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: