Primary hyperparathyroidism (pHPT) rarely (10%) occurs as hereditary disease. GCM2 germline mutations have been recently described as responsible for the development of a novel variant of hereditary pHPT. This study was aimed to determine the prevalence of GCM2 germline variants in pHPT and evaluate the main features of this variant.

Demographics, laboratory, surgical data were assessed in a series of 10 index cases carrying GCM2 mutations undergoing surgery for pHPT.

The GCM2 germline pathogenetic variants c.1181A>C p.(Tyr394Ser) was detected in 80% of cases. GCM2-related pHPT affected subjects of both sexes (F/M= 6/4); it was diagnosed at a median age of 60 yrs (range 49 - 71). Preoperative median calcemia and PTH levels were 2.9 mmol/L (range 2.7-3.4) and 215 pg/ml (range 103-459), respectively. Family history of pHPT was absent in 70% of cases; multiglandular involvement was preoperatively suspected because of equivocal preoperative imaging studies (absent, multiple or discordant localization) in 60% of patients. Complete clinical, surgical and follow-up data were available for 5 patients. Bilateral neck exploration with subtotal parathyroidectomy was performed in 4/5 patients and focused exploration with selective parathyroidectomy in 1 case. All patients undergoing subtotal parathyroidectomy were cured and are disease-free at a median follow up of 4 years (range 3-10), while the patient undergoing selective parathyroidectomy had persistent pHPT.

GCM2 germline mutations may cause hereditary pHPT, even if it may mimic sporadic variant because of the absence of familial history and late onset. The main feature is multiglandular involvement, needing bilateral neck exploration and subtotal parathyroidectomy.