Endocrine Abstracts

Calcium-sensing receptor gene (CASR) loss-of-function mutations lead to familial hypocalciuric hypercalcaemia (FHH), neonatal severe hyperparathyroidism, and primary hyperparathyroidism. FFH is characterized by mild hypercalcaemia, hypocalciuria, calcium clearance/creatinine clearance (CaCl/CrCl) <0.01, normal or high PTH level. Nevertheless the phenotype may vary (Thakker 2012). The aim of this work was to compare the phenotypes of patients bearing or not a pathogenic CASR-mutation. Patients included (n=131; 96 females, median (IQR) age 63 (40–77)) referred either for a calcium disorder not explained by sporadic hyperparathyroidism (n=118) or pulmonary hypertension (n=13 controls), were sequenced for CASR gene after written informed consent. Patients taking diuretics, diphosphonates, lithium, with kidney failure, CaSR-antibodies or gain-of-function CASR-mutations had been excluded. Gender, age, nephrolithiasis, bone DEXA, blood calcium, phosphate, creatinine, 25-hydroxyvitamin D and PTH levels, 24-H calciuria, and CaCl/CrCl were compared according to the level of calcaemia <100, 100–105, or >105 mg/l and the presence of a pathogenic CASR mutation. The CASR-mutated group (n=21) showed higher calcaemia (108 (105–116) mg/l vs 105 (98–111) mg/l) and lower PTH (50 (32–91) pg/ml vs 83 (52–107) pg/ml) than the non-mutated group (n=110), with no difference for other parameters, especially 25-hydroxyvitamin D (27 (21–35) ng/ml vs 23 (15–33) ng/ml, calciuria (120 (45–183) mg/24 h vs 123 (65–188) mg/24 h), and CaCl/CrCl (0.01 (0.00–0.02) vs 0.01 (0.01–0.02)). The non-mutated group included 51 normal CASR, 50 heterozygous, and nine homozygous or composite heterozygous variants. The comparison of these three sub-groups with the CASR-mutated group also differed for calcaemia and PTH (P=0.01). CASR-mutations and CASR-variants were identified respectively in none and 15 (53%) of the 28 patients with calcaemia <100 mg/l, 4 (14%) and 14 (50%) of the 28 patients with calcaemia between 100 and 105 mg/l, and 17 (22%) and 30 (40%) of the 75 patients with calcaemia >105 mg/l. Seven/13 (53%) patients tested without any calcium disorder bore CASR-variants.

Conclusion: 50% of patients with calcaemia <105 mg/l showed a CASR-variant, whereas 40% with calcaemia >105 mg/l showed a CASR-mutation, with lower PTH levels, but no difference in terms of calciuria or (CaCl/CrCl) despite similar vitamin D status. Calcemia/PTH ratio could be a better marker of pathogenic CASR-mutation than (CaCl/CrCl) <0.01.