Neonatal severe hyperparathyroidism (NSHPTH) and FHH, usually defined as a ratio of calcium clearance/creatinin clearance <0.01 with normal kidney function and vitamin D status, are caused by respectively heterozygote and homozygote inactivating mutations of the CaSR gene. The aim of this study was to assess the interest of analyzing CaSR in hypercalcalcemic subjects suspected to have FHH.
Patients and methods: Forty hypercalcaemic subjects from 38 families were evaluated because of hypercalcaemia associated to relative hypocalciuria (n=34), familial hypercalcaemia (n=12) or post-surgical recurrence (n=3).
Results: Five subjects from 4 families (11.7% of index cases) had a CaSR gene mutation, 3 never described before (P666L, G94R, A295T, R648X). One patient presented an insertion in the intra-cellular domain of the CaSR protein of unknown signification. CaSR gene polymorphisms were identified in 31 patients (A986S:12, R990G:4, A986S+Q1011E: 2). Three patients had strictly normal CaSR gene. The phenotypic characteristics of patients showing mutations, polymorphisms or normal CaSR gene were not different except for a younger age in mutated patients (P<0.05). Among mutated patients, hypocalciuria was not always present. After exclusion of the NSPHPT, the ratio calcium clearance/creatinin clearance, did not appear to be a good diagnosis criterium for FFH, with a sensitivity of 60%, a specificity of 45%, a positive predictive value (PV) of 16% and a negative PV of 90%.
Conclusion: In concordance with recent data (Nissen JCEM 2007), these results suggest that a variety of biochemical phenotypes are linked with the genetic diagnosis of FFH. This could depend on the type of mutation but also on vitamin D status (Zajickova JCEM 2007). By contrast, a certain number of typical cases are not associated with CaSR gene abnormality, suggesting anomalies of another calcium receptor, of CaSR transduction protein, or antiCaSR antibodies (Makita PNAS 2007).
03 - 07 May 2008
European Society of Endocrinology