Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype

Abstract

BackgroundSevere congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2.MethodsWe report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature.ResultsThe siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood.ConclusionsThis family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

Identification of two novel mutations in the SLC45A2 gene in a Hungarian pedigree affected by unusual OCA type 4

“…This hypothesis is further supported by the literature, since a previous study reporting a sister and a brother affected by congenital neutropenia and oculocutaneous albinism identified a nonsense mutation in the G6PC3 gene (c.829C > T, p.Gln277*) responsible for the development of congenital neutropenia and frameshift mutation in the SLC45A2 gene (c.986delC, p.T329Rfs*68), which could explain the OCA phenotype [10]. In this previous study, the investigated brother is also affected by Chron’s disease, suggesting a putative association between the mutations of the SLC45A2 gene and Chron’s disease [10]. …”

Resolution of Inflammatory Colitis With Pegfilgrastim Treatment in a Case of Severe Congenital Neutropenia Due to Glucose 6 Phosphatase Catalytic Subunit-3 Deficiency

“…Moreover, a few of them underwent hemicolectomy due to uncontrollable IBD before diagnosis of G6PC3 mutation. 10,13,14 As presented in our case, persistent diarrhea, abdominal pain, and malnutrition in association with elevated a 1 -AT levels are strong predictors of IBD. [10][11][12][13][14]19 Although elevated fecal calprotectin is a better noninvasive marker used to monitor disease activity in patients with IBD, examining fecal a1-AT level is a widely available laboratory test that can also be used for this purpose.…”

“…Most of the patients with IBD were adolescents or adults with late onset SCN and had the syndromic variant of G6PC3 mutation (Table 1). [10][11][12][13][14] To the best of our knowledge, this is the first case of IBD reported in a child with G6PC3 deficiency. This case differs from the previously reported cases in terms of earlier diagnosis of SCN, the apparently nonsyndromic variant of G6PC3 deficiency, and childhood onset of IBD.…”

“…3 However, it has rarely been described in association with G6PC3 mutation. [10][11][12][13][14] The pathogenesis of IBD in GSD-Ib is thought to be intestinal damage caused by chronic lowgrade infection and inflammation secondary to neutropenia and/or neutrophils dysfunction. 12,15,16 In addition, T-lymphocyte defect might be a potential contributory factor to the development of IBD in patients with G6PC3 deficiency.…”

“…[4][5][6][7][8][9] The age of onset and spectrum of clinical manifestations are highly variable among previously reported patients. 4,5,10 Inflammatory colitis resembling ulcerative colitis or the Crohn disease occur frequently in GSD-Ib, but it has rarely been reported in SCN due to G6PC3 mutation. [10][11][12][13][14] In this study, we describe a case of a 12-year-old girl with G6PC3 mutation complicated with severe IBD, unresponsive to filgrastim but treated successfully with pegylated filgrastim (pegfilgrastim).…”