* [(subsets,)37( )1(and mutation analysis )1(of genes )1(related to )1(immunode)]TJ 0 Tw (-)Tj 0.305 Tw T* (\037ciency/immune-dysregulated disorders has identi\037ed patho)Tj 0 Tw (-)Tj -0.037 Tw T* [(genic )1(variants )1(in )1(individual )1(cases.)]TJ 0 Tw 5.247 0 0 5.247 179.1851 318.9731 Tm (42)Tj -0.037 Tw 9 0 0 9 185.0197 315.9761 Tm [( )38(The )1(GL-WG )1(agreed )1(that )1(this )]TJ -0.051 Tw -14.891 -1.111 Td [(group of pediatric or adolescent patients,)37( provisionally classi\037ed )]TJ 0.022 Tw T* [(as acquired idiopathic,)37( need )1(a thorough work-up )1(to exclude an )]TJ 0 Tw T* (underlying genetic cause.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 8 0 0 8 51 258.9224 Tm (DIAGNOSIS)Tj /T1_4 1 Tf 0 -1.906 TD [(What is important to know fr)18(om patient/family history?)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.037 Tw 9 0 0 9 61 233.6704 Tm [(The initial step )1(for the investigation of patients )1(with neutro)]TJ 0 Tw (-)Tj 0.039 Tw -1.111 -1.111 Td [(penia is a detailed past medical and family history)92(.)37( )37(A summary )]TJ 0.042 Tw 0 -1.111 TD [(of recommendations )1(on the )1(content of )1(patient/family )1(history is )]TJ 0 Tw T* (presented in Box 1.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_5 1 Tf 8 0 0 8 51 183.6168 Tm [(General inquir)-6(es)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf -0.05 Tw 9 0 0 9 61 173.6168 Tm (The age of first detection of neutropenia is an important piece )Tj -0.002 Tw -1.111 -1.111 Td [(of )1(information; )1(in fact,)37( )1(although CN )1(can )1(rarely be )1(diagnosed )1(in )]TJ 0 Tw T* (adulthood,)Tj 5.247 0 0 5.247 93.5249 156.6138 Tm (43\22647)Tj -0.063 Tw 9 0 0 9 107.8177 153.6168 Tm [( it is usually diagnosed in early childhood.)37( Results )]TJ 0.067 Tw -6.313 -1.111 Td (of previous cell blood counts \(CBC\) could clarify the duration )Tj 0.262 Tw T* [(of )1(neutropenia )1(and )1(differentiate )1(between )1(acute )1(and )1(chronic )]TJ 0 Tw T* (neutropenia.)Tj 5.247 0 0 5.247 100.0136 126.6138 Tm (1,10,11,19)Tj 0.169 Tw 9 0 0 9 124.8107 123.6168 Tm ( It is also important to know whether the )Tj 0.133 Tw -8.201 -1.111 Td [(neutropenia )1(was an )1(incidental )1(\037nding or )1(part of )1(an acute )1(ill)]TJ 0 Tw (-)Tj 0.023 Tw T* [(ness.)37( )37(The )1(clinical history )1(should investigate )1(the frequency)92(,)37( type,)37( )]TJ 0.216 Tw T* [(severity of infections,)37( and need for hospitalization.)37( Inquiries )]TJ 0.138 Tw T* [(about )1(clinical )1(events )1(such )1(as )1(fever)111(,)37( )1(mouth )1(ulcers,)37( )1(sore )1(throat/)]TJ -0.054 Tw T* [(odynophagia,)37( )1(gingivitis,)37( )1(sinusitis,)37( )1(otitis,)37( )1(skin )1(ulcers )1(and )1(cellulitis,)37( )]TJ 0.113 Tw T* [(deep tissue infections,)37( episodes of pneumonia,)37( gastrointestinal )]TJ 0.142 Tw T* [(symptoms,)37( and )1(perianal infections )1(are particularly important.)37( )]TJ 0.174 Tw T* (Periodic patterns of recurrent infections could indicate cyclic )Tj -0.004 Tw 29 75.818 Td [(neutropenia )1(\(CyN\).)]TJ 0 Tw 5.247 0 0 5.247 387.9641 728.9731 Tm (1,10,11,19)Tj -0.004 Tw 9 0 0 9 412.7612 725.9761 Tm [( )1(It is )1(also )1(important )1(to )1(know whether )]TJ 0.031 Tw -11.196 -1.111 Td (previous febrile or in\036ammatory episodes were associated with )Tj 0 Tw T* [(a spontaneous increase in )37(ANC and how they were treated.)]TJ 5.247 0 0 5.247 542.1909 708.9731 Tm (1)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_5 1 Tf 8 0 0 8 312 684.984 Tm [(Additional medical histor)-18(y)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.171 Tw 9 0 0 9 322 674.984 Tm [(For )1(suspected )1(CN,)37( )1(the medical )1(history )1(should include )1(any )]TJ 0.034 Tw -1.111 -1.111 Td (involvement of extrahematological sites \(typical manifestations )Tj 0.153 Tw T* [(are )1(described )1(in )37(T)86(able\035)-152(2\).)37( )37(A )1(detailed )1(history should )1(be taken )]TJ 0.214 Tw T* (of any symptoms denoting underlying autoimmune or other )Tj 0.203 Tw T* [(diseases )1(that may )1(result in )1(secondary )1(neutropenia \(T)86(able\035)-203(3\).)37( )]TJ 0.049 Tw T* [(Notably)92(,)37( many adult patients with )37(AIN may present with vari)]TJ 0 Tw (-)Tj 0.068 Tw T* [(ous autoimmune manifestations \(e.g.,)37( sicca symptoms,)37( arthral)]TJ 0 Tw (-)Tj 0.084 Tw T* [(gias,)37( and Raynaud\) without ful\037lling the criteria for a de\037nite )]TJ 0.228 Tw T* [(diagnosis )1(of an )1(autoimmune )1(disease.)]TJ 0 Tw 5.247 0 0 5.247 462.2107 597.981 Tm (10,11)Tj 0.228 Tw 9 0 0 9 475.3386 594.984 Tm [( Many )1(patients )1(also )]TJ 0.185 Tw -18.149 -1.111 Td (report chronic fatigue and malaise.)Tj 0 Tw 5.247 0 0 5.247 454.1784 587.981 Tm (1,10,11,19)Tj 0.185 Tw 9 0 0 9 478.9756 584.984 Tm ( History of chronic )Tj 0.155 Tw -18.553 -1.111 Td (viral infections such as viral hepatitis or HIV should also be )Tj 0.298 Tw T* [(obtained.)37( Careful inquiry should be made concerning drug )]TJ 0.234 Tw T* [(administration,)37( including )1(over the counter )1(drugs,)37( substances )]TJ 0.256 Tw T* [(often denominated as natural supplements,)37( and recreational )]TJ 0.188 Tw T* (drugs; neutropenia can be linked not only to drugs that the )Tj 0.022 Tw T* (patient has recently started but also to drugs that have recently )Tj 0 Tw T* (been discontinued.)Tj 5.247 0 0 5.247 384.5213 517.981 Tm (1,10,11,19,36\22639)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_5 1 Tf 8 0 0 8 312 493.9919 Tm [(Family histor)-18(y)]TJ 0 0 0 1 k /GS1 gs /T1_3 1 Tf 0.298 Tw 9 0 0 9 322 483.9919 Tm [(Detailed family history)92(,)37( including consanguinity and eth)]TJ 0 Tw (-)Tj 0.068 Tw -1.111 -1.111 Td [(nic origin,)37( is important and should be extended as far back as )]TJ 0.041 Tw T* [(possible,)37( especially if other members of the family have similar )]TJ 0.024 Tw T* [(symptoms or laboratory \037ndings.)37( )37(Also,)37( it is important to know )]TJ 0.174 Tw T* (whether family members have died from infections or MDS/)Tj 0.157 Tw T* [(AML.)37( Unexplained infant deaths or miscarriages can be also )]TJ -0.03 Tw T* (linked to CN.)Tj 0 Tw 5.247 0 0 5.247 364.9697 426.989 Tm (1,19,48,49)Tj -0.03 Tw 9 0 0 9 389.7668 423.9919 Tm [( Notably)92(,)37( the family history for neutropenia )]TJ 0.072 Tw -8.641 -1.111 Td [(might be negative,)37( because a mild or even moderate neutrope)]TJ 0 Tw (-)Tj 0.114 Tw T* [(nia might have been overlooked in previous blood tests; also,)37( )]TJ 0.058 Tw T* [(neutropenia may have varying severity within the same family)92(.)37( )]TJ 0.151 Tw T* [(Therefore,)37( CBCs from family members will de\037nitely help to )]TJ 0 Tw T* (establish a diagnosis of familial neutropenia.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_4 1 Tf 8 0 0 8 312 351.9999 Tm (What should a detailed clinical examination comprise?)Tj 0 0 0 1 k /GS1 gs /T1_3 1 Tf -0.01 Tc 0.095 Tw 9 0 0 9 322 341.9999 Tm [(A summary of recommendations on the clinical examination)-10( )]TJ 0.096 Tw -1.111 -1.111 Td [(of patients with neutropenias is presented in Box 2.)37( Depending)-10( )]TJ 0.11 Tw T* [(on the severity of neutropenia and the underlying pathogenetic)-10( )]TJ 0.192 Tw T* [(mechanism,)37( physical examination may reveal aphthous ulcers,)27( )]TJ 0.129 Tw T* [(tooth and gum abnormalities due to chronic periodontitis,)37( evi)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.08 Tw T* [(dence of acute or chronic sinusitis,)37( pharyngitis or otitis; or skin)-10( )]TJ -0.078 Tw T* [(abnormalities such as hyperpigmentation,)37( partial albinism,)37( rashes,)27( )]TJ 0.068 Tw T* [(ulcers or abscesses,)37( and nail dystrophy)92(.)37( )37(Abdominal examination)-10( )]TJ 0.067 Tw T* (in the setting of pain and fever may raise concerns of neutrope)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.012 Tw T* [(nic colitis and abdominal sepsis.)37( )37(The perianal and perirectal area)-10( )]TJ 0.052 Tw T* (should also be carefully examined to exclude necrotizing celluli)Tj 0 Tc 0 Tw (-)Tj -0.01 Tc 0.013 Tw T* (tis due to )Tj /T1_6 1 Tf 0.01 Tw (Clostridium)Tj /T1_3 1 Tf 0.013 Tw [( species or other anaerobes,)37( as neutropenic)-10( )]TJ -0.015 Tw T* [(patients may have only subtle signs or symptoms of infection due)-10( )]TJ 0.067 Tw T* (to reduced in\036ammatory response.)Tj 0.01 Tw 5.247 0 0 5.247 445.4403 214.9969 Tm (19)Tj 0.067 Tw 9 0 0 9 451.17 211.9999 Tm [( )37(The presence of lymphade)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc -0.004 Tw -15.463 -1.111 Td [(nopathy)92(,)37( splenomegaly)92(,)37( and hepatomegaly may indicate infection)-10( )]TJ 0.187 Tw T* [(or an associated underlying disease such as myeloid/lymphoid)-10( )]TJ 0 Tw T* [(malignancy and metabolic disorders,)37( among others.)]TJ 0 Tc 0.115 Tw 1.111 -1.111 Td [(In children,)37( growth and development should be assessed in )]TJ 0.175 Tw -1.111 -1.111 Td [(addition to examination of mucous membranes,)37( gums,)37( teeth,)37( )]TJ -0.021 Tw T* [(skin,)37( nails,)37( and tympanic membranes.)37( Mutations in )]TJ /T1_6 1 Tf 0 Tw (ELANE)Tj /T1_3 1 Tf -0.021 Tw ( are )Tj 0.016 Tw T* (very commonly associated with the development of periodonti)Tj 0 Tw (-)Tj 0.088 Tw T* [(tis in patients )1(with severe )1(CN,)37( )1(whereas neurological )1(problems )]TJ 0.156 Tw T* (may be present in up to 30% of patients with )Tj /T1_6 1 Tf 0 Tw (HAX1)Tj /T1_3 1 Tf 0.156 Tw ( muta)Tj 0 Tw (-)Tj T* (tions.)Tj 5.247 0 0 5.247 333.5098 114.9969 Tm (50,51)Tj 0.123 Tw 9 0 0 9 346.6377 111.9999 Tm [( Short stature,)37( chondrodysplasia,)37( skeletal,)37( heart,)37( uro)]TJ 0 Tw (-)Tj 0.215 Tw -3.849 -1.111 Td [(genital abnormalities,)37( increased visibility of super\037cial veins,)37( )]TJ 0.064 Tw T* [(myopathy)92(,)37( nail,)37( hair)111(,)37( or skin abnormalities,)37( signs of bronchiec)]TJ 0 Tw (-)Tj 0.103 Tw T* [(tasis due to recurrent chest infections,)37( hepatosplenomegaly)92(,)37( as )]TJ 0.067 Tw T* [(well as )1(photophobia,)37( nystagmus,)37( and )1(oculocutaneous )1(albinism )]TJ 0 Tw T* [(may be associated with speci\037c CN syndromes \(T)86(able\0352\).)]TJ 5.247 0 0 5.247 532.7226 64.9969 Tm (15,52)Tj 0.226 Tw 9 0 0 9 322 51.9999 Tm [(In )1(adults,)37( it )1(is important )1(to )1(assess )1(signs )1(related )1(to possi)]TJ 0 Tw (-)Tj 0.299 Tw -1.111 -1.111 Td (ble underlying autoimmune or other neutropenia-associated )Tj 0 0 0 0 k /GS0 gs 0 Tw -31.889 61.789 Td (T2)Tj 0 -2.778 TD (T3)Tj -0.704 -44.151 Td [(A)37(Q10)]TJ ET endstream endobj 812 0 obj <>stream q /GS0 gs /Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 287.276 24.0881 Tm (2)Tj ET q 0 g /GS0 gs /Fm1 Do Q BT 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 8 0 0 8 36 727.1401 Tm (INTRODUCTION)Tj 0 0 0 1 k /GS1 gs /T1_2 1 Tf 0.094 Tw 9 0 0 9 46 712.8881 Tm [(Neutropenia,)37( de\037ned as a reduction in the absolute neutro)]TJ 0 Tw (-)Tj 0.139 Tw -1.111 -1.111 Td (phil count \(ANC\) below the lower limit of the normal range )Tj 0.082 Tw 0 -1.111 TD [(for the age and ethnic origin of the affected subject,)37( is a com)]TJ 0 Tw (-)Tj -0.021 Tw T* [(mon cause of referral to both adult and pediatric hematologists.)37( )]TJ 0.022 Tw T* [(The disorder)111(,)37( as an isolated blood cell de\037ciency)92(,)37( may be acute/)]TJ 0.308 Tw T* [(transient or )1(chronic/persistent; )1(acquired,)37( likely acquired,)37( )1(or )]TJ 0.092 Tw T* (congenital; primary or secondary to a number of disease enti)Tj 0 Tw (-)Tj 0.283 Tw T* [(ties; benign or premalignant,)37( predisposing to myelodysplas)]TJ 0 Tw (-)Tj 0.166 Tw T* [(tic neoplasms \(MDS\),)37( or acute myeloid leukemia \(AML\).)]TJ 0 Tw 5.247 0 0 5.247 267.0955 635.8851 Tm (1)Tj 0.166 Tw 9 0 0 9 270.0128 632.8881 Tm ( In )Tj 0.081 Tw -26.001 -1.111 Td [(recent years,)37( advances in genomics have identi\037ed novel genes )]TJ 0.004 Tw T* [(implicated in the pathogenesis and/or evolution of neutropenia,)37( )]TJ 0.098 Tw T* [(unraveled the underlying pathogenic mechanisms,)37( and opened )]TJ 0.122 Tw T* [(the )1(way for )1(novel )1(tailored )1(therapies.)]TJ 0 Tw 5.247 0 0 5.247 181.9936 595.8851 Tm (2\2267)Tj 0.122 Tw 9 0 0 9 190.4517 592.8881 Tm [( )38(The role )1(of )1(well-orga)]TJ 0 Tw (-)Tj 0.08 Tw -17.161 -1.111 Td [(nized patient registries,)37( by studying individual cases and fami)]TJ 0 Tw (-)Tj -0.033 Tw T* [(lies,)37( )1(has )1(been )1(particularly )1(important )1(for )1(the )1(recognition )1(of )1(novel )]TJ 0.158 Tw T* (entities and accumulating and sharing experience on diseases )Tj 0 Tw T* [(natural history)92(.)]TJ 5.247 0 0 5.247 95.1927 555.8851 Tm (8)Tj 0.015 Tc 0.129 Tw 9 0 0 9 46 542.8881 Tm [(A number of comprehensive reviews have been produced)15( )]TJ 0.082 Tw -1.111 -1.111 Td [(by experts in the \037eld aiming to disseminate this knowledge)15( )]TJ 0.235 Tw T* [(and )1(guide )1(clinicians )1(for )1(the )1(accurate )1(diagnosis,)37( )1(follow-up,)52( )]TJ -0.031 Tw T* [(and treatment of neutropenia patients,)37( particularly those with)15( )]TJ 0.03 Tw T* (chronic disease.)Tj -0.015 Tw 5.247 0 0 5.247 99.4438 505.8851 Tm (1\2267,9\22612)Tj 0.03 Tw 9 0 0 9 121.3656 502.8881 Tm [( Real world data,)37( however)111(,)37( arising from)15( )]TJ 0.118 Tw -9.485 -1.111 Td [(a survey within the Cooperation in Science and )37(T)86(echnology)15( )]TJ 0.648 Tw T* [(European Network for the Innovative Diagnosis and)15( )]TJ 0.092 Tw T* [(T)67(reatment of Chronic Neutropenias \(EuNet-INNOCHR)45(ON;)15( )]TJ 0.308 Tw T* (https://eunet-innochron.eu/\) involving physicians with spe)Tj 0 Tc 0 Tw (-)Tj 0.015 Tc 0.274 Tw T* [(cial )1(interest )1(in )1(neutropenias )1(from )1(28 )1(European )1(countries,)52( )]TJ -0.043 Tw T* [(Armenia,)37( Israel,)37( )37(T)86(urkey and the United States of )37(America have)15( )]TJ 0.13 Tw T* (shown that the work-up of patients with chronic neutrope)Tj 0 Tc 0 Tw (-)Tj 0.015 Tc 0.137 Tw T* [(nia is mostly based on the physicians\222 experience and local)15( )]TJ 0.168 Tw T* [(practices rather than on the guided clinical and laboratory)15( )]TJ -0.015 Tw T* (evidence)Tj 0 Tc 0 Tw (.)Tj 0.015 Tc -0.015 Tw 5.247 0 0 5.247 72.7104 405.8851 Tm (13)Tj -0.035 Tw 9 0 0 9 78.7025 402.8881 Tm [( )37(Thus,)37( the diagnosis and monitoring of neutropenic)15( )]TJ 0.006 Tw -4.745 -1.111 Td [(patients remains varied and challenging.)37( It is also challenging)15( )]TJ 0.058 Tw T* [(to perform a smooth transition of neutropenic patients from)15( )]TJ 0.158 Tw T* [(pediatric )1(to adult )1(medical care,)37( and the )1(treating )1(physicians)15( )]TJ 0.025 Tw T* [(need to be aware of the complications related to neutropenia)15( )]TJ 0.16 Tw T* [(and the risk of progression to MDS/AML,)37( and \037nally they)15( )]TJ -0.022 Tw T* [(need to be familiar with speci\037c situations like pregnancy and)15( )]TJ -0.036 Tw T* [(genetic )1(counseling.)37( Overall,)37( continuous )1(education of hematol)]TJ 0 Tc 0 Tw (-)Tj 0.015 Tc 0.057 Tw T* [(ogists on known and arising neutropenia entities and guided)15( )]TJ 0.198 Tw T* [(diagnostic,)37( follow-up,)37( and treatment strategies are particu)]TJ 0 Tc 0 Tw (-)Tj 0.015 Tc T* (larly important.)Tj 0 Tc -0.019 Tw 1.111 -1.111 Td [(T)86(aking )1(into )1(account )1(the )1(research )1(advances )1(in )1(the )1(\037eld )1(of )1(neu)]TJ 0 Tw (-)Tj 0.101 Tw -1.111 -1.111 Td [(tropenias and their translation to clinical practice,)37( progress in )]TJ 0.024 Tw T* (genomics and the availability of genetic testing in routine prac)Tj 0 Tw (-)Tj -0.008 Tw T* (tice and the accumulated experience from long-standing patient )Tj -0.053 Tw T* [(registries,)37( the European Hematology )37(Association \(EHA\) has col)]TJ 0 Tw (-)Tj -0.011 Tw T* [(laborated with the EuNet-INNOCHR)45(ON to develop guidelines )]TJ 0.148 Tw T* [(for the )1(classi\037cation,)37( diagnosis,)37( monitoring,)37( and management )]TJ 0.046 Tw T* [(of patients across the whole spectrum of chronic neutropenias.)37( )]TJ 0.049 Tw T* (Our hope is that these recommendations are widely used clini)Tj 0 Tw (-)Tj T* [(cally to bene\037t patients,)37( families,)37( and treating physicians.)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 8 0 0 8 36 176.8881 Tm (METHODS)Tj 0 0 0 1 k /GS1 gs /T1_2 1 Tf 0.261 Tw 9 0 0 9 46 162.6361 Tm (The guidelines working group \(GL-WG\) consisted of the )Tj -0.039 Tw -1.111 -1.111 Td [(chairs,)37( )1(steering )1(committee,)37( )1(and )1(expert )1(panel )1(including )1(the )1(chairs )]TJ 0.139 Tw T* (of the European and North-American Branches of the Severe )Tj 0.048 Tw T* [(Chronic )1(Neutropenia )1(International )1(registry)92(.)37( )37(All )1(17 )1(members )1(of )]TJ 0.071 Tw T* [(the GL-WG are active members of EuNet-INNOCHR)45(ON and )]TJ -0.019 Tw T* (were selected for their recognized expertise in research and clin)Tj 0 Tw (-)Tj -0.029 Tw T* [(ical practice on neutropenias.)37( )37(A memorandum of understanding )]TJ 0.012 Tw T* (was signed between the EHA and the GL-WG chairs represent)Tj 0 Tw (-)Tj -0.046 Tw T* [(ing also the EuNet-INNOCHR)45(ON,)37( to verify the absence of con)]TJ 0 Tw (-)Tj 0.074 Tw T* (\036ict of interests of the GL-WG members and their compliance )Tj -0.033 Tw T* [(with the rules adopted by the EHA Guidelines Committee.)37( EHA )]TJ -0.001 Tw T* (provided organizational assistance and support as well as fund)Tj 0 Tw (-)Tj T* [(ing for the systemic literature review)92(.)]TJ 0.013 Tw 30.111 75.927 Td (Five main topics were identi\037ed: \(1\) de\037nition and classi\037ca)Tj 0 Tw (-)Tj 0.112 Tw -1.111 -1.111 Td [(tion of neutropenias,)37( \(2\) diagnostic approach,)37( \(3\) natural his)]TJ 0 Tw (-)Tj -0.044 Tw T* [(tory and follow-up,)37( \(4\) treatment,)37( and \(5\) special situations,)37( and )]TJ 0.018 Tw T* [(a number of key questions were formulated for each topic.)37( )37(The )]TJ -0.091 Tw T* (GL-WG members were further divided into subgroups and based )Tj 0.035 Tw T* [(on )1(the )1(literature )1(review )1(and )1(their )1(own )1(experience,)37( responses )1(to )]TJ -0.027 Tw T* [(the topic questions were generated.)37( Literature review on all top)]TJ 0 Tw (-)Tj -0.018 Tw T* [(ics )1(except )1(treatment,)37( )1(comprised )1(case )1(control )1(and )1(cohort )1(studies.)37( )]TJ -0.045 Tw T* [(The treatment )1(topic,)37( having much higher evidence )1(based on ran)]TJ 0 Tw (-)Tj -0.011 Tw T* [(domized trials,)37( was reviewed by Cochrane Hematology \(https://)]TJ 0.024 Tw T* [(haematology)92(.cochrane.org/de\) and was decided to be presented )]TJ 0 Tw T* (as a separate document.)Tj 0.157 Tw 1.111 -1.111 Td (Expert recommendations were developed and discussed by )Tj -0.007 Tw -1.111 -1.111 Td (the entire panel in multiple rounds of communication with sub)Tj 0 Tw (-)Tj -0.049 Tw T* [(sequent adjustments based on the replies.)37( )37(T)98(o achieve the greatest )]TJ 0.005 Tw T* [(possible agreement,)37( a voting procedure was followed according )]TJ 0.051 Tw T* [(to )1(the Delphi )1(approach.)]TJ 0 Tw 5.247 0 0 5.247 390.8929 568.9731 Tm (14)Tj 0.051 Tw 9 0 0 9 396.7275 565.9761 Tm [( )1(Consensus )1(was reached )1(if )1(agreement )]TJ 0 Tw -11.081 -1.111 Td (was obtained from >75% of the panelists.)Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_1 1 Tf 8 0 0 8 297 526.9761 Tm [(DEFINITION AND CLASSIFICA)74(TION OF NEUTROPENIA)]TJ /T1_3 1 Tf 0 -1.907 TD [(De\037nition of neutr)18(openia)]TJ 0 0 0 1 k /GS1 gs /T1_2 1 Tf -0.047 Tw 9 0 0 9 307 501.7241 Tm [(The de\037nition of neutropenia varies according to the patient\222)74(s )]TJ -0.014 Tw -1.111 -1.111 Td [(ethnic origin and age \()36(T)86(able\035)14(1\).)37( )37(The widely accepted cutoff level )]TJ -0.064 Tw 0 -1.111 TD [(of )38(ANC )1(for )1(the )1(de\037nition )1(of )1(neutropenia )1(in )1(Caucasian )1(newborns )]TJ -0.035 Tw T* (and infants up to the age of 1 year is 1.0)Tj ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 307 501.7241 Tm 15.989 -3.333 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 452.053 471.7271 Tm (\327)Tj ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 307 501.7241 Tm 16.673 -3.333 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 458.182 471.7271 Tm (10)Tj 0 Tw 5.247 0 0 5.247 468.1914 474.7211 Tm (9)Tj 9 0 0 9 471.1087 471.7241 Tm (/L;)Tj 5.247 0 0 5.247 481.6117 474.7211 Tm (15)Tj -0.035 Tw 9 0 0 9 487.4463 471.7241 Tm [( however)111(,)37( neu)]TJ 0 Tw (-)Tj -0.01 Tw -21.161 -1.111 Td [(tropenia is de\037ned as an )37(ANC level of 2.5)]TJ ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 487.4463 471.7241 Tm -3.219 -1.111 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 459.6273 461.7251 Tm (\327)Tj ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 487.4463 471.7241 Tm -2.535 -1.111 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 465.7563 461.7251 Tm (10)Tj 0 Tw 5.247 0 0 5.247 475.7634 464.7211 Tm (9)Tj -0.01 Tw 9 0 0 9 478.6807 461.7241 Tm [(/L for term/near)55(-)]TJ 0.015 Tw -20.187 -1.111 Td [(term )1(neonates )1(72\226240 )1(hours )1(following )1(delivery)92(,)37( )1(and )1(1.0)]TJ ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 478.6807 461.7241 Tm 4.015 -1.111 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 515.9407 451.7251 Tm (\327)Tj ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 478.6807 461.7241 Tm 4.696 -1.111 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 522.0697 451.7251 Tm (10)Tj 0 Tw 5.247 0 0 5.247 532.0818 454.7211 Tm (9)Tj 9 0 0 9 534.9991 451.7241 Tm (/L )Tj 0.085 Tw -26.444 -1.111 Td (for preterm neonates.)Tj 0 Tw 5.247 0 0 5.247 382.0212 444.7211 Tm (4,16,17)Tj 0.085 Tw 9 0 0 9 399.5251 441.7241 Tm [( )37(A more detailed characterization of )]TJ -0.052 Tw -11.392 -1.111 Td [(neutropenia in newborns is given in the )74(\223Speci\037c situations\224)74( sec)]TJ 0 Tw (-)Tj -0.074 Tw T* [(tion )1(of )1(this )1(article.)37( )1(From )1(the )1(age )1(of )1(1 year )1(to )1(adulthood the )1(cutoff )]TJ -0.003 Tw T* [(level for )1(neutropenia is 1.5)]TJ ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 399.5251 441.7241 Tm 0.154 -3.333 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 402.0271 411.7271 Tm (\327)Tj ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 399.5251 441.7241 Tm 0.834 -3.333 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 408.1561 411.7271 Tm (10)Tj 0 Tw 5.247 0 0 5.247 418.1693 414.7211 Tm (9)Tj 9 0 0 9 421.0866 411.7241 Tm (/L.)Tj 5.247 0 0 5.247 431.5895 414.7211 Tm (1,14,18,19)Tj -0.003 Tw 9 0 0 9 456.3867 411.7241 Tm [( For Caucasian )1(adults,)37( )]TJ -0.027 Tw -17.71 -1.111 Td [(the )37(ANC threshold of 1.8)]TJ ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 456.3867 411.7241 Tm -6.798 -1.111 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 396.3387 401.7251 Tm (\327)Tj ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 456.3867 411.7241 Tm -6.116 -1.111 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 402.4677 401.7251 Tm (10)Tj 0 Tw 5.247 0 0 5.247 412.4814 404.7211 Tm (9)Tj -0.027 Tw 9 0 0 9 415.3987 401.7241 Tm (/L is adopted for the de\037nition of )Tj 0.12 Tw -13.155 -1.111 Td [(neutropenia according to the )37(W)86(orld Health Organization and )]TJ 0 Tw T* (the MDS/AML expert groups.)Tj 5.247 0 0 5.247 414.0081 384.7211 Tm (20\22622)Tj 0.263 Tw 9 0 0 9 307 371.7241 Tm [(It should be noted that some individuals of )37(African and )]TJ -0.014 Tw -1.111 -1.111 Td [(Middle )1(Eastern )1(descent )1(display )1(normal )37(ANCs )1(in )1(the )1(range )1(from )]TJ -0.153 Tw T* [(0.5 )-157(to )-157(1.5)]TJ ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 307 371.7241 Tm 3.122 -2.222 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 307 371.7241 Tm 3.247 -2.222 Td (\327)Tj ET BT /Span <>BDC /T1_2 1 Tf 9 0 0 9 307 371.7241 Tm 3.803 -2.222 Td ( )Tj EMC ET BT /T1_2 1 Tf 9 0 0 9 307 371.7241 Tm 3.928 -2.222 Td (10)Tj 0 Tw 5.247 0 0 5.247 352.3555 354.7211 Tm (9)Tj 0.004 Tw 9 0 0 9 355.2728 351.7241 Tm [(/L and less frequently even lower)111(.)]TJ 0 Tw 5.247 0 0 5.247 484.4669 354.7211 Tm (23\22625)Tj -0.033 Tw 9 0 0 9 498.7597 351.7241 Tm [( This )-37(varia)]TJ 0 Tw (-)Tj 0.057 Tw -22.418 -1.111 Td [(tion,)37( previously termed ethnic neutropenia,)37( is usually inherited )]TJ 0.291 Tw T* (as an autosomal recessive trait associated with a polymor)Tj 0 Tw 27 0 Td (-)Tj 0.026 Tw -27 -1.111 Td [(phism \(rs2814778,)37( \03446T>C\) in the GA)74(T)74(A box in the promoter )]TJ -0.032 Tw T* [(region )1(of )1(the )1(atypical )1(chemokine )1(receptor)55(-1 )1(\()]TJ /T1_4 1 Tf 0 Tw [(A)37(CKR1)]TJ /T1_2 1 Tf -0.032 Tw [(\) )1(gene,)37( )1(also )]TJ 0.087 Tw T* [(known )1(as )1(the )1(duffy )1(antigen )1(receptor )1(for )1(chemokines )1(\()]TJ /T1_4 1 Tf 0 Tw [(D)45(ARC)]TJ /T1_2 1 Tf -0.037 Tc 0.037 Tw [(\))-37(. )]TJ 0 Tc -0.037 Tw T* [(In homozygosity \(C/C\),)37( the polymorphism results in the absence )]TJ 0.164 Tw T* [(of Duffy antigen expression speci\037cally on red blood cells,)37( a )]TJ 0.23 Tw T* [(phenotype )1(known )1(as )1(Duffy-null.)]TJ 0 Tw 5.247 0 0 5.247 429.2398 274.7211 Tm (26)Tj 0.23 Tw 9 0 0 9 435.0745 271.7241 Tm [( )38(The )1(GL-WG )1(suggests )1(the )]TJ -0.039 Tw -15.342 -1.111 Td (introduction of the term )Tj /T1_4 1 Tf 0 Tw [(A)37(CKR1/D)45(ARC-)]TJ /T1_2 1 Tf -0.039 Tw (associated neutropenia )Tj -0.052 Tw T* [(\(AD)60(AN\),)37( instead of ethnic )1(neutropenia,)37( to )1(emphasize )1(the genetic )]TJ 0 Tw T* [(rather than the ethnic basis of this entity)92(.)]TJ 5.247 0 0 5.247 455.6955 244.7211 Tm (27)Tj 9 0 0 9 461.5302 241.7241 Tm ( )Tj 0.975 0.687 0.124 0.015 k /GS0 gs /T1_3 1 Tf 8 0 0 8 297.0001 218.7241 Tm [(Classi\037cation of neutr)18(openia)]TJ 0 0 0 1 k /GS1 gs /T1_2 1 Tf 0.194 Tw 9 0 0 9 307.0001 208.7241 Tm (It has long been recognized that the risk and outcome of )Tj 0.079 Tw -1.111 -1.111 Td (bacterial infections resulting from neutropenia depends on the )Tj -0.019 Tw T* [(individual\222)74(s capacity )1(to recruit )1(and )1(deliver neutrophils )1(to tissues )]TJ 0.08 Tw T* [(rather )1(than )1(only )1(on )1(the )38(ANC )1(in )1(the )1(peripheral )1(blood )1(\(PB\).)]TJ 0 Tw 5.247 0 0 5.247 529.8722 181.7211 Tm (28,29)Tj 9 0 0 9 543.0001 178.7241 Tm ( )Tj 0.084 Tw -27.333 -1.111 Td [(However)111(,)37( validated methods to estimate total body neutrophil )]TJ 0 0 0 0 k /GS0 gs -0.037 Tc 0.037 Tw -32.314 26.254 Td [(AQ)-37(4)]TJ 0 Tc 0 Tw 61.314 9.871 Td (T1)Tj -0.037 Tc 0.037 Tw -0.426 -20 Td [(AQ)-37(5)]TJ 0 -10.333 TD [(AQ)-37(6)]TJ ET q 1 0 0 1 297 141.097702 cm 0.24 0.08 0.08 0.4 K 12 w 0 0 m 34.896 0 l S Q q 1 0 0 1 297 122.347702 cm 0 0 0 1 K 0.5 w /GS1 gs 0 0 m 246 0 l S Q BT /T1_5 1 Tf 0 Tc 0 Tw 8 0 0 8 300 138.0977 Tm [(T)111(able 1)]TJ 0 0 0 1 k /GS1 gs /T1_1 1 Tf -0.375 -1.5 Td [(ANC Cutof)18(f Level for Definition of Neutr)18(openia Accor)18(ding to Age)]TJ ET q 1 0 0 1 297 104.9857025 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 206.25 0 l S Q q 1 0 0 1 503.2496948 104.9857025 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 39.75 0 l S Q q 1 0 0 1 297 70 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 206.25 0 l S Q q 1 0 0 1 503.2496948 70 cm 0 0 0 1 K 0.5 w /GS2 gs 0 0 m 39.75 0 l S Q BT /T1_6 1 Tf 8 0 0 8 297 109.1857 Tm (Age )Tj 27.479 0 Td (ANC)Tj /T1_7 1 Tf 4.664 0 0 4.664 530.1711 111.8497 Tm (a)Tj /T1_6 1 Tf 8 0 0 8 532.4144 109.1857 Tm ( )Tj /T1_8 1 Tf -29.427 -1.77 Td (From 14 d to 1 yr)Tj -0.115 Tw 26.156 0 Td (<1.0)Tj ET BT /Span <>BDC /T1_8 1 Tf 8 0 0 8 532.4144 109.1857 Tm -1.471 -1.77 Td ( )Tj EMC ET BT /T1_8 1 Tf 8 0 0 8 532.4144 109.1857 Tm -1.346 -1.77 Td (\327)Tj ET BT /Span <>BDC /T1_8 1 Tf 8 0 0 8 532.4144 109.1857 Tm -0.746 -1.77 Td ( )Tj EMC ET BT /T1_8 1 Tf 8 0 0 8 532.4144 109.1857 Tm -0.621 -1.77 Td (10)Tj 0 Tw 4.664 0 0 4.664 535.1293 97.6878 Tm (9)Tj 8 0 0 8 537.368 95.0238 Tm (/L)Tj -30.046 -1.251 Td (Children >1 y to adulthood*)Tj -0.115 Tw 26.156 0 Td (<1.5)Tj ET BT /Span <>BDC /T1_8 1 Tf 8 0 0 8 537.368 95.0238 Tm -2.09 -1.251 Td ( )Tj EMC ET BT /T1_8 1 Tf 8 0 0 8 537.368 95.0238 Tm -1.965 -1.251 Td (\327)Tj ET BT /Span <>BDC /T1_8 1 Tf 8 0 0 8 537.368 95.0238 Tm -1.365 -1.251 Td ( )Tj EMC ET BT /T1_8 1 Tf 8 0 0 8 537.368 95.0238 Tm -1.24 -1.251 Td (10)Tj 0 Tw 4.664 0 0 4.664 535.1293 87.6759 Tm (9)Tj 8 0 0 8 537.368 85.0119 Tm (/L)Tj -30.046 -1.251 Td (Adults)Tj /T1_9 1 Tf 4.664 0 0 4.664 314.6156 77.664 Tm (a)Tj /T1_8 1 Tf -0.115 Tw 8 0 0 8 506.2497 75 Tm (<1.8)Tj ET BT /Span <>BDC /T1_8 1 Tf 8 0 0 8 520.6497 75 Tm ( )Tj EMC ET BT /T1_8 1 Tf 8 0 0 8 521.6497 75 Tm (\327)Tj ET BT /Span <>BDC /T1_8 1 Tf 8 0 0 8 526.4497 75 Tm ( )Tj EMC ET BT /T1_8 1 Tf 8 0 0 8 527.4496 75 Tm (10)Tj 0 Tw 4.664 0 0 4.664 535.1293 77.664 Tm (9)Tj 8 0 0 8 537.368 75 Tm (/L)Tj /T1_9 1 Tf 4.081 0 0 4.081 297 62.331 Tm (a)Tj /T1_8 1 Tf -0.115 Tw 7 0 0 7 298.7385 60 Tm [(ANC )-115(<1.5)]TJ ET BT /Span <>BDC /T1_8 1 Tf 7 0 0 7 323.9105 60 Tm ( )Tj EMC ET BT /T1_8 1 Tf 7 0 0 7 324.7854 60 Tm (\327)Tj ET BT /Span <>BDC /T1_8 1 Tf 7 0 0 7 328.9854 60 Tm ( )Tj EMC ET BT /T1_8 1 Tf 7 0 0 7 329.8604 60 Tm (10)Tj 0 Tw 4.081 0 0 4.081 336.58 62.331 Tm (9)Tj 7 0 0 7 338.5388 60 Tm [(/L are considered normal in individuals from )37(African and the Middle Eastern )]TJ -5.934 -1.286 Td [(ancestr)-18(y)55(.)]TJ 0 -1.286 TD (ANC = absolute neutrophil count.)Tj ET q 0 0 594 792 re W n q 0 -0.698822 -0.698822 0 324.2524872 802.4822845 cm 0 0 0 RG 2 J /GS3 gs 27.5 425.5 849 23 re S Q Q endstream endobj 813 0 obj <> endobj 814 0 obj <> endobj 815 0 obj <>stream q /GS0 gs /Fm0 Do Q q /GS0 gs /Fm1 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf 8 0 0 8 302.276 24.0881 Tm (1)Tj 0 0 0 0.5 k /GS0 gs /T1_1 1 Tf 11 0 0 11 51 686.9012 Tm (Guideline Article \226 Consensus based)Tj ET q 0 g /Fm2 Do Q BT 0.975 0.687 0.124 0.015 k /T1_1 1 Tf 20 0 0 20 51 641.8452 Tm [(The Eur)18(opean Guidelines on Diagnosis and )]TJ 0 -1 TD [(Management of Neutr)18(openia in Adults and )]TJ T* [(Childr)18(en: A Consensus Between the )]TJ T* [(Eur)18(opean Hematology Association and the )]TJ T* (EuNet-INNOCHRON COST Action)Tj 0 0 0 1 k /GS1 gs /T1_2 1 Tf 10.5 0 0 10.5 51 533.9452 Tm [(Francesca\037Fior)18(edda)]TJ 6.1215 0 0 6.1215 140.2908 537.4417 Tm (1)Tj 10.5 0 0 10.5 143.6943 533.9452 Tm (, Julia\037Skokowa)Tj 6.1215 0 0 6.1215 214.6949 537.4417 Tm (2)Tj 10.5 0 0 10.5 218.0984 533.9452 Tm [(, Hannah\037T)111(amary)]TJ 6.1215 0 0 6.1215 294.5481 537.4417 Tm (3,4)Tj 10.5 0 0 10.5 303.057 533.9452 Tm (, Michail\037Spanoudakis)Tj 6.1215 0 0 6.1215 401.8503 537.4417 Tm (5)Tj 10.5 0 0 10.5 405.2538 533.9452 Tm [(, Pier)18(o\037Farruggia)]TJ 6.1215 0 0 6.1215 479.3829 537.4417 Tm (6)Tj 10.5 0 0 10.5 482.7865 533.9452 Tm (, )Tj -41.123 -1.143 Td (Antonio\037Almeida)Tj 6.1215 0 0 6.1215 124.7091 525.4417 Tm (7,8)Tj 10.5 0 0 10.5 133.2179 521.9452 Tm [(, Daniela\037Guar)18(do)]TJ 6.1215 0 0 6.1215 208.8907 525.4417 Tm (1)Tj 10.5 0 0 10.5 212.2943 521.9452 Tm (, Petter\037H\366glund)Tj 6.1215 0 0 6.1215 286.4022 525.4417 Tm (9,10,11)Tj 10.5 0 0 10.5 306.8235 521.9452 Tm (, Peter E.\037Newburger)Tj 6.1215 0 0 6.1215 401.7632 525.4417 Tm (12)Tj 10.5 0 0 10.5 408.5703 521.9452 Tm (, Jan\037Palmblad)Tj 6.1215 0 0 6.1215 475.864 525.4417 Tm (10,11)Tj 10.5 0 0 10.5 491.18 521.9452 Tm [(, Ivo P)153(.\037T)111(ouw)]TJ 6.1215 0 0 6.1215 547.743 525.4417 Tm (13)Tj 10.5 0 0 10.5 554.5502 521.9452 Tm (, )Tj -47.957 -1.143 Td [(Cor)-18(nelia\037Zeidler)]TJ 6.1215 0 0 6.1215 121.2124 513.4417 Tm (14)Tj 10.5 0 0 10.5 128.0195 509.9452 Tm [(, Alan J.\037W)37(arr)18(en)]TJ 6.1215 0 0 6.1215 199.6079 513.4417 Tm (15,16,17)Tj 10.5 0 0 10.5 223.4327 509.9452 Tm (, David C.\037Dale)Tj 6.1215 0 0 6.1215 290.9263 513.4417 Tm (18)Tj 10.5 0 0 10.5 297.7334 509.9452 Tm [(, Karl\037W)18(elte)]TJ 6.1215 0 0 6.1215 349.2774 513.4417 Tm (19)Tj 10.5 0 0 10.5 356.0846 509.9452 Tm (, Carlo\037Dufour)Tj 6.1215 0 0 6.1215 419.1047 513.4417 Tm (1)Tj 10.5 0 0 10.5 422.5082 509.9452 Tm (, Helen A.\037Papadaki)Tj 6.1215 0 0 6.1215 511.7993 513.4417 Tm (20,21)Tj /T1_3 1 Tf -0.005 Tc 0.005 Tw 10.5 0 0 10.5 51 485.9452 Tm [(Corr)18(espondence:)]TJ /T1_2 1 Tf 0 Tw [( Francesca Fior)18(edda \(francesca\036or)18(edda@gaslini.org\); Helen A. Papadaki \(e.papadaki@uoc.gr\).)]TJ 0.975 0.687 0.124 0.015 k /GS0 gs /T1_3 1 Tf 0.04 Tc -0.04 Tw 8 0 0 8 51 455.9452 Tm [(ABSTRACT)40( )]TJ 0 0 0 1 k /GS1 gs /T1_2 1 Tf -0.01 Tc 0.01 Tw 9 0 0 9 51 444.9452 Tm [(Neutr)18(o)]TJ 0.002 Tw [(penia, as an isolated blood cell de\036ciency)92(, is a featur)18(e of a wide spectrum of acquir)18(ed or congenital, benign or pr)18(emalignant dis)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.018 Tw 0 -1.222 TD [(or)18(ders with a )1(pr)18(edisposition to )1(develop myelodysplastic )1(neoplasms/acute )1(myeloid leukemia that )1(may arise )1(at any age. )1(In )1(r)18(ecent years,)-10( )]TJ -0.016 Tw T* [(advances in diagnostic methodologies, particularly in the \036eld of gen\ omics, have r)18(evealed novel genes and mechanisms r)18(esponsible for)-10( )]TJ 0.05 Tw T* [(etiology and disease evolution and opened new perspectives for tailor)18(ed tr)18(eatment. Despite the r)18(esear)18(ch and diagnostic advances in)-10( )]TJ 0.025 Tw T* [(the )1(\036eld, )1(r)18(eal )1(world )1(evidence, )1(arising )1(fr)18(om )1(inter)-18(national )1(neutr)18(openia )1(patient )1(r)18(egistries )1(and )1(scienti\036c )1(networks, )1(has )1(shown )1(that )1(the )1(diag)]TJ 0 Tc 0 Tw (-)Tj -0.01 Tc 0.041 Tw T* [(nosis and management of neutr)18(openic patients is mostly based on the physicians\222 experience and loc\ al practices. Ther)18(efor)18(e, experts)-10( )]TJ -0.007 Tw T* [(participating in the Eur)18(opean Network for the Innovative Diagnosis and T)92(r)18(eatment of Chr)18(onic Neutr)18(openias have collaborated under the)-10( )]TJ -0.014 Tw T* [(auspices of the Eur)18(opean Hematology Association to pr)18(oduce r)18(ecommendations for the diagnosis and management of patients acr)18(oss)-10( )]TJ 0.102 Tw T* [(the whole spectrum of chr)18(onic neutr)18(openias. In the pr)18(esent article, we describe evidence- and consensus-based guidelines for \ the)-10( )]TJ 0.002 Tw T* [(de\036nition and classi\036cation, diagnosis, and follow-up of patients \ with chr)18(onic neutr)18(openias including special entities such as pr)18(egnancy)-10( )]TJ -0.01 Tw T* [(and the neonatal period. W)18(e particularly emphasize the importance of combining the clinical \036nd\ ings with classical and novel laboratory)-10( )]TJ 0.067 Tw T* (testing, and advanced germline and/or somatic mutational analyses, for t\ he characterization, risk strati\036cation, and monitoring)Tj [( of the)-10( )]TJ 0.074 Tw T* [(entir)18(e spectrum of neutr)18(openia patients. W)18(e believe that the wide clinical use of these practical r)18(ecommendations will be particularly)-10( )]TJ 0 Tw T* [(bene\036cial for patients, families, and tr)18(eating physicians.)]TJ 0 0 0 0 k /GS0 gs /T1_4 1 Tf -0.037 Tc 0.037 Tw -3.314 16.125 Td [(AQ)-37(1)]TJ 0 -1.667 TD [(AQ)-37(2)]TJ 60.889 -5.667 Td [(AQ)-37(3)]TJ ET q 1 0 0 1 51 251.75 cm 0 0 0 1 K 0.5 w /GS1 gs 0 0 m 246 0 l S Q BT 0 0 0 1 k /GS1 gs /T1_5 1 Tf 0 Tc 0 Tw 4.081 0 0 4.081 51 245.831 Tm (1)Tj 7 0 0 7 53.269 243.5 Tm [(Unit of Hematology)92(, IRCCS Istituto Giannina Gaslini, Genova, Italy)]TJ 4.081 0 0 4.081 51 236.831 Tm (2)Tj 7 0 0 7 53.269 234.5 Tm [(Department of Oncology)92(, Hematology)92(, Immunology)92(, Rheumatology)92(, and Clinical )]TJ -0.324 -1.286 Td [(Immunology)92(, University Hospital T)46(\374bingen, Germany)]TJ 4.081 0 0 4.081 51 218.831 Tm (3)Tj 7 0 0 7 53.269 216.5 Tm [(The Rina Zaizov Hematology/Oncology Division, Schneider Children\222)55(s Medical )]TJ -0.324 -1.286 Td [(Center of Israel, Petah T)5(ikva, Israel)]TJ 4.081 0 0 4.081 51 200.831 Tm (4)Tj 7 0 0 7 53.269 198.5 Tm [(Sackler School of Medicine, T)92(el A)18(viv University)92(, Israel)]TJ 4.081 0 0 4.081 51 191.831 Tm (5)Tj 7 0 0 7 53.269 189.5 Tm [(Department of Hematology)92(, W)18(arrington and Halton T)92(eaching Hospitals NHS )]TJ -0.324 -1.286 Td [(foundation T)92(rust, W)18(arrington, United Kingdom)]TJ 4.081 0 0 4.081 51 173.831 Tm (6)Tj 7 0 0 7 53.269 171.5 Tm [(Pediatric Onco-Hematology)92(, ARNAS Civico Di Cristina Benfratelli Hospital, )]TJ -0.324 -1.286 Td (Palermo, Italy)Tj 4.081 0 0 4.081 51 155.831 Tm (7)Tj 7 0 0 7 53.269 153.5 Tm [(Department of Hematology)92(, Hospital da Luz Lisboa, Portugal)]TJ 4.081 0 0 4.081 51 146.831 Tm (8)Tj 7 0 0 7 53.269 144.5 Tm (Faculdade de Medicina, Universidade Cat\363lica Portuguesa, Lisbon, Port\ ugal)Tj 4.081 0 0 4.081 51 137.831 Tm (9)Tj 7 0 0 7 53.269 135.5 Tm [(Clinical Immunology and T)92(ransfusion Medicine Clinic, Karolinska University )]TJ -0.324 -1.286 Td (Hospital, Stockholm, Sweden)Tj 4.081 0 0 4.081 51 119.831 Tm (10)Tj 7 0 0 7 55.538 117.5 Tm (Center for Hematology and Regenerative Medicine \(HERM\), Department of \ )Tj -0.648 -1.286 Td (Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden)Tj 4.081 0 0 4.081 51 101.831 Tm (11)Tj 7 0 0 7 55.538 99.5 Tm [(Department of Hematology)92(, Karolinska University Hospital, Stockholm, Sweden)]TJ 4.081 0 0 4.081 51 92.831 Tm (12)Tj 7 0 0 7 55.538 90.5 Tm [(Department of Pediatrics, UMass Chan Medical School, W)18(orcester)92(, MA, USA)]TJ 4.081 0 0 4.081 51 83.831 Tm (13)Tj 7 0 0 7 55.538 81.5 Tm (Department of Hematology and Erasmus MC Cancer Institute, Erasmus )Tj -0.648 -1.286 Td [(University Medical Center)92(, Rotterdam, Netherlands)]TJ 4.081 0 0 4.081 51 65.831 Tm (14)Tj 7 0 0 7 55.538 63.5 Tm [(Department of Oncology)92(, Hematology)92(, Immunology and Bone Marrow )]TJ -0.648 -1.286 Td [(T)92(ransplantation, Hannover Medical School, Hannover)92(, Germany)]TJ ET q 1 0 0 1 312 251.7521057 cm 0 0 0 1 K 0.5 w 0 0 m 246 0 l S Q BT /T1_5 1 Tf 4.081 0 0 4.081 312 245.8331 Tm (15)Tj 7 0 0 7 316.5381 243.5021 Tm [(Department of Hematology)92(, University of Cambridge, United Kingdom)]TJ 4.081 0 0 4.081 312 236.8331 Tm (16)Tj 7 0 0 7 316.5381 234.5021 Tm (Cambridge Institute for Medical Research, University of Cambridge, Unite\ d )Tj -0.648 -1.286 Td (Kingdom)Tj 4.081 0 0 4.081 312 218.8331 Tm (17)Tj 7 0 0 7 316.5381 216.5021 Tm [(W)18(ellcome T)92(rust\226Medical Research Council Stem Cell Institute, University of )]TJ -0.648 -1.286 Td (Cambridge, United Kingdom)Tj 4.081 0 0 4.081 312 200.8331 Tm (18)Tj 7 0 0 7 316.5381 198.5021 Tm [(University of W)18(ashington, Seattle, W)25(A, USA)]TJ 4.081 0 0 4.081 312 191.8331 Tm (19)Tj 7 0 0 7 316.5381 189.5021 Tm [(University Children\222)55(s Hospital T)46(\374bingen, Germany)]TJ 4.081 0 0 4.081 312 182.8331 Tm (20)Tj 7 0 0 7 316.5381 180.5021 Tm [(Hemopoiesis Research Laborator)-18(y)92(, School of Medicine, University of Crete, )]TJ -0.648 -1.286 Td (Heraklion, Greece)Tj 4.081 0 0 4.081 312 164.8331 Tm (21)Tj 7 0 0 7 316.5381 162.5021 Tm [(Department of Hematology)92(, University Hospital of Heraklion, Crete, Greece)]TJ -0.648 -1.286 Td (JS and HT have contributed equally to this work.)Tj 0 -1.286 TD (Supplemental digital content is available for this article.)Tj 0.02 Tc T* [(Copyright \251 2023 the Author\(s\). Published by W)18(olters Kluwer Health, Inc.)20( )]TJ T* [(on behalf of the European Hematology Association. This is an open-access\ )20( )]TJ T* (article distributed under the terms of the Creative Commons Attribution-\ )Tj T* [(Non Commercial-No Derivatives License 4.0 \(CCBY)74(-NC-ND\), where it is)20( )]TJ T* [(permissible to download and share the work provided it is properly cited\ . 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