Case history: A 38-year-old man was referred with a 12-month history of recurrent bouts of transient hyponatraemia (serum sodium ranging from 115 to 125 mmol/l). Citalopram, which he was taking for depression, was discontinued, but the episodes continued.
Initial investigations: Whilst symptomatic, and clinically euvolaemic, his biochemical profile was consistent with a syndrome of inappropriate antidiuresis (SIAD): sodium 124 mmol/l, potassium 4.5 mmol/l, glucose 6 mmol/l, urea 4.7 mmol/l, creatinine 76 μmol/l, serum osmolality 268 mOsm/kg, urine osmolality 652 mOsm/kg, and urine sodium 154 mmol/l. A contemporaneous anterior pituitary profile, including short Synacthen test, was normal, as were urinary porphobilinogens. Head, chest, and abdominal CT were unremarkable.
Laboratory studies: A water load test was arranged: after 4 h he had excreted just 15% of a 20 ml/kg oral load (normal range 7882%) and his serum sodium fell from a baseline of 134 mmol/l to a nadir of 125 mmol/l (serum osmolality 266 mOsm/kg and urine 808 mOsm/kg), consistent with inappropriate antidiuresis. Despite this, his AVP levels were profoundly low (0.40.9 pmol/l) throughout the test, indicating a nephrogenic syndrome of inappropriate antidiuresis. Sanger sequencing of AVPR2 revealed a missense mutation (X-linked) in a highly conserved arginine residue in the second intracellular loop (R137C). The mutant receptor exhibits constitutive activity when compared with its WT counterpart in transient transfection assays.
Discussion: Confirmed cases with activating mutations in AVPR2 causing nephrogenic SIAD are rare, with only sixteen cases reported worldwide since the syndrome was first described in 2005. However, this disorder may be underdiagnosed, based on historical reports of AVP levels in unexplained hyponatraemia. The ability to find a definitive cause in this case has provided validation to our patient, given a rational for preventative management with fluid restriction, and allows the potential for family screening.