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Bone Abstracts (2019) 7 P122 | DOI: 10.1530/boneabs.7.P122

ICCBH2019 Poster Presentations (1) (226 abstracts)

Congenital hyperinsulinism of infancy in a child with autosomal dominant hypocalcaemia type 1 due to an activating calcium sensing receptor mutation

Ana Sastre 1 , Pratik Shah 2 & Evelien Gevers 1,

1Royal London Hospital. Barts Health NHS Trust, London, UK; 2Great Ormond Street Hospital, London, UK; 3Centre for Endocrinology, Queen Mary University, London, UK.

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

Presenting problem and clinical management: A female infant, born at term from non-consanguineous parents. She presented on D2 with persistent asymptomatic hypoglycaemia requiring 11mg/kg/min 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 15 months, on a dose of 2.5 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 11weeks of age she was started on treatment with subcutaneous continuous PTH via a Medtronic pump, after which seizures improved and calcium supplements were successfully stopped. From early age, she had difficulties in gaining weight, and had polyuria, raised urea and creatinine, hypokalemia and hyperaldosteronism, in line with a Bartter typeV, requiring 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. (KCNJ11, ABCC8, AKT2, GLUD1, GCK, GPC3, HADH, HNF4A, INSR, KDM6A, KMT2D, SCL16A1, CACNA1D, PMM2, TRMT10A, HNF1A).

Discussion: 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 the thick ascending limb of Henle’s loop. No link between hyperinsulinism and ADH has been previously described. However, CaSR is expressed in the alpha and beta cells of the pancreas and CaSRNuf/Nuf mice that harbor an activating CaSR show hyperglycemia due to impaired beta-cell function and higher number of alpha-cells. We hypothesize that 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.

Disclosure: The authors declared no competing interests.

Volume 7

9th International Conference on Children's Bone Health


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