OR43-2 Identification and Functional Characterization of a Homozygous, Inactivating Calcium-Sensing Receptor Mutation in a Patient with Rickets

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR43-Disorders of Calcium Homeostasis
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:30 AM
Room 122 (Moscone Center)
Dorothea Barbara Szczawinska*1, Bernard Mayr1, Saskia Letz1, Ramona Rus1, Dirk Schnabel2 and Christof Schofl3
1Universitätsklinikum Erlangen, Erlangen, Germany, 2Charite Humboldt University, Berlin, Germany, 3Univerisitätsklinikum Erlangen, Erlangen, Germany
Background: The calcium-sensing receptor (CaSR) is a key controller of calcium homeostasis by modulating PTH secretion and renal calcium reabsorption. Over 200 mutations in the human CaSR gene have been reported. Heterozygous inactivating mutations can result in Familial Hypocalciuric Hypercalcemia (FHH), whereas homozygous inactivating mutations can cause life-threatening Neonatal Severe Hyperparathyroidism (NSHPT). We report an unusual case of homozygous mutation of the CaSR gene that resulted in a clinical picture of FHH.

Clinical case: A 16 year old Lebanese female presented with valgus deformity and severe Vitamin D deficiency (5.6 ng/ml, n: 9-45 ng/ml). On presentation her calcium was low normal (2.17 mmol/l, n: 2.1-2.6 mmol/l), with significantly elevated PTH level (1220 pg/ml, n: 16-59 pg/ml). A 24-hour urine collection showed hypocalciuria (Ca/Crea i.U. 0.036 g/gCrea, n< 0.200 g/gCrea). Laboratory evaluation 6 months after the commencement of vitamin D treatment revealed a high calcium level (3.2 mmol/l n: 2.1-2.6 mmol/l) and inappropriately normal PTH (69 pg/ml n: 16-69 pg/ml). Notably, the urinary calcium to creatinine level was low (0.026 g/gCrea, n< 0.2 g/gCrea), suggestive of FHH. Subsequent DNA sequencing revealed a homozygous mutation in the CaSR gene in which glutamine in position 459 was replaced by arginine. In vitro studies: The functional in vitro analysis revealed mildly impaired calcium response to the stimulation of the mutant transfected cells with increasing calcium concentration. This is suggestive of the presence of a mild functional inactivation of the Q459R mutant. Finally, the in vitro treatment of the mutant transfected cells with calcimimetic was able to sensitize the mutated receptor to calcium, thus improve its signaling function.

Conclusion: Homozygous inactivating mutations of the CaSR usually result in severe hypercalcemia in neonates. Homozygosity for a mildly inactivating CaSR mutation can however result in a much less severe phenotype resembling FHH. When FHH and rickets coincide, vitamin D deficiency and CaSR inactivation may mutually compensate and mask their effects on serum calcium but may worsen the skeletal complications. This data provided some support for the potential use of calcimimetics in the management of genetic disorders associated with inactivating mutations of the CaSR.

Nothing to Disclose: DBS, BM, SL, RR, DS, CS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm