OBJECTIVE: Genetic disorders of calcium metabolism arise in a familial or 
sporadic setting. The calcium-sensing receptor (CASR) plays a key role in 
maintaining calcium homeostasis and study of the CASR gene can be clinically 
useful in determining etiology and appropriate therapeutic approaches. We report 
two cases of novel CASR gene mutations that illustrate the varying clinical 
presentations and discuss these in terms of the current understanding of CASR 
function.
PATIENTS AND METHODS: A 16-year-old patient had mild hypercalcemia associated 
with low-normal urinary calcium excretion and normal-to-high parathyroid hormone 
(PTH) levels. Because of negative family history, familial hypocalciuric 
hypercalcemia was originally excluded. The second patient was a 54-year-old man 
with symptomatic hypocalcemia, hyperphosphatemia, low PTH, and mild 
hypercalciuria. Familial investigation revealed the same phenotype in the 
patient's sister. The coding region of the CASR gene was sequenced in both 
probands and their available first-degree relatives.
RESULTS: The first patient had a novel heterozygous inactivating CASR mutation 
in exon 4, which predicted a p.A423K change; genetic analysis was negative in 
the parents. The second patient had a novel heterozygous activating CASR 
mutation in exon 6, which predicted a p.E556K change; the affected sister of the 
proband was also positive.
CONCLUSIONS: We reported two novel heterozygous mutations of the CASR gene, an 
inactivating mutation in exon 4 and the first activating mutation reported to 
date in exon 6. These cases illustrate the importance of genetic testing of CASR 
gene to aid correct diagnosis and to assist in clinical management.