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Anne-Sophie Lia-Baldini, Corinne Magdelaine, Angélique Nizou, Coraline Airault, Jean-Pierre Salles, Pierre Moulin, Brigitte Delemer, Mina Aitouares, Benoît Funalot, Franck Sturtz, and Anne Lienhardt-Roussie

Objective

Gain-of-function mutations of the calcium-sensing receptor (CASR) gene have been identified in patients with sporadic or familial autosomal dominant hypocalcemia (ADH). Inactivating mutations of the CASR gene cause familial hypocalciuric hypercalcemia (FHH). Here, we report two novel CASR mutations affecting the same amino acid (p.N802); one causes ADH and the other atypical FHH.

Patients and methods

The first patient, an 11-year-old girl suffering from hypocalcemia, developed nephrocalcinosis when she was only 5 years old. The second patient is a 30-year-old woman who presented with mild hypercalcemia. PCR amplification of CASR coding exons and direct sequencing of PCR products were used to identify mutations. Site-directed mutagenesis was used to generate mutated CASR cDNAs in an expression plasmid. Using the MAPK assay system and transient transfection of Cos-7 cells with wild-type (WT) and mutated CASR, we studied the responses of these mutated receptors to extracellular Ca2 + and to the negative allosteric CASR modulator, NPS2143.

Results

Two heterozygous missense mutations (p.N802I and p.N802S) affecting a residue in the sixth transmembrane domain of CASR were identified. In functional tests, the response of the p.N802S mutant to calcium was typical of an inactivating mutation. However, the p.N802I mutant had 70% of the maximally stimulated WT receptor activity even in the absence of extracellular calcium. This constitutive activity was only partially inhibited by the inhibitor, NPS2143.

Conclusions

The asparagine at amino acid position 802 appears to be essential for the activity of the CASR protein and is implicated in the mechanism of CASR signaling.

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Yasmine El Allali, Coralie Hermetet, Justine Bacchetta, Cyril Amouroux, Anya Rothenbuhler, Valérie Porquet-Bordes, Marie-Alexandrine Champigny, Sabine Baron, Pascal Barat, Helene Bony-Trifunovic, Karine Bourdet, Kanetee Busiah, Maryse Cartigny-maciejewski, Florence Compain, Regis Coutant, Jessica Amsellem-jager, Marc De Kerdanet, Nathalie Magontier, Brigitte Mignot, Odile Richard, Sylvie Rossignol, Soskin Sylvie, Aurélie Berot, Naud-saudreau Catherine, Jean-pierre Salles, Agnès Linglart, Thomas Edouard, and Anne Lienhardt-Roussie

Aim: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.

Methods: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.

Results: Compared to older children, infants were often asymptomatic (54 vs. 15%, p = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, ‘CaSR group’; 94% of mutated infants) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, ‘cell proliferation group’; 69% of mutated children and adolescents). Although serum calcium levels did not differ between the 2 groups (p = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in ‘cell proliferation group’ patients compared to those in the ‘CaSR group’ (p = 0.001 and 0.028, respectively).

Conclusion: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.