Novel Gene Mutation in a Chinese Boy with Severe Congenital Neutropenia

Excerpt

To the Editor: Severe congenital neutropenia (SCN) is a heterogeneous group of bone marrow failure syndromes caused by different gene mutations [1]. We encountered a 2 y and 9-mo-old boy presenting with 2 wk of fever. He had a past history of recurrent infection every 1–2 mo after 1 y of age, including recurrent upper respiratory infection, mycotic stomatitis, a perianal abscess, and pneumonia. His development was normal and without any congenital malformation suggestive of specific syndromes. His parents and elder sister were all healthy. The parents were not consanguineous. A physical examination revealed pale skin, cervical lymphadenopathy, weakened breathing sounds in the left lung and hepatosplenomegaly. A laboratory examination revealed severe neutropenia [Absolute neutrophil count (ANC) 0.2 × 10⁹/L], mild anemia, increased humoral immunity and normal cellular immunity. Autoantibodies were all negative. A tuberculin skin test was positive. A CT scan revealed a consolidation shadow in the left lower lobe, hilar and mediastinal lymphadenopathy and left pleural effusion (Fig. 1a). Bone marrow aspiration showed maturation arrest at the promyelocyte/myelocyte stage and markedly decreased mature neutrophils. The anti-tubercular treatment was initiated since the administration of broad-spectrum antibiotic was ineffective. The patient’s temperature eventually recovered to a normal level after 25 d of anti-tubercular treatment and the pulmonary lesions returned to normal eventually (Fig. 1b). During treatment, the ANC was always less than 0.5 × 10⁹/L. SCN was suspected and a genetic analysis was undertaken. The exons of ELANE, GFI1, HAX1, G6PC3, WAS, SBDS and their respected flanking regions were amplified by PCR and sequenced by first generation sequencing. A heterozygous mutation located in exon 3 of ELANE (c.290A > C) was found (Fig. 2), which has never been reported in NCBI (dbSNP). Several previous studies have reported series of mutations in ELANE caused by autosomal dominant or sporadic forms [2‐5]. In this patient, we considered the novel variant as putative pathogenic mutation because the clinical characteristic was typical. Since the parents were both healthy, the mutation was more likely caused by sporadic form. However, a deletion of 40 bases in intron 3 of GFI1 (c.298 + 28_68del40) was also found and we could not identify if it can interact with the previous mutation. Developing a functional test to identify the pathogenic mechanisms of novel gene mutation is the aim of our future work on this disease.

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