Pseudohypoaldosteronism
In pseudohypoaldosteronism, aldosterone is elevated (hyperaldosteronism), but because the body fails to respond to it, it appears similar to hypoaldosteronism.
Specialty	Nephrology

Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism.^[1] However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback inhibition.^{[citation needed]}

Types

Presentation

PHA2 is clinically characterised by hypertension, hyperkalaemia, metabolic acidosis and normal renal function.^[3]

Mechanism

PHA2 is also known as Gordon's syndrome or familial hyperkalemic hypertension. The underlying genetic defect leads to increased sodium chloride reabsorption in the distal tubule in the kidney, leading to volume expansion, hypertension and lowered renin levels. The hyperkalemia found in PHA2 is proposed to be a function of diminished sodium delivery to the cortical collecting tubule (potassium excretion is mediated by the renal outer medullary potassium channel (ROMK) in which sodium reabsorption plays a role). Alternatively, WNK4 mutations that result in a gain of function of the Na-Cl co-transporter may inhibit ROMK activity resulting in hyperkalemia.^[4] Unlike in PHA1 in which aldosterone resistance is present, in PHA2 the volume expansion leads to relatively low aldosterone levels.^[3]

Treatment

Treatment of severe forms of PHA1 requires relatively large amounts of sodium chloride.^[5] These conditions also involve hyperkalemia.^[6]

In contrast, PHA2 (Gordon's syndrome) requires salt restriction and use of thiazide diuretics to block sodium chloride reabsorption and normalise blood pressure and serum potassium.^{[citation needed]}

History

This syndrome was first described by Cheek and Perry in 1958.^[7] Later pediatric endocrinologist Aaron Hanukoglu reported that there are two independent forms of PHA with different inheritance patterns: A renal form with autosomal dominant inheritance exhibiting salt loss mainly from the kidneys, and a multi-system form with autosomal recessive form exhibiting salt loss from kidney, lung, and sweat and salivary glands.^[8][9]

The hereditary lack of responsiveness to aldosterone could be due to at least two possibilities: 1. A mutation in the mineralocorticoid receptor that binds aldosterone, or 2. A mutation in a gene that is regulated by aldosterone. Linkage analysis on patients with the severe form of PHA excluded the possibility of linkage of the disease with the mineralocorticoid receptor gene region.^[10] Later, the severe form of PHA was discovered to be due to mutations in the genes SCNN1A, SCNN1B, and SCNN1G that code for the epithelial sodium channel subunits, α, β, and γ, respectively.^[11]

A stop mutation in the SCNN1A gene has been shown to be associated with female infertility.^[12]