ESPE Abstracts

Background: PHA1 is a rare inherited disease characterized by resistance to aldosterone action and distinguished in two forms: the autosomal dominant renal form caused by mutations of the NR3C2 gene (MR) and the autosomal recessive systemic form caused by mutations of the subunit genes SCNN1A, SCNN1B, SCNN1G of the epithelial sodium channel (ENaC). The classic phenotype of the autosomal recessive form of PHA1 is usually severe, lifelong, and expressed with multiorgan symptoms, whereas the autosomal dominant form is milder, transient and restricted to the kidneys.

Objective: In this study we describe the clinical and biochemical manifestations and genetic analysis in nine children diagnosed with PHA1, all members of a large consanguineous family.

Patients and methods: Nine patients and their parents were studied. Clinical and biochemical data were analysed. The coding regions of the genes NR3C2 and SCNN1A were bidirectionally sequenced. A structural model of the SCNN1A was constructed based on the protein threading method. In silico analysis was carried out.

Results: Patients were diagnosed between 5 and 60 days of age presenting with failure to thrive or during the course of a respiratory illness, with hyperkalaemia, hyponatremia, elevated renin and aldosterone levels and a positive sweat test. All patients responded well to sodium supplementation with decreasing requirements with age until discontinuation of treatment. All patients were homozygotes, whereas their parents were heterozygotes for the mutation F226C. The in silico analysis of the mutation revealed that it is pathogenic. The structural model constructed revealed that F226 is located at the extracellular domain of the α subunit and possibly affects the formation of the epithelial Na⁺ channel by disrupting its interactions with the β and γ subunits that form it.

Conclusions: We present a large family with a mild and transient form of autosomal recessive PHA1 due to a novel homozygous mutation in the SCNN1A gene.