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.

Figure 1

Pedigrees of one large and one small nuclear family are represented. Both the families belong to a single kindred although the exact relationship between them is not certain.

Figure 2

(a, b) Front and profile of patient 2 showing full cheeks (similar to what is seen in GSD1), prominent lips and low hairlines.

Figure 3

(a) Homozygous mutation c.758G>A in exon 6 of G6PC3 of patient 1. (b) Corresponding normal sequence from a control subject.