Endocrine Abstracts

Familial hypocalciuric hypercalcaemia (FHH) is a rare autosomal dominant condition due to a mutation in the calcium-sensing receptor gene (CaSR). The CaSR is located on chromosome 3 and mutations are commonly heterozygote mutations causing loss of function. Heterozygote mutations demonstrate benign disease with mild, asymptomatic hypercalcaemia. Homozygous mutations in the CaSR usually present with neonatal severe hyperparathyroidism (NSHPT) in the first few weeks of life and is characterised by failure to thrive, dehydration and can be fatal. This report discusses two siblings who present in adulthood with homozygous mutations in the CaSR. Mr A was found incidentally to have hypercalcaemia (adjusted calcium 3.1mmol/l) aged 39 years. PTH was raised at 29.8 pmol/l and urine calcium creatinine clearance ratio (CCCR) was low (0.0085). Genetic testing revealed a homozygous variant in the CaSR gene (c.-10C>T) causing an inactivating mutation. There were no end organ complications including nephrocalcinosis or osteoporosis, but he has CKD3 of unclear aetiology. Mr A’s sister, Mrs B was diagnosed with presumed PHPT in 1995, aged 16 years, and she underwent a subtotal parathyroidectomy with 3.5 glands removed resulting in iatrogenic hypoparathyroidism. Following the genetic testing in Mr A, testing in Mrs B confirms the same homozygous mutation in the CaSR. The parents of Mr A and Mrs B are consanguineous (first cousins). Their mother has a heterozygous mutation and is normocalcaemic, and the father is deceased. Further cascade analysis is in progress. This is an unusual case of siblings presenting with homozygous CaSR mutations in adulthood and an FHH phenotype, despite this genotype usually associated with NSHPT. Mr A requires cinacalcet to manage his hypercalcaemia which is unusual when compared to heterozygote mutations, and this is partly due CKD3. Further work is required to identify the result of these gene mutations on CaSR function and the corresponding phenotype.