Congenital Neutropenia in a Newborn

K Walkovich and LA Boxer Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, MI, USA

in HAX1, ELANE (previously ELA2), GFI1, WAS, CSF3R and Severe congenital neutropenia (SCN) is a genetically heterogenous, rare G6PC3.6,7 Regardless of the mode of inheritance or specific À3 disorder defined by a persistent absolute neutrophil count <500k mm mutation, newborns with SCN have severe neutropenia, defined with neutrophil maturation arrest at the promyelocyte stage and an as an absolute neutrophil count (ANC) <500 k mmÀ3, often increased risk for infection as well as a propensity towards developing appreciable at birth or shortly thereafter.1,8 Frequent episodes of myelodysplastic syndrome and acute myelogenous leukemia. We report a fever, skin infections, gingivitis, stomatitis, pneumonia and case of incidentally identified SCN in a full-term, otherwise healthy infant perirectal abscesses are common in the first few months of life and girl. Routine complete blood counts obtained for follow up of ABO before the advent of G-CSF therapy death from overwhelming incompatibility-induced jaundice and anemia identified mild neutropenia serious infection was common by 1 year of age.8 Prompt diagnosis at birth followed by severe persistent neutropenia by 1 week of birth. Genetic of SCN in infancy and initiation of treatment to prevent infection is testing confirmed the clinical suspicion of SCN with the identification of a crucial to decreasing morbidity and mortality. Care must also be mutation in the ELANE gene. Prompt identification and treatment of taken to monitor for the development of myelodysplasia and infants with SCN is critical to minimizing morbidity and mortality; as such, leukemia transformation. a diagnosis of SCN must be considered in all infants with neutropenia even in the absence of infection. Case Journal of Perinatology (2011) 31, S22–S23; doi:10.1038/jp.2010.166 Our patient presented in infancy with incidentally recognized Keywords: neutropenia; newborn; ELANE neutropenia. She was born full term to a health gravida 1 para 1 mother after an uneventful pregnancy, but her neonatal course was complicated by anemia and jaundice from ABO incompatibility Introduction requiring phototherapy and subsequent monitoring of her blood À3 Severe congenital neutropenia (SCN) is a rare disease entity with a counts. At birth, her white blood cell count was 7400 k mm with À3 prevalence of two cases per million people.1,2 Clinically, SCN is an ANC of 1110 k mm . After 1 week, however, her white blood À3 À3 characterized by a paucity of peripherally circulating neutrophils cell count was 8100 k mm with an ANC of 405 k mm . Sepsis with arrest of neutrophil maturation at the promyelocyte stage and evaluation was negative. A diagnosis of alloimmune neutropenia 9 consequent increased susceptibility to severe and recurrent was considered, but anti-neutrophil antibodies were negative. infections. Besides increased infection risk, patients with SCN Furthermore, she had multiple repeat blood counts obtained over a treated with granulocyte colony stimulating factor (G-CSF) also 8 week period that revealed a persistently low ANC ranging from À3 have an underlying predisposition to myelodysplastic syndrome/ 0 to 1110 k mm with the majority of the ANC values below À3 acute myelogenous leukemia revealed with increasing age.3 200 k mm , concerning for congenital neutropenia. She was Although the first description of the disease in 1956 by the asymptomatic with no fever, mouth sores, gingivitis, vaginal sores, Swedish pediatrician, Rolf Kostmann, detailed the autosomal folliculitis or other infections. Family history did not identify recessive form of SCN most commonly because of HAX1 anyone with cytopenias, death from overwhelming infection in mutations,4 it is now recognized that SCN is a genetically childhood nor any consanguineous unions. Her evaluation heterogenous disorder with multiple modes of inheritance culminated in a bone marrow aspirate obtained at 3 months of age including autosomal recessive (accounting for B30% of patients), that demonstrated neutrophil arrest at the promyelocyte stage and autosomal dominant (accounting for B60% of patients), X-linked an increase in eosinophil precursors consistent with a diagnosis of and sporadic.5 Mutations associated with SCN have been identified congenital neutropenia. Cytogenetics from the bone marrow sample were normal, that is, 46 XX. Confirmation of the diagnosis Correspondence: Dr LA Boxer, Department of Pediatrics and Communicable Disease, of congenital neutropenia was obtained through gene mutation University of Michigan, D3251 MPB, 1500 E. Medical Center Drive, SPC 5718, Ann Arbor, MI 48109-5178, USA. analysis for ELANE that revealed a heterozygous P110L mutation in E-mail: [email protected] exon 4 of the ELANE gene previously reported as a recognized Congenital neutropenia, newborn K Walkovich and LA Boxer S23 cause of congenital neutropenia.10 The patient was started on References À1 filgastrim 7.5 mcg kg daily, titrated to maintain her ANC between 1 Ancliff PJ. Congenital neutropenia. Blood Rev 2003; 17: 209–216. À3 1000 and 2000 k mm , to minimize her risk of infection. 2 Welte K, Boxer LA. Severe chronic neutropenia: pathophysiology and therapy. At 11 months of age she has had no serious infections to date. Semin. Hematol 1997; 34: 267–278. 3 Rosenberg P, Zeidler C, Bolyard AA, Alter BP, Bonilla MA, Dror Y et al. Stable long-term risk of leukemia in patients with severe congenital neutropenia maintained on G-CSF Discussion therapy. Brit J Haematol 2010; 150: 196–199. ELANE mutations are associated with the autosomal dominant and 4 Kostmann R. Infantile genetic agranulocytosis infantilis hereditaria. Acta Paediatric sporadically inherited forms of SCN.10 Mutations in the ELANE Supple 1956; 45: 1–78. gene are the most frequently identified genetic basis for SCN with 5 Zeidler C, Germeshausen M, Klein C, Welte K. Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (GSF3R) mutations in severe congenital neutropenia. Brit J 35–63% of SCN patients found to have a mutation in the Haematol 2009; 144: 459–467. 11–13 neutrophil elastase gene. Thus, all patients with suspected 6 Newburger P, Boxer LA. A molecular classification of congenital neutropenia 13 SCN are recommended to have ELANE genotyping performed. syndromes. Pediatr Blood Cancer 2007; 49: 609–614. Those patients identified to have an ELANE mutation do not 7 Boztug K, Appaswamy G, Ashikov A, Scha¨ffer AA, Salzer U, Diestelhorst J et al. A require further testing. Patients with negative ELANE testing should syndrome with congenital neutropenia and mutations in G6PC3. N Eng J Med 2009; undergo further gene testing as dictated by their clinical and family 360: 32–43. 8 Kostmann R. Infantile genetic agranulocytosis Acta Paediatric. Scand 1975; 64: history. 362–368. Treatment of SCN focuses on the prevention of infection. 9 Boxer L. Immune neutropenia: clinical and biological implications. Amer J Pediatr Recombinant human G-CSF has been the mainstay of treatment Hemat/Oncol 1981; 3: 89–96. since its introduction in 1987 and is considered the standard of 10 Dale DC, Person R, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA et al. Mutations in the care for preventing life-threatening bacterial sepsis.14,15 For patients gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000; 96: 2317–2322. who do not respond to G-CSF, or who develop myelodysplastic 11 Bellanne´-Chantelot C, Clauin S, Leblanc T, Cassinat B, Rodrigues-Lima F, syndrome/leukemia, stem cell transplantation is the only Beaufils S et al Mutations in the ELA2 gene correlate with more severe expression of 16,17 alternative treatment. neutropenia: a study of 81 patients from the French Neutropenia Register. Blood 2004; SCN is recognized as a pre-leukemic condition with B20% of 103: 4119–4125. patients developing leukemia.3 Leukemic transformation has been 12 Rosenberg PS, Alter BP, Link DC, Stein S, Rodger E, Bolyard AA et al. Neutrophil noted in both the autosomal recessive18 and dominant11subtypes of elastase mutations and risk of leukemia in severe congenital neutropenia. Brit J Haematol 2008; 140: 210–213. SCN. The majority of leukemic transformation results in acute 13 Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC et al. Prevalence of myelogenous leukemia. mutations in ELANE, GFI1, HAX1, SBDS, WAS and G5PC3 in patients with severe The Severe Chronic Neutropenia International Registry is now congenital neutropenia. Brit J Haematol 2009; 147: 535–542. gathering data on those ELANE mutations that appear to 14 Bonilla MA, Gillio AP, Ruggeiro M, Kernan NA, Brochstein JA, Abboud M et al. Effects of predispose to leukemic transformation. Our patient thus far has a recombinant human granulocyte colony-stimulating factor on neutropenia in patients mutation, which appears not to be associated with leukemic with congenital agranulocytosis. N Engl J Med 1989; 320: 1574–1580. 19 15 Dale DC, Bonilla MA, Davis MW, Nakaniski A, Hammond WP, Kurtzberg J et al. transformation. Because of the risk of myelodysplasia and A randomized controlled phase III trial of recombinant human G-CSF for treatment of leukemic predisposition; however, a yearly bone marrow is severe chronic neutropenia. Blood 1993; 81: 2496–2502. recommended for patients, including our patient, with SCN to 16 Zeidler C, Welte K, Barak Y, Barriga F, Bolyard AA, Boxer LA et al. Stem cell monitor for morphological and cytogenetic changes as well as the transplantation in patients with severe congenital neutropenia without evidence of development of G-CSF receptor mutations that may herald the leukemic transformation. Blood 2000; 95: 1195–1198. development of leukemic transformation.16 Our patient will also 17 Choi SW, Boxer LA, Pulsipher MA, Roulston D, Hutchinson RJ, Yanik GA et al. Stem cell transplantation in patients with severe congenital neutropenia with evidence of have quarterly complete blood counts to monitor the risk for leukemic transformation. Bone Marrow Transpl 2005; 35: 475–477. malignant changes. 18 Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Scha¨ffer AA et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann Conflict of interest disease). Nat Genet 2007; 39(1): 86–92. 19 Dale DC, Makaryan V, Bolyard AA, Elin R, Aprikyan AAG, Bonilla MA et al. Neutrophil Dr Walkovich has received support from the NIH Loan Repayment elastase mutations and the risk of leukemia in patients with cyclic and congenital Program. Dr Boxer owns Amgen stock. neutropenia. Blood 2010 (in press).

Journal of Perinatology