CONTEXT: Three siblings of Pakistani origin presented neonatally with isolated hyperreninemic hypoaldosteronism and were well controlled on fludrocortisone therapy during childhood and adolescence. OBJECTIVE/ DESIGN: These individuals were reevaluated as adults after fludrocortisone withdrawal to investigate the biochemical and molecular basis of their disorder. RESULTS: When reassessed off fludrocortisone treatment, hyperreninemic hypoaldosteronism was confirmed in all subjects but with significant hyperkalemia in only one case. Profiling of urinary steroid metabolites showed a biochemical pattern (elevated tetrahydrocorticosterone to 18-hydroxytetrahydro-11-dehydrocorticosterone ratio but normal 18-hydroxytetrahydro-11-dehydrocorticosterone to tetrahydroaldosterone ratio) consistent with partial type 1 aldosterone synthase deficiency. Sequencing of the CYP11B2 gene showed that affected subjects were homozygous for a single nucleotide substitution (T925C) in exon 5, corresponding to a serine to proline mutation (S308P) in the predicted protein, with unaffected family members being heterozygous. Consistent with structural modeling showing that the mutated residue is located within the alpha-helix I, close to the hemebinding, active site of the enzyme, functional characterization of the S308P mutant protein in vitro showed complete loss of enzyme activity. However, administration of dexamethasone further reduced levels of circulating aldosterone and its urinary metabolites in affected subjects, suggesting that some mineralocorticoid biosynthesis occurs in vivo. CONCLUSION: We have identified the first CYP11B2 gene defect in a family of Asian origin, associated with a type 1 aldosterone synthase deficiency phenotype. Preservation of some aldosterone production suggests either residual mutant CYP11B2 enzyme activity in vivo or mineralocorticoid biosynthesis via an alternative pathway.
CONTEXT: Three siblings of Pakistani origin presented neonatally with isolated hyperreninemic hypoaldosteronism and were well controlled on fludrocortisone therapy during childhood and adolescence. OBJECTIVE/ DESIGN: These individuals were reevaluated as adults after fludrocortisone withdrawal to investigate the biochemical and molecular basis of their disorder. RESULTS: When reassessed off fludrocortisone treatment, hyperreninemic hypoaldosteronism was confirmed in all subjects but with significant hyperkalemia in only one case. Profiling of urinary steroid metabolites showed a biochemical pattern (elevated tetrahydrocorticosterone to 18-hydroxytetrahydro-11-dehydrocorticosterone ratio but normal 18-hydroxytetrahydro-11-dehydrocorticosterone to tetrahydroaldosterone ratio) consistent with partial type 1 aldosteronesynthase deficiency. Sequencing of the CYP11B2 gene showed that affected subjects were homozygous for a single nucleotide substitution (T925C) in exon 5, corresponding to a serine to proline mutation (S308P) in the predicted protein, with unaffected family members being heterozygous. Consistent with structural modeling showing that the mutated residue is located within the alpha-helix I, close to the hemebinding, active site of the enzyme, functional characterization of the S308P mutant protein in vitro showed complete loss of enzyme activity. However, administration of dexamethasone further reduced levels of circulating aldosterone and its urinary metabolites in affected subjects, suggesting that some mineralocorticoid biosynthesis occurs in vivo. CONCLUSION: We have identified the first CYP11B2 gene defect in a family of Asian origin, associated with a type 1 aldosteronesynthase deficiency phenotype. Preservation of some aldosterone production suggests either residual mutant CYP11B2 enzyme activity in vivo or mineralocorticoid biosynthesis via an alternative pathway.