Autosomal recessive pseudohypoaldosteronism type I is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Laboratory evaluation shows ... Autosomal recessive pseudohypoaldosteronism type I is characterized by renal salt wasting and high concentrations of sodium in sweat, stool, and saliva. The disorder involves multiple organ systems and is especially threatening in the neonatal period. Laboratory evaluation shows hyponatremia, hyperkalemia, and increased plasma renin activity with high serum aldosterone concentrations. Respiratory tract infections are common in affected children and may be mistaken for cystic fibrosis (CF; 219700). Aggressive salt replacement and control of hyperkalemia results in survival, and the disorder appears to become less severe with age (review by Scheinman et al., 1999). A milder, autosomal dominant form of type I pseudohypoaldosteronism (PHA1A; 177735) is caused by mutations in the mineralocorticoid receptor gene (MCR, NR3C2; 600983). Gitelman syndrome (263800), another example of primary renal tubular salt wasting, is due to mutation in the thiazide-sensitive sodium-chloride cotransporter (SLC12A3; 600968).
Cheek and Perry (1958) first described pseudohypoaldosteronism in infancy due to a renal tubular defect; other reports soon followed by Donnell et al. (1959) and Raine and Roy (1962).
Pseudohypoaldosteronism is characterized by salt wasting in ... Cheek and Perry (1958) first described pseudohypoaldosteronism in infancy due to a renal tubular defect; other reports soon followed by Donnell et al. (1959) and Raine and Roy (1962). Pseudohypoaldosteronism is characterized by salt wasting in infancy that is responsive to supplementary sodium but not to mineralocorticoids. Marked aldosterone excess is present in all reported cases and the renin level is increased in most. Sweat and salivary glands, the distal renal tubule, and colonic mucosa are unresponsive to mineralocorticoids (Oberfield et al., 1979; Rosler, 1984; Speiser et al., 1986). Barakat et al. (1974) described American black sister and brother with hyponatremia, hyperkalemia, and normal excretion of 17-ketosteroids. Increased urinary excretion of aldosterone was documented in the girl. She differed from other reported cases of pseudohypoaldosteronism in having persistent hyperkalemia and acidemia which failed to respond to sodium chloride replacement. A defect in cell membrane transport was postulated. The girl was brought to hospital at age 6 days because of vomiting and refusal to feed. She died on the 28th hospital day. Two years later, the boy, then aged 1 week, was admitted and died after only a few hours despite intensive therapy. The patients resembled those described by Shackleton et al. (1973). Bosson et al. (1986) described 2 offspring of a first-cousin marriage who presented with severe salt wasting. Generalized pseudohypoaldosteronism was diagnosed on the basis of markedly elevated sodium concentration in urine, sweat, saliva, and stool, hyponatremia, and hyperkalemia in the presence of increased plasma aldosterone, increased plasma renin activity, and increased urinary aldosterone. Both parents, investigated under basal conditions and under sodium restricted diet, appeared to be normal. Hanukoglu (1991) reported 2 sibs, born of consanguineous parents, with severe PHA type I. The proband developed severe renal salt wasting 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 years; at 5 years, she still required high amounts of salt supplements. A sister died at 9 days of age with PHA symptoms. Six close relatives, including parents, 3 sibs, and a maternal uncle, showed no biochemical abnormalities. Hanukoglu et al. (1994) pointed out the simulation of cystic fibrosis in patients with type I PHA. In 4 patients with the disorder in severe form, they observed recurring lower respiratory tract infections and persistently elevated sweat and saliva electrolyte values. They suggested that increased saliva electrolyte values affect normal mucociliary function in the respiratory tract and facilitate the occurrence of frequent lower respiratory tract involvement. Chang et al. (1996) reported 5 unrelated consanguineous families with autosomal recessive PHA type I. One of the families had been reported by Hanukoglu (1991). Most affected individuals were diagnosed in the neonatal period, and all had severe dehydration, hypotension, hyponatremia, hyperkalemia, and metabolic acidosis, despite a normal glomerular filtration rate. Plasma renin activity and aldosterone levels were markedly elevated. Several had affected sibs who died in the first days of life. Dietary sodium supplementation resulted in clinical improvement; none of these patients showed amelioration of the dependence on supplemental dietary salt.
In 5 families with PHA type I, Chang et al. (1996) identified homozygous mutations in either the SCNN1A gene (600228.0001-600228.0002) or the SCNN1B gene (600760.0003). These mutations cosegregated with the disease, and introduced frameshift, premature termination, or missense ... In 5 families with PHA type I, Chang et al. (1996) identified homozygous mutations in either the SCNN1A gene (600228.0001-600228.0002) or the SCNN1B gene (600760.0003). These mutations cosegregated with the disease, and introduced frameshift, premature termination, or missense mutations that resulted in loss of channel activity. Since the epithelial sodium channel plays a major role in the removal of salt and water from the alveolar space in lung, it was of note that some PHA I patients had recurrent respiratory problems. Chang et al. (1996) studied these genes because mutations resulting in constitutive activation of ENaC activity were demonstrated to cause Liddle syndrome (177200), an autosomal dominant form of hypertension characterized by volume expansion, hypokalemia, and alkalosis. This finding in pseudoaldosteronism raised the possibility that mutations causing loss of function of ENaC activity could cause the converse phenotype of volume depletion, hyperkalemia, and acidosis characteristic of patients with PHA I. Strautnieks et al. (1996) showed that a homozygous splice site mutation of the SCNN1G gene (600761.0002) can cause PHA1B. Arai et al. (1999) studied the SCNN1A, SCNN1B, and SCNN1G cDNAs in 5 sporadic cases of PHA, all of whom had nonconservative homozygous and/or conservative heterozygous substitutions in their mineralocorticoid receptor (MCR; 600983) cDNAs that were also present at high frequencies in a control population with apparently normal salt conservation. The authors identified a nonconservative substitution (thr663 to ala) in the SCNN1A cDNAs of all 5 patients (2 were homozygous, and 3 were heterozygous) that was also present in the homozygous and heterozygous form in 31% and 64% of control subjects, respectively; they concluded that this substitution is a polymorphism. Arai et al. (1999) also identified a nonconservative homozygous substitution in the SCNN1B cDNAs and 3 nonconservative and conservative homozygous substitutions in the SCNN1G cDNAs of all patients and control subjects examined. They hypothesized that these polymorphisms might influence salt conservation negatively if they are present concurrently with other genetic defects of the MCR gene or other proteins that participate in sodium homeostasis. The latter would be compatible with a sporadic presentation and digenic or multigenic expression and heredity in PHA.