Pseudohypoaldosteronism in Eight Families: Different Forms of Inheritance Are Evidence for Various Genetic Defects

Abstract

Pseudohypoaldosteronism is a rare hereditary disorder presenting in early infancy with renal salt loss leading to hyponatremia and hyperkalemia despite high levels of plasma aldosterone. The patients are insensitive to mineralocorticoids; however, sodium supplementation is able to correct electrolyte abnormalities. Absent or greatly diminished type I aldosterone receptors in peripheral mononuclear leucocytes have been recently demonstrated and explain the lack of response to mineralocorticoids. We have studied the mode of inheritance in eight families with a total of nine patients. There was evidence for an autosomal recessive form of inheritance in four families, while the other four families appeared to have an autosomal dominant mode of transmission. In three families the autosomal recessive form was characterized by normal receptor as well as hormone data in both parents, while in one family receptor levels in both parents were greatly reduced, but hormone levels were normal. In the four families with an autosomal dominant mode of transmission there was always one parent with reduced receptor binding in peripheral mononuclear leucocytes and elevated serum hormone levels. These parents were entirely asymptomatic. In an extended family we were able to study an aunt and her newborn daughter, who were both also biochemically affected but clinically asymptomatic. It, therefore, appears that this dual pattern of genetic transmission may indicate differing genetic defects which cause the same clinical picture of pseudohypoaldosteronism.

Clinical and Molecular Features of Type 1 Pseudohypoaldosteronism

“…Medical treatment consists of sodium supplementation what is usually sufficient to lower the elevated potassium levels. Sodium supplementation becomes generally unnecessary by 1–3 years of age [39, 42], what is explained by the maturation of the renal salt conservation abilities by the replacement of distal sodium reabsorption through proximal parts of the tubulus. Overall adPHA1 is the milder PHA1 form as the salt loss is strictly restricted to the kidney.…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations

“…Older children are generally clinically asymptomatic. Nevertheless, a recent case-control study investigating 39 adult patients with renal PHA1 carriers of NR3C2 mutations showed that they show lifelong increased plasma renin and aldosterone levels as well as increased salt appetite, with normal blood pressure and potassium levels (Escoubet et al 2013), confirming evidence from earlier case reports suggesting persistence of hormonal abnormalities in adulthood (Kuhnle et al 1990, Zennaro et al 1992, Geller et al 2006. Remarkably, high aldosterone levels and salt intake in the context of low MR activity are not associated with adverse cardiovascular outcome in these patients, but rather with improved diastolic left ventricular function (Escoubet et al 2013).…”

“…The disease presents as a salt-wasting syndrome in the neonatal period, with weight loss, failure to thrive, vomiting and dehydration, associated with hyperkalemia and metabolic acidosis, despite extremely elevated levels of plasma renin and aldosterone (Zennaro et al 2012). Seminal work by Armanini and coworkers and Kuhnle and coworkers has characterized the clinical and pathogenic mechanisms of PHA1 and paved the way to the discovery of the underlying genetic abnormalities, showing abnormalities of aldosterone binding on mononuclear leukocytes from patients with PHA1 and different transmission of the hormonal and binding defects (Armanini et al 1985, Kuhnle et al 1990). These results were further confirmed by clinical studies describing the existence of two distinct clinical and genetic entities associated with different severity and evolution: a renal form, in which signs of mineralocorticoid resistance are restricted to the kidney and a generalized form, where systemic mineralocorticoid resistance in the kidney, but also in the colon, salivary and sweat glands and the lungs, leads to severe salt loss from multiple organs (Hanukoglu 1991).…”

Resistência aos mineralocorticóides: pseudo-hipoaldosteronismo tipo 1

“…No PHA1 existe um defeito no transporte de sódio no néfron distal, secundário a uma resistência à ação dos mineralocorticóides. Existem duas formas de PHA1, a forma sistêmica, com padrão de herança autossômico recessivo, e a forma restrita aos rins, com padrão de herança autossômico dominante (28)(29)(30)(31).…”