Endocrine Abstracts

Introduction: Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia, which, in general, is not associated with significant morbidity. FHH1, the most common type of the disease, is inherited in an autosomal dominant pattern and caused by inactivating mutations in the Calcium Sensing Receptor (CaSR) gene, located in chromosome 3. Inactivation of CaSR in parathyroid cells results in a shift of calcium set point to higher values with consequent hypercalcemia. Mutations in GNA11 and AP2S1 have been associated to the less frequent FHH2 and 3 disease types. FHH should be recognized and differentiated from primary hyperparathyroidism, in the workup of hypercalcemia, since FHH is not curable by surgery.

Objective: We describe a novel CaSR mutation in a female subject with FHH type 1.

Case: A 37-year-old female with no specific symptoms was referred for hypercalcemia, with normal PTH levels and low urinary calcium excretion confirmed at several occasions (table). Physical examination was unremarkable. Upon recommendation, other members of her family were tested for hypercalcemia. Her father, two paternal aunts and one of her two siblings also presented with asymptomatic hypercalcemia. It was reported that the paternal grandmother had been diagnosed with primary hyperparathyroidism and had been submitted to parathyroid surgery, years before.

Genetic testing: Sequencing results showed that patient carried a heterozygous novel mutation c.1657G>T in exon 6 of the CaSR gene. The novel mutation is a G to T transition at nucleotide 553 resulting in a Gly553Trp (Glycine to Tryptophan) missense mutation. The pathogenicity of the novel mutation was classified with several online tools as SIFT, PolyPhen and Align-GVGD. In silico analysis classified the mutation as ‘likely-pathogenic’. The G556W mutation could markedly change the structure of protein.

Conclusions: We report a novel missense mutation of CaSR gene, in association with FHH in a pedigree. Asymptomatic hypercalcemia seems to be the only manifestation, so far, associated with this specific mutation. The diagnosis of FHH, could prevent patients from an unnecessary parathyroidectomy.