title: Familial hypocalciuric hypercalcemia with a de novo heterozygous mutation of calcium-sensing receptor.
abstract: A de novo heterozygous inactivating mutation of calcium-sensing receptor (CASR) gene typically causes neonatal hyperparathyroidism (NHPT) with moderate hypercalcemia and hyperparathyroid bone disease. We present a case of asymptomatic hypocalciuric hypercalcemia with a de novo heterozygous mutation in CASR, S591C, which is primarily reported to be responsible for NHPT. A 54-year-old female was referred for investigation of asymptomatic hypercalcemia that was initially found in the 1980s but without a history of bone disease during the perinatal period. She had moderate hypercalcemia (12.4 mg/dl) and relative hypocalciuria (fractional extraction of calcium 1.07%) but normal intact parathyroid hormone and serum 1,25-dihydroxyvitamin D3. Pedigree analysis revealed that she carried a de novo heterozygous mutation of S591C, which she transmitted to an affected child with moderate hypercalcemia but not to other children, who had normal serum calcium levels. A de novo heterozygous CASR mutation that is responsible for NHPT may also present in individuals with asymptomatic hypocalciuric hypercalcemia. Caution is required when predicting course and outcome in a pedigree with CASR mutation, as well as incidental hypercalcemia, because of its variable phenotypes.
  
  
  CONCLUSIONS
  The phenotype and severity of CASR mutations are thought to be dependent on genotypes.We report an asymptomatic case of the de novo heterozygous S591C mutation in CASR, which has previously been reported as a responsible mutation of NHPT with bone diseases.Variable phenotypes of CASR raise a cautionary note about predicting outcome by genotyping in a pedigree with CASR mutation.
authors.affiliation: Department of Internal Medicine , Fujiyoshida Municipal Medical Center , Yamanashi, 403-0005 , Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Taki
authors.affiliation: Department of Infection Control and Clinical Laboratory Medicine , Dokkyo Medical University , Tochigi, 321-0293 , Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kogai
authors.affiliation: Department of Infection Control and Clinical Laboratory Medicine , Dokkyo Medical University , Tochigi, 321-0293 , Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sakumoto
authors.affiliation: Clinical Research Center, Dokkyo Medical University , Tochigi, 321-0293 , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Namatame
authors.affiliation: Department of Infection Control and Clinical Laboratory Medicine , Dokkyo Medical University , Tochigi, 321-0293 , Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hishinuma