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Renal pseudohypoaldosteronism type 1

Orpha number ORPHA171871
Synonym(s) Autosomal dominant pseudohypoaldosteronism type 1
Prevalence <1 / 1 000 000
Inheritance Autosomal dominant
Not applicable
Age of onset Infancy
Neonatal
ICD-10
  • N25.8
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT -

Summary

Renal pseudohypoaldosteronism type 1 (renal PHA1) is a mild form of primary mineralocorticoid resistance restricted to the kidney. Prevalence is unknown. Clinical expression of renal PHA1 is variable: in general, patients present with a salt wasting syndrome in the neonatal period, with weight loss, failure to thrive, vomiting and dehydration. Occasionally, polyhydramnios has been noted. Symptoms of renal PHA1 usually improve in early childhood and older children are generally asymptomatic with normal growth and psychomotor development. Renal PHA1 results from a defect in the tubular response to aldosterone caused by inactivating mutations in the NR3C2 gene (4q31) encoding the mineralocorticoid receptor. Both familial cases with autosomal dominant transmission and sporadic cases have been reported and heterozygous NR3C2 mutations have been identified at a high frequency in both cases. Among sporadic cases, only one third of patients carry de novo mutations, suggesting that carriers develop clinically evident disease in only a small proportion of kindreds. Diagnosis is based on the disease history and clinical examination, family history, detection of NR3C2 mutations, and biological findings (hyponatremia, hyperkalemia and inappropriately high urinary sodium excretion, low urinary potassium excretion with reduced fractional potassium excretion and transtubular potassium gradient, and, occasionally, hypercalciuria). The diagnosis is confirmed by the presence of high plasma and urinary aldosterone levels and high plasma renin levels. High plasma aldosterone levels persist into adulthood, while plasma renin activity decreases with age to within the normal range. Differential diagnoses include generalized PHA1, congenital adrenal hyperplasia (CAH) associated with 21-hydroxylase deficiency or 3-beta-hydroxysteroid dehydrogenase deficiency, hypoaldosteronism (HA) due to aldosterone deficiency, antenatal or infantile Bartter syndrome (in particular, type 2 Bartter syndrome caused by ROMK mutations) and transient PHA (see these terms). Although antenatal diagnosis is not necessary for renal PHA1, neonatal genetic analysis of cord blood may allow rapid diagnosis and management of affected offspring from PHA1 families with identified mutations. Treatment consists of salt and fluid replacement, as well as correction of hyperkalemia and acidosis in the acute phase of the disease. As CAH and HA due to aldosterone deficiency are the major differential diagnoses, fludrocortisone and hydrocortisone replacement therapy may be initiated while confirming the diagnosis by hormonal measurements. Ion exchange resins are also often administered to normalize potassium levels. The prognosis for patients is good: salt supplementation is usually followed by rapid clinical and biochemical improvement. As renal PHA1 improves with age, treatment can be discontinued at around 18-24 months in the majority of patients.

Expert reviewer(s)

  • Dr Maria-Christina ZENNARO

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