Pseudohypoaldosteronism type I (PHA I) is a rare inherited salt-wasting disorder that was first described in 1958 as a defective renal-tubular response to mineralocorticoid in infancy.30 Patients present in the neonatal period with dehydration, hyponatremia, hypokalemia, metabolic acidosis, and failure to thrive despite normal glomerular filtration and normal renal and adrenal function.5 When patients fail to respond to mineralocorticoid therapy, PHA I should be considered the underlying disorder. Diagnosis includes an elevated plasma aldosterone level and increased plasma renin activity. PHA I can be inherited either as a recessive or dominant trait. Neonates affected with PHA I have a primary defect that affects the renal reabsorption of sodium.30a

Further analysis of PHA I has revealed that it can be divided into two distinct disorders with unique physiologic and genetic characteristics—the renal form of PHA I and a multiorgan form of PHA I. The renal form of PHA I follows mendelian inheritance and is transmitted in an autosomal-dominant manner. This disease is limited to a mineralocorticoid resistance only in the kidneys. Interestingly, the patient’s condition spontaneously improves within the first several years of his or her life, thus allowing discontinuation of therapy.

The multiorgan or generalized form of PHA I also follows mendelian inheritance but is transmitted as an autosomal-recessive trait.31 There is a high incidence of consanguinity in the families; the parents of these patients usually have physiologically normal levels of aldosterone and renin.31 The two main characteristics that distinguish this form of PHA I from the renal form are (a) the patient has a multiorgan disorder such that mineralocorticoid resistance is not limited to the kidneys (it can be seen in the kidney, sweat and salivary glands, and the colonic mucosa), and (b) this condition does not spontaneously improve with age31,31a; hence, it is considered to be more severe. Because sodium reabsorption is coupled to potassium and hydrogen ion secretion, patients often exhibit decreased potassium- and hydrogenion secretion with decreased sodium reabsorption; hence, potassium and hydrogen ions accumulate in the body, ultimately causing hyperkalemia and metabolic acidosis. Moreover, a decrease in vascular volume is detected by vessels in the juxtaglomerular region, leading to increased secretion of renin. Elevated plasma renin levels will ultimately cause an increase in aldosterone secretion through the indirect impact of angiotensin II.

Originally, it had been thought that PHA I, analogous to a steroid-hormone resistance syndrome, might result from a defect in the mineralocorticoid receptor, either because of an absence or deficiency of receptors or because of an abnormality in the structure of the receptor (such as, perhaps, a defect in the aldosterone-binding domain). The mineralocorticoid-receptor gene was mapped to chromosome 4 by somatic cell hybridization and regionally localized to 4q31.1-31.2 by fluorescent in situ hybridization. Although evidence supporting a defect in the gene coding for the mineralocorticoid receptor was found in some studies, most studies have been inconsistent.32

Although the involvement of the mineralocorticoid receptor in PHA I was not completely ruled out, it has been hypothesized that PHA I may be a heterogeneous condition resulting from a disorder either at the prereceptor level or at the postreceptor level. At the prereceptor level, there may be some factor that competes for the aldosterone-binding site or causes the cleavage of the mineralocorticoid receptor. At the postreceptor level, it was hypothesized that PHA I might result from a defect
in one or both of the aldosterone-induced proteins: the Na⁺/K⁺-ATPase and/or the ENaC.31,31a