Endocrine Abstracts (2008) 17 OC2

Persistent AVP production and hyponatraemia in a male infant with an activating mutation of the AVPR2 and his heterozygous mother: new insights into NSAID

S Gupta1, T Cheetham2, H Lambert1, C Roberts3, D Bourn3, M Coulthard1 & S Ball2


1Royal Victoria Infirmary, Newcastle Upon Tyne, UK; 2University of Newcastle, Newcastle Upon Tyne, UK; 3Centre for Human Genetics, Newcastle Upon Tyne, UK.


Introduction: The Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked condition characterised by reduced renal water clearance and hyponatraemia resulting from gain of function mutations in the type 2 Vasopressin (AVP) receptor (AVPR2). Female carriers were thought not to express a phenotype. We describe a kindred with NSIAD, highlighting molecular and physiological characteristics that extend understanding of this condition and of AVP production.

Methods: The male index case presented with seizures and persistent hyponatraemia (120 mmol/l) at 6 months of age. Subsequent screening confirmed persistent hyponatraemia in his mother (128 mmol/l). Exon 8 of the AVPR2 gene was amplified from genomic DNA and sequenced by standard methods. Plasma AVP was measured by in-house radio-immunoassay: lower limit of detection 0.3 pmol/l with inter-assay CV 5–7%. Mother and child were investigated by water load test with parallel assessment of plasma osmolality and AVP production. Mother also underwent a hypertonic saline test to assess thirst and AVP regulation over the physiological range.

Results: The index case was hemizygote for the activating c.409C>T (p.R137C) AVPR2 mutation. His mother was heterozygote mutant/wild type for the same mutation. Both demonstrated impaired free water clearance on water load testing (47% and 19% at 4h for mother and child respectively). AVP was detectable throughout, (0.7 to 1.0 pmol/l in the child and 0.4 to 1.5 pmol/l in mother). Thirst assessment in mother indicated an increased thirst component at lower plasma osmolalities when compared to the norm. She had, nevertheless, learnt to avoid excess fluid consumption because of associated malaise.

Conclusions: We conclude that female carriers of activating mutations of the V2R are susceptible to hyponatraemia and therefore need to be provided with advice regarding fluid requirement. The presence of measurable amounts of AVP in patients with hyponatraemia does not exclude the diagnosis of NSIAD and points towards on-going non-osmoregulated AVP production in these patients.

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