Pseudohypoaldosteronism (PHA), characterized by congenital resistance to
aldosterone and excessive
salt loss, has been traditionally treated with
salt replacement. Although the
mineralocorticoid receptor (MR) has been suggested as a potential locus of the defect in this disease, no such abnormality has been identified as yet. We studied a 17-yr-old male patient with congenital multifocal target organ resistance to
aldosterone. Both
carbenoxolone, an
11 beta-hydroxysteroid dehydrogenase inhibitor, and a high dose of
fludrocortisone normalized the patient's serum
electrolyte concentrations and decreased his urinary excretion of
sodium, suggesting that this patient's resistance was partial and could be overcome by high concentrations of endogenous or exogenous
mineralocorticoids. We hypothesized that the beneficial effect of these treatments was mostly mediated by the MR, because the administration of
dexamethasone, while this patient was receiving a therapeutic dose of
carbenoxolone, caused its reversal. These findings convinced us that there was functional, albeit possibly defective, MR in this patient and led us to perform molecular studies. Both alleles of the MR gene were expressed in the patient and his clinically and biochemically normal father. A conservative heterozygous mutation (A760-->G760, Ileu180-->Val180) and a nonconservative homozygous mutation (C944-->T944, Ala241-->Val241) were identified in the
complementary DNA of both the patient and his father. The first untranslated exon and 0.9 kilobase of the 5'-regulatory region were also identical in the two men. It appears that the mutations causing amino acid substitutions represent polymorphisms, as we found high frequencies of both in the general population. We conclude that
carbenoxolone and
fludrocortisone may help define the presence of functional MR in patients with PHA and that the former could be used in the long term
therapy of this disease. We hypothesize that the defect causing PHA in this patient might be in a post-MR step of
aldosterone action.