Endocrine Abstracts

Bartter’s syndrome (BS) and Gitelman’s syndrome (GS) are renal tubular disorders affecting reabsorption of sodium, potassium and chloride. Common clinical features include muscle cramps and weakness, hypokalaemia, hypochloraemic metabolic alkalosis and elevated plasma aldosterone concentrations. Urinary calcium excretion and plasma magnesium concentrations may be differentiating features, such that hypomagnesaemia and hypocalciuria are typical of GS, and hypercalciuria is typical for BS. GS is due to SLC12A3 mutations, whereas BS may be due to mutations involving one of six genes (SLC12A1, KCNJ1, CLCNKA, CLCNKB, BSND and CASR). Here, we report the utility of DNA sequence analysis using whole genome sequencing (WGS), for establishing the correct diagnosis in a patient who had features of BS and GS. The patient presented aged 10-years in 1959 with periodic tetany precipitated by vomiting or diarrhoea. Trousseau’s and Chvosteks’ signs were present. Serum biochemistry revealed her to have a hypokalaemia with a hypochloraemic metabolic alkalosis, in association with hyponatraemia, hypercalcaemia, and normomagnesaemia. However, she was subsequently found to have hypocalciuria and hypomagnesaemia. A renal biopsy did not reveal evidence for juxta-glomerular hyperplasia. Plasma renin and aldosterone concentrations were not elevated, and in 2003 she developed chronic kidney failure. In 2014 ocular schlerochoroidal calcification was identified which has previously been associated with both BS and GS. The clinical features in this patient overlapped with those of GS and BS, and to enable a parallel assessment of all of the 7 known causative genes, we undertook WGS, instead of Sanger DNA sequencing, after obtaining informed consent. This identified a homozygous c.226C>T variant in CLCNKB resulting in a nonsense mutation pArg76Ter, which has previously been reported in BS type-3 (Nozu et al. 2010 JCEM). Thus, our results, which demonstrate the importance of WGS in diagnosing disorders with overlapping phenotypes, reveal the patient has BS type-3.