Pseudohypoaldosteronism: options for consideration

Pseudohypoaldosteronism (PHA), or mineralocorticoid resistance, displays several features which distinguish it from other steroid resistance syndromes: while at presentation the clinical manifestations may be severe, patients almost invariably survive into adulthood without ill effects in the absence of ongoing treatment; patterns of inheritance are very variable; and, in addition to the more common primary form, it may develop secondary to a variety of conditions. Although the clinical presentation and the finding of absent or greatly diminished binding of aldosterone by peripheral blood leukocytes strongly suggest an underlying abnormality involving the mineralocorticoid receptor (MR), no abnormality in the MR has been identified, unlike other forms of resistance to hormones in the steroid superfamily, in which the underlying abnormality has been traced to a defect in the gene encoding the receptor 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 normal, 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 about the underlying mechanism for PHA and the mechanisms by which homeostasis is achieved in the absence of effective aldosterone action. With respect to the mechanism(s) of PHA, several possibilities can be envisaged. It is possible, albeit unlikely, that by unfortunate chance small mutations have been missed as a result of cloning only normal alleles in heterozygous patients.(ABSTRACT TRUNCATED AT 250 WORDS)