Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3

Abstract

Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive condition, which was defined recently with identification of the causative mutations in G6PC3. To date there are only three reports in the literature describing patients with SCN4 with mutations in the G6PC3 gene. We report four individuals with SCN4 who belong to a single large consanguineous kindred. We provide an overview of the non-haematological features of the condition with a focus on the adult phenotype, which has not been previously described in detail. We show that the superficial venous changes seen in SCN4 patients can develop into varicose veins and venous ulcers in adulthood. We review the range of congenital anomalies associated with SCN4. We demonstrate that secundum atrial septal defect, patent ductus arteriosus and valvular defects are the most frequent cardiac anomalies in SCN4. Drawing parallels with type 1 glycogen storage disease, we propose that poor growth of prenatal onset, mild-to-moderate learning disability, primary pulmonary hypertension, delayed or incomplete puberty, hypothyroidism and dysmorphism likely represent features of this syndrome. We also suggest monitoring for lipid anomalies, and kidney and liver function in affected patients. Delineation of the SCN4 phenotype may help in appropriate treatment and management and provide further insights into the pathogenesis of this multisystem disease.

Survival and differentiation defects contribute to neutropenia in glucose-6-phosphatase-β (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation

“…9 Mutations in G6PC3 in humans cause SCN [10][11][12] and additional problems in various organ systems. 1,13 Peripheral blood neutrophils isolated from patients with G6PC3 deficiency showed increased apoptosis in vitro and fibroblasts derived from these patients underwent increased apoptosis upon treatment with dithiothreitol. 10 Mice genetically deficient in G6PC3 display neutropenia, and neutrophils isolated from these mice show a defect in oxidative burst, calcium flux and chemotaxis toward fMLP, KC and MIP-2.…”

Testicular failure in a patient with G6PC3 deficiency

“…Cryptorchidism, micropenis, and ambiguous genitalia, as detected in our patient, are common features in patients with G6PC3 mutations, documented in up to 44% of patients, and were considered as structural urogenital abnormalities (2,11,16,17). These findings on physical examination are usually the result of either undervirilization in a male or overvirilization in a female.…”

“…To note, G6PC3 -/-mice exhibit significant reduction in g6p hydrolytic activity in the testes, although without any known phenotypic consequence (16). Our findings may lead to further assessment of older subjects previously described with this mutation, with regard to hormonal profile, and offer an insight into the role this enzyme plays in sexual differentiation.…”

“…Previous studies of adult patients with G6PC3 deficiency reported males with clinical hypogonadism, which included delayed puberty and gynecomastia. In contrast, females had a slight delay of puberty with normal menarche and menses, which continued during adult life (11,16). No endocrine work-up was reported to have been carried out, and the mechanism of pubertal delay was not explained.…”

Cardiovascular abnormalities in primary immunodeficiency diseases

“…Prominent superficial venous pattern, myopathy, increased skin laxity, congenital hydronephrosis, and thrombocytopenia, which might be intermittent, are observed in some patients (Boztug et al 2009;Banka et al 2011).…”