Context: The autosomal dominantly inherited condition familial hypocalciuric hypercalcemia (FHH) is characterised by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to moderately elevated plasma PTH. The condition is difficult to distinguish clinically from primary hyperparathyroidism, and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene.

Objective: We sought to define the mutation spectrum of the CASR gene in a Danish FHH population, and to establish genotype–phenotype relationships regarding the different mutations.

Design and participants: 213 subjects clinically suspected to have FHH, and 121 subjects enrolled as part of a family-screening program were studied. Genotype–phenotype relationships were established in 66 mutation positive index patients and family members.

Main outcome measures: We determined CASR gene mutations, and correlating levels of plasma calcium (albumin corrected), ionized calcium (pH 7.4) and PTH were measured.

Results: We identified 22 different mutations in 39 FHH families. We evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes, ranging from calcium concentrations moderately above the upper reference limit, to calcium levels more than 20% above the upper reference limit. Furthermore, the mean plasma PTH concentration was within the normal range in eight of 11 studied mutations, but mild to moderately elevated in families with the mutations p.C582Y, p.C582F and p.G553R.

Conclusions: The present data adds 19 novel mutations to the catalogue of inactivating CASR mutations and illustrates a variety of biochemical phenotypes in patients with the molecular genetic diagnosis FHH.