Three siblings of Pakistani origin presented shortly after birth with failure to thrive and hyperkalemia and were found to have isolated hyperreninaemic hypoaldosteronism. They were all well controlled on fludrocortisone therapy during childhood and adolescence. When reassessed in adult life off fludrocortisone treatment, hyperreninaemic hypoaldosteronism was confirmed in all subjects, but with significant hyperkalemia in only one case. None of the subjects developed orthostatic hypotension or salt craving. Profiling of urinary steroid metabolites showed a biochemical pattern (elevated Tetrahydrocorticosterone/18-OH tetrahydro-11-dehydrocorticosterone (THB/18-OH THA) ratio but normal 18-OH tetrahydro-11-dehydrocorticosterone/tetrahydroaldosterone (18-OH-THA/THaldo) ratio consistent with partial type 1 aldosterone synthase deficiency (ASD1). The CYP11B2 gene was sequenced and affected subjects were homozygous for a single nucleotide substitution (C925T) in exon 5, corresponding to a Serine to Proline mutation (S308P) in the predicted protein sequence. Two unaffected siblings and both parents were heterozygous for the mutation. Structural modelling indicates that the S308P mutation, located within the I alpha helix, is close to the haem binding and active site of the enzyme and therefore likely to be deleterious. We have identified the first CYP11B2 gene defect in patients of Asian origin in association with an ASD1 phenotype. Functional characterisation of the S308P mutant will determine the extent of loss of enzyme activity and its relationship to defective aldosterone biosynthesis in vivo.
01 - 05 Apr 2006
European Society of Endocrinology