Endocrine Abstracts (2007) 14 P497

Neonatal severe hyperparathyroidism associated with a novel de novo heterozygous R551K inactivating mutation and a heterozygous A986S polymorphism of the calcium-sensing receptor gene

Judit Toke1, Gábor Czirják2, Attila Patócs1, Balázs Enyedi2, Péter Gergics1, Violetta Csákváry3, Péter Enyedi2 & Miklós Tóth1

1Semmelweis University, 2nd Department of Medicine, Budapest, Hungary; 2Semmelweis University, Department of Physiology, Budapest, Hungary; 3Markusovszky Teaching Hospital of Vas County, Department of Pediatrics, Szombathely, Hungary.

Objectives: Neonatal severe hyperparathyroidism (NSHPT) is induced by inactivating mutations of human calcium-sensing receptor (CaSR). We report the case of a now 11 year-old boy with NSHPT. We characterize a novel inactivating mutation with the results of some functional analyses.

Case: In the neonatal age the patient presented the clinical syndrome of NSHPT. At the age of 6 years, persisting hypercalcemia without clinical symptoms was documented, and the patient remained completely symptom-free without parathyroid surgery until his present age of 11 years.

Methods: The entire coding region of the CaSR gene of the patient, and exons 6 and 7 from his family members were sequenced. Functional investigation was performed in HEK-293 cells, transiently transfected with wild type and mutant CaSR plasmid constructs.

Results: Sequence analysis revealed a novel de novo heterozygous mutation at codon 551 (AGG→AAG) predicting a change of arginine to lysine (R551K) and a known heterozygous polymorphism (A986S) on the same allele, which was inherited from the father. We demonstrated that the novel R551K mutation significantly reduced the calcium sensitivity of CaSR (EC50: from 3.38±0.62 to 6.10±0.83 mmol/l) which was not alleviated by the simultaneous presence of A986S polymorphism.

Conclusion: We present the fourth NSHPT case induced by a novel de novo heterozygous inactivating mutation (R551K) of the CaSR gene. The disease gradually reverted to a symptomless, benign condition resembling familial hypocalciuric hypercalcemia without any surgical intervention.

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