Aldosterone-receptor deficiency in pseudohypoaldosteronism

Pseudohypoaldosteronism, a syndrome characterized by salt wasting and failure to thrive, usually presents in infancy as high urinary levels of sodium despite hyponatremia, hyperkalemia, hyperreninemia, and elevated aldosterone levels. We have investigated this syndrome for the possibility of abnormal Type I or "mineralocorticoid-like" receptors, which have intrinsic steroid specificity indistinguishable from that of renal mineralocorticoid receptors and are found in many tissues and cells, including mononuclear leukocytes. We have studied three patients with pseudohypoaldosteronism: the 28-year-old index case in Melbourne (Patient 1) and two siblings in Munich, eight and two years of age (Patients 2 and 3); clinically, Patient 3 had a less severe case than his sister. Percoll-separated control monocytes bound [3H]aldosterone with high affinity (Kd approximately 3 nM) and limited capacity (150 to 600 sites per cell). On repeated examination, no [3H]aldosterone binding was found in monocytes from Patients 1 and 2; in Patient 3, the levels were 62 sites per cell, more than 2 S.D. below those of the control. Levels in the parents of the Munich patients (first cousins) were normal. It appears that pseudohypoaldosteronism is caused by a Type I receptor defect, that the defect may be complete or partial, that transmission may be autosomal recessive, and that the study of patients with pseudohypoaldosteronism may indicate physiologic roles for Type I receptors in nonepithelial tissues.