Endocrine Abstracts (2015) 38 P10 | DOI: 10.1530/endoabs.38.P10

A mutation in the calcium sensing receptor (previously known to cause neonatal severe hyperparathyroidism in the homozygote state) causing familial benign hypocalciuric hypercalcaemia in the heterozygote

John Hinnie, Andrew Gallagher & Angela Collie

South Glasgow University Hospital, Glasgow, UK.

Familial Benign Hypocalciuric Hypercalcaemia (FBHH) is a benign autosomal dominant condition characterised by elevated serum calcium and parathyroid hormone (PTH) and low urine calcium. It is a genetically heterogeneous disorder but the majority of cases (type 1 FBHH) can be shown to be due inactivating mutations in the Calcium Sensing Receptor (CASR). This is a guanine nucleotide-binding-protein (G-protein) coupled receptor that signals through the G-protein subunit α11 (G α11). Patients who are homozygotes for inactivating CASR mutations present with Neonatal Severe Hyperparathyroidism (NHPT) which, in contrast to FBHH, is characterised by severe hypercalcaemia and early death. Three sub types of FBHH are recognized. Type 1 is the most common and is due to inactivating mutations in the CASR. Type 2 is due to mutations effecting Gα11 which result in loss of function, while type 3 is due to adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations which result in altered calcium-sensing receptor endocytocis. In FBHH, mutations result in the CaSR being less sensitive to serum calcium so that the ‘set point’ for serum calcium is reset at a higher value, leading to hypercalcaemia and increased PTH secretion. Although FBHH is a benign condition it can be confused with primary hyperparathyroidism because the two are similar in terms of biochemistry. It is important therefore to confirm the diagnosis of FBHH in patients with hypercalcemia and raised PTH in order to avoid unnecessary parathyroidectomy.

We report a kindred with FBHH type1 due to a CASR mutation that changes Cysteine to Tyrosine at amino acid 582 in the CASR. This mutation is listed in the ‘Professional’ version of the Human Genome Mutation Database as causing NHPT in the homozygote but there are no instances listed of this mutation being causative for FBHH type 1 in the heterozygote.

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