Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) caused by a gain-of-function mutation in the vasopressin V2 receptor gene

NSIAD is an X-linked disorder of water/electrolyte balance caused by an AVPR2 gain-of-function mutation that leads to constitutive activation of the encoded vasopressin V2 receptor. Defective urine dilution results in eu-/hypervolemic hyponatremia, resembling SIADH. We report a turkish family with NSIAD. Index case was a 6 months old girl hospitalised for obstructive bronchitis. Initial serum natrium was 131 mmol/l, after fluid infusion it declined to 126 mmol/l. High amounts of NaCl (about 9 mmol/kg) had to be continuously substituted. Her low serum osmolarity (273 mosmol/l) was in contrast to high urine osmolarity (424 mosmol/l). After discharge, NaCl substitution was continued, a salt wasting tubulopathy was supposed. This was in contrast to euvolemic hydration status. The girl´s father had a hyponatremic seizure in infancy; Hyponatremia recently re-occurred during surgery, but otherwise he gets along by drinking very little. The father’s brother also experienced recurrent hyponatremia, first observed at the age of 7 months. At 13 years of age, he was hospitalised with recurrent episodes of hyponatremia (120 mmol/l). We suspected NSIAD in this family, sequenced the AVPR2 gene, and were able to identify the heterozygous missense mutation c.409C>T (p.R137C) in the proposita, subsequently shown to segregate with the phenotype in her father and uncle. This mutation has already been described in the literature as gain-of-function mutation. The patient’s sister also carries the mutation, but is clinically fine most likely due to favourable X-inactivation of the mutant allele, recently corroborated by an unremarkable water loading test performed in her. Given that patients benefit from fluid restriction and osmotic diuresis with orally taken urea, an early diagnosis is helpful to protect them from episodes of severe hyponatremia. In conclusion, NSIAD should be considered in patients with recurrent or persistent eu- or hypervolemic hyponatremia and can be easily confirmed by sequencing of the small AVPR2 gene.

AVPR2 gain of function mutation - NSIAD - nephrogenic syndrome of inapproriate antidiuresis