A novel germline inactivating mutation in the CASR gene in an Italian kindred affected by familial hypocalciuric hypercalcemia.

[familial hypocalciuric hypercalcemia]

Familial hypocalciuric hypercalcemia (FHH ) syndrome is a rare benign condition , inherited as an autosomal dominant trait , in which inactivating mutations of the calcium-sensing receptor (CASR ) gene affects the body 's ability to regulate calcium homeostasis . Its outcome is featured by increased levels of serum calcium , moderate hypophosphatemia , and inadequately normal or elevated circulating parathyroid hormone levels . Affected patients are mostly asymptomatic and do not benefit from surgical resection of their mildly enlarged parathyroids .We evaluated for hypercalcemia an Italian family that was identified via a young adult male proband referred to our center for parathyroidectomy .The patients and the family members were evaluated both biochemically and genetically as suspected FHH subjects . An in vitro functional study was performed by site-directed mutagenesis , and CASR activity was monitored by measuring intracellular calcium ([Ca (2 )(+)](i )).The patient had a novel germline heterozygous CASR mutation (c .361 _364 GATT ; p .D 121 del /fsX 122 ). The mutation caused a premature stop codon at codon 122 , exiting a truncated protein . The biochemical phenotype of all family members carrying the heterozygous deletion was concordant with classic FHH syndrome .Our findings confirm the role of CASR gene mutational analysis to offer a valuable addition for the recognition of FHH in hypercalcemic patients not yet characterized for a positive familial history of hypercalcemia , the only condition that identifies CASR gene mutations in hypercalcemia .

Diseases
Validation

Diseases presenting "mildly enlarged parathyroids" symptom

familial hypocalciuric hypercalcemia

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