Endocrine Abstracts

Introduction: Autosomal dominant hypocalcaemia (ADH) is caused by activating mutations of the calcium sensing receptor (CaSR). Symptomatology ranges from asymptomatic hypocalcaemia to paraesthesia, tetani, laringospasm and, seizures. This is the first report of congenital hyperinsulinism (CHI) in a child with ADH.

Case report: A female infant, born at term from non-consanguineous parents, presented on D2 with persistent asymptomatic hypoglycaemia requiring 11 mg/kg/m in glucose. Investigations showed raised insulin and C-peptide, low beta-hydroxybutyrate and NEFA, consistent with CHI. She was started on diazoxide and chlorothiazide by D15. Diazoxide was stopped thrice, unsuccessfully, and she is currently, at the age of 7 months, on a dose of 3.7 mg/kg/day. On D4 she developed tonic-clonic seizures, with hypocalcemia and hypomagnesemia. She had undetectable PTH and high calcium/creatinine ratio, suggestive of ADH. Hypocalcemic seizures were difficult to control with high doses of alpha-calcidol, calcium and magnesium. At 11 weeks of age she was started on treatment with subcutaneous continuous PTH via a Medtronic pump, after which, seizures improved. From early age, she had difficulties in gaining weight, and had polyuria, raised urea and creatinine, hypokalemia and hyperaldosteronism, in line with a Bartter type V and requires potassium supplementation. Sequencing of CASR showed a de novo mutation c.2528C>A(Ala843Glu) previously described in ADH with Bartter Syndrome. Functional studies show constitutively active CaSR. No mutations in genes on the extended CHI panel were found.

Conclusions: c.2528C>A(Ala843Glu) CaSR leads to severe ADH1 and can cause Bartter Syndrome typeV, likely due to the effect of constitutively active CaSR on the Na:K:2Clco-transporter and ROMK in thick ascending limb of Henle’s loop. No link between hyperinsulinism and ADH has been previously described. CaSR^Nuf/Nuf mice that harbor an activating CaSR show hyperglycemia due to impaired b-cell function and higher number of a-cells. We hypothesized that, like in other forms of CHI, the active CaSR interferes with regulation of insulin secretion at young age, resulting in CHI, and at later age, results in beta cell defects. Further work is required to understand the relation between CaSR, potassium transport and beta cell function in ADH.