PSEUDOHYPOALDOSTERONISM - OPTIONS FOR CONSIDERATION

Pseudohypoaldosteronism (PHA), or mineralocorticoid resistance, displa ys several features which distinguish it from other steroid resistance syndromes: while at presentation the clinical manifestations may be s evere, patients almost invariably survive into adulthood without ill e ffects in the absence of ongoing treatment; patterns of inheritance ar e very variable; and, in addition to the more common primary form, it may develop secondary to a variety of conditions. Although the clinica l presentation and the finding of absent or greatly diminished binding of aldosterone by peripheral blood leukocytes strongly suggest an und erlying abnormality involving the mineralocorticoid receptor (MR), no abnormality in the MR has been identified, unlike other forms of resis tance to hormones in the steroid superfamily, in which the underlying abnormality has been traced to a defect in the gene encoding the recep tor protein. Molecular studies of the index case have excluded a major cytogenetic abnormality and major deletions or rearrangements of the MR gene. They have also shown that the cDNA sequence corresponding to the open reading frame of the mineralocorticoid receptor molecule is n ormal, compared with the published human MR cDNA sequence, and that MR mRNA is expressed in apparently normal quantities in peripheral blood mononuclear leukocytes. These findings raise a number of questions ab out the underlying mechanism for PHA and the mechanisms by which homeo stasis is achieved in the absence of effective aldosterone action. Wit h respect to the mechanism(s) of PHA, several possibilities can be env isaged. lt is possible, albeit unlikely, that by unfortunate chance sm all mutations have been missed as a result of cloning only normal alle les in heterozygous patients. It is possible that the abnormality lies in the promoter region of the molecule, leading to disordered tissue- specific expression of the receptor protein, or in the 3'-untranslated region, leading to instability of MR mRNA. It is conceivable that, un like other steroid hormone resistance syndromes, in PHA the underlying abnormality is not in the MR gene but in an independent gene which co ntributes to non-receptor processes, either intracellular or extracell ular, which interfere with the ability of the receptor to bind hormone , perhaps through a (yet to be identified) cofactor which is specific for the binding of the MR molecule to aldosterone. Normal sodium homeo stasis after infancy could be due to the development of non-mineraloco rticoid receptor-mediated mechanisms of sodium retention acting indepe ndently of aldosterone, to the action of high levels of aldosterone on mineralocorticoid receptors of much reduced affinity, or via glucocor ticoid receptor effects in Na+ transporting cells. At the present stag e all these possibilities remain speculative, and the underlying patho logy of PHA remains to be elucidated.