Germline mutations of GCM2 cause a novel variant of hereditary primary hyperparathyroidism.

Primary hyperparathyroidism (pHPT) occurs as hereditary disease in approximately 10% of cases. GCM2 germline mutations have been recently described as responsible for the development of a novel variant of hereditary pHPT. This study aimed to determine the features of GCM2-related pHPT. Demographics, laboratory, and surgical data were assessed in a series of 17 index cases carrying GCM2 mutations undergoing surgery for pHPT. The GCM2 germline pathogenic variant c.1181 A>C p.(Tyr394Ser) was detected in 59% of cases. GCM2-related pHPT was diagnosed at a median age of 57 years (range 32-82) with a Female/Male ratio 1.8. Preoperative median calcemia was 2.89 mmol/L (range 2.69-3.8). Family history of pHPT was absent in 65% of cases. Complete clinical, surgical and follow-up data were available for 13 patients. At initial surgery, bilateral neck exploration with subtotal parathyroidectomy was performed in 46% of patients; achieving cure in all cases at a median follow-up of 51 months (range 7-60). In the remaining cases undergoing selective parathyroidectomy, a persistent pHPT occurred in 3 cases; recurrent pHPT in 1 patient (after a disease-free interval of 4 years) while 3 are disease free at a mean follow-up of 21 months. Thus, at an overall prolonged follow-up (median 48 months, range 7-216), multiglandular involvement occurred in 77% of cases. GCM2 germline mutations may cause hereditary pHPT, even if it may mimic sporadic variant due to the absence of familial history and late onset. The main feature is multiglandular involvement, needing bilateral neck exploration and subtotal parathyroidectomy to achieve long-term cure.