Pseudohypoaldosteronism: Options for consideration

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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. 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, unlike other steroid hormone resistance syndromes, in PHA the underlying abnormality is not in the MR gene but in an independent gene which contributes to non-receptor processes, either intracellular or extracellular, 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 homeostasis after infancy could be due to the development of non-mineralocorticoid receptor-mediated mechanisms of sodium retention acting independently of aldosterone, to the action of high levels of aldosterone on mineralocorticoid receptors of much reduced affinity, or via glucocorticoid receptor effects in Na+ transporting cells. At the present stage all these possibilities remain speculative, and the underlying pathology of PHA remains to be elucidated.

Original languageEnglish
Pages (from-to)168-172
Number of pages5
Issue number1
Publication statusPublished - 1 Jan 1995
Externally publishedYes


  • aldosterone receptors
  • differential promoter usage
  • mRNA stability
  • salt loss

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