Novel ELANE Gene Mutation in a Newborn with Severe Congenital Neutropenia: Case Report and Literature Review

Abstract

Severe neutropenia is defined as an absolute neutrophil count (ANC) of less than 0.5 × 10⁹/L. Severe congenital neutropenia (SCN) is an inborn disorder with maturation arrest of granulocytes due to various genetic abnormalities, which may lead to immunodeficiency. Among several associated genetic mutations, the variants or heterozygous mutations of the ELANE gene coding neutrophil elastase comprise approximately 50% of the genetic causes of SCN. We present a newborn (male) with severe neutropenia due to a novel ELANE gene mutation. The newborn was born at 38^6/7 weeks gestation to a 25-year-old mother with hypertension and morbid obesity. Pregnancy and delivery were uncomplicated but the baby obtained a complete blood count (CBC) on day of life 2 for a work up of hyperbilirubinemia. He was noted to initially have an ANC of 0.2 × 10⁹/L and 0 on subsequent blood counts. A bone marrow biopsy showed a left shift and consistent with myeloid maturation arrest. In direct DNA sequencing analysis, we found an ELANE gene mutation (Val119Glu, V119E), which may be a new gene mutation to cause SCN. The diagnosis of SCN in newborns is usually based on neutropenia identified on a routine CBC. Sufficient awareness and high suspicion of this rare disease can prevent missed or delayed diagnosis of SCN. Our analysis also suggests a new pathological mutation in the ELANE gene and supports the important role of molecular testing in SCN.

Keywords

severe congenital neutropenia - ELANE mutation - newborn

• References

• 1 Ancliff PJ. Congenital neutropenia. Blood Rev 2003; 17 (04) 209-216
• 2 Severe congenital neutropenia. Genetics Home Reference 2018. Available at: http://ghr.nlm.nih.gov/condition/severe-congenital-neutropenia . Accessed September 30, 2018
• 3 Bellanné-Chantelot C, Clauin S, Leblanc T. , et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood 2004; 103 (11) 4119-4125
• 4 Xia J, Bolyard AA, Rodger E. , et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol 2009; 147 (04) 535-542
• 5 Welte K, Zeidler C, Dale DC. Severe congenital neutropenia. Semin Hematol 2006; 43 (03) 189-195
• 6 Newburger PE, Pindyck TN, Zhu Z. , et al. Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes. Pediatr Blood Cancer 2010; 55 (02) 314-317
• 7 Boztug K, Klein C. Novel genetic etiologies of severe congenital neutropenia. Curr Opin Immunol 2009; 21 (05) 472-480
• 8 Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 2007; 109 (05) 1817-1824
• 9 Walkovich K, Boxer LA. Congenital neutropenia in a newborn. J Perinatol 2011; 31 (Suppl. 01) S22-S23
• 10 Vu QV, Wada T, Tran TT. , et al. Severe congenital neutropenia caused by the ELANE gene mutation in a Vietnamese boy with misdiagnosis of tuberculosis and autoimmune neutropenia: a case report. BMC Hematol 2015; 15: 2
• 11 Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K. Severe congenital neutropenias. Nat Rev Dis Primers 2017; 3: 17032
• 12 Shim YJ, Kim HJ, Suh JS, Lee KS. Novel ELANE gene mutation in a Korean girl with severe congenital neutropenia. J Korean Med Sci 2011; 26 (12) 1646-1649
• 13 Lee W-I, Chen S-H, Huang J-L. , et al. Identifying patients with neutrophil elastase (ELANE) mutations from patients with a presumptive diagnosis of autoimmune neutropenia. Immunobiology 2013; 218 (05) 828-833
• 14 Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am 2013; 27 (01) 19-41 , vii
• 15 Shu Z, Li XH, Bai XM. , et al. Clinical characteristics of severe congenital neutropenia caused by novel ELANE gene mutations. Pediatr Infect Dis J 2015; 34 (02) 203-207
• 16 Borregaard N. Severe congenital neutropenia: new lane for ELANE. Blood 2014; 123 (04) 462-463
• 17 Germeshausen M, Deerberg S, Peter Y, Reimer C, Kratz CP, Ballmaier M. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat 2013; 34 (06) 905-914
• 18 Kurnikova M, Maschan M, Dinova E. , et al. Four novel ELANE mutations in patients with congenital neutropenia. Pediatr Blood Cancer 2011; 57 (02) 332-335
• 19 Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol 2011; 29: 399-413
• 20 Boztug K, Klein C. Genetic etiologies of severe congenital neutropenia. Curr Opin Pediatr 2011; 23 (01) 21-26
• 21 Dale DC, Person RE, Bolyard AA. , et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000; 96 (07) 2317-2322
• 22 Nayak RC, Trump LR, Aronow BJ. , et al. Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. J Clin Invest 2015; 125 (08) 3103-3116
• 23 Nustede R, Klimiankou M, Klimenkova O. , et al. ELANE mutant-specific activation of different UPR pathways in congenital neutropenia. Br J Haematol 2016; 172 (02) 219-227
• 24 Makaryan V, Zeidler C, Bolyard AA. , et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol 2015; 22 (01) 3-11
• 25 Dale DC, Welte K. Cyclic and chronic neutropenia. Cancer Treat Res 2011; 157: 97-108
• 26 Olcay L, Ünal Ş, Onay H. , et al. Both granulocytic and non-granulocytic blood cells are affected in patients with severe congenital neutropenia and their non-neutropenic family members: an evaluation of morphology, function and cell death. Turk J Haematol 2018; 35 (04) 229-259
• 27 Donadieu J, Beaupain B, Fenneteau O, Bellanné-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol 2017; 179 (04) 557-574
• 28 Hauck F, Klein C. Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. Curr Opin Allergy Clin Immunol 2013; 13 (06) 596-606
• 29 Tidwell T, Wechsler J, Nayak RC. , et al. Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms. Blood 2014; 123 (04) 562-569
• 30 Vandenberghe P, Beel K. Severe congenital neutropenia, a genetically heterogeneous disease group with an increased risk of AML/MDS. Pediatr Rep 2011; 3 (Suppl. 02) e9
• 31 Keightley MC, Lieschke GJ. Splicing dysfunction and disease: the case of granulopoiesis. Semin Cell Dev Biol 2018; 75: 23-39
• 32 Touw IP. Game of clones: the genomic evolution of severe congenital neutropenia. Hematology (Am Soc Hematol Educ Program) 2015; 2015: 1-7
• 33 Wiesmeier M, Gautam S, Kirschnek S, Häcker G. Characterisation of neutropenia-associated neutrophil elastase mutations in a murine differentiation model in vitro and in vivo. PLoS One 2016; 11 (12) e0168055