Endocrine Abstracts

Familial Hypocalciuric Hypercalcaemia (FHH), originally described in 1966, was first linked to mutations in the Calcium-Sensing Receptor (CaSR) gene in 1993. FHH results from inactivating mutations affecting a single allele inherited in an autosomal dominant pattern. The calcium-sensing receptor is a cell surface-expressed G protein-coupled receptor with 1078 amino acids. Gene mutations are usually single-point in nature and result in an elevated set point for calcium sensing giving rise to mild to moderate hypercalcaemia, lower than expected urinary calcium concentrations and generally normal circulating PTH levels.

The index case presented aged 63 as an incidental finding of hypercalcaemia while being investigated for peptic ulcer disease. Serum calcium was 2.98 millimoles per litre, PTH slightly raised at 97 nanograms per litre with urinary calcium low at 2 millimoles in 24 hours. Treatment for her hypercalcaemia was conservative with generous fluid intake encouraged. At routine outpatient review in 2004 we learned her daughter (A) recently had a parathyroid resection in another hospital. Family history revealed another daughter (B) suffered constipation and had documented hypercalcaemia. A grandson attended a children's' hospital with renal calculi aged 5. Both daughters attended our OPD. (B) had a PTH elevated at 86 nanograms per litre, serum calcium raised at 2.75 millimoles per litre and normal urinary calcium concentration. (A) had a histological diagnosis of parathyroid hyperplasia of 2 glands and was normocalcaemic.

Genetic testing on this family found a point mutation in the 4th exon of the CaSR gene (CGG to CCG) leading to a change (R220P) in the large extra cellular domain of the protein. This point mutation has never been described before.

Identification and reporting of novel mutations in the CaSR gene in conjunction with clinical phenotypes will further help our as yet limited knowledge of the workings of this important receptor.