Type I Pseudohypoaldosteronism Includes Two Clinically and Genetically Distinct Entities with either Renal or Multiple Target Organ Defects

Abstract

Type I pseudohypoaldosteronism (PHA) is a hereditary disease characterized by salt wasting resulting from target organ unresponsiveness to mineralocorticoids. We have studied two kindreds including a total of nine patients with PHA. In kindred I, the propositus presented with renal salt wasting in infancy (vomiting, failure to thrive, short stature, hyponatremia, hyperkalemia) and responded dramatically to a high salt diet (2.5 g/day). Sodium supplementation was discontinued at the age of two. In seven additional family members from three generations, clinical expression of PHA varied from asymptomatic to moderate. In affected members (propositus, mother, and two brothers), hyperaldosteronism persisted over 13 yr; however, the PRA decreased gradually to near normal values. Persistent hyperaldosteronism in the face of a decrease in PRA indicated the development of tertiary hyperaldosteronism due to autonomously functioning zona glomerulosa. The pedigree was consistent with an autosomal dominant mode of transmission with variable expression. In kindred II, the propositus, who was the product of a consanguineous marriage, developed severe renal salt losing at age 9 days. She had also increased salivary and sweat electrolytes consistent with PHA resulting from multiple organ unresponsiveness to mineralocorticoids. Life threatening episodes of salt wasting recurred beyond the age of 2 yr. At 5 yr of age she still requires high amounts of salt supplements (14 g/day). A sister died at 9 days of age with PHA symptoms. Six close relatives (parents, three siblings, maternal uncle) showed no biochemical abnormalities. This pedigree was consistent with an autosomal recessive mode of inheritance. In view of the findings on these two kindreds and the analysis of those in the literature, we conclude that type I PHA includes two clinically and genetically distinct entities with either renal or multiple target organ defects.

Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1

“…However, this could be a selection bias due to the collaboration among the centers as other groups did not corroborate this (29,30,31). Two of our patients even carried the same mutation.…”

Identification of the roles of conserved charged residues in the extracellular domain of an epithelial sodium channel (ENaC) subunit by alanine mutagenesis

“…This is a severe salt-wasting disease that can lead to neonatal death, if not diagnosed and treated early (12,14). Most of these mutations have been observed in the region coding for the ECD of ENaC.…”

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).…”