Endocrine Abstracts

Introduction: Primary Hyperparathyroidism (PHPT) has a prevalence of 0.2% to 1.3% worldwide. 10% of all PHPT cases are hereditary. These include multiple endocrine neoplasia (MEN) 1, MEN2A, familial hypocalciuric hypercalcemia (FHH), familial isolated hyperparathyroidism (FIHP), neonatal severe hyperparathyroidism and hyperparathyroidism jaw tumour syndrome (HPT-JT). GCM2 variant gain-of-function heterozygous mutations have been reported in FHIP (which can mimic FHH) and sporadic PHPT in 1.5%-26.9% cases, seen more often in the Ashkenazi Jewish population [1]. There is often multiglandular involvement. A loss of function mutation in GCM2 is associated with hypoparathyroidism. There are no reported cases of GCM2 mutations and non-parathyroid cancers.

Case presentation: We present the case of a 49-yr old woman of Ashkenazi Jewish descent who had mild hyperparathyroidism, renal cell carcinoma, basal cell carcinoma along with a family history of hyperparathyroidism, breast cancer and kidney cancer. Her BRCA1 gene test was negative. She had borderline hypercalcemia (2.59 mmol/l), normal PTH (5.4 pmol/l), low urine calcium excretion (CCCR 0.83%), suggestive of FHH; an R151 gene panel test was sent which revealed a heterozygous variant GCM2 c.1181A>C p.(Tyr394Ser). She was osteopenic and a possible parathyroid adenoma was identified on ultrasound. Upon repeat testing, she had normal serum calcium levels and was asymptomatic. No further localising scans were performed as she was not for surgery.

Conclusion: This case highlights GCM2 gene activation and a possible link with non-parathyroid cancers. It is essential to take an in-depth family history and consider familial genetic screening for GCM2 mutations to identify FHIP and other possibly associated cancers; further studies on this mutation and other cancers are warranted to deduce whether there is an actual association.

Reference: 1. Guan B et al. Ethnicity of patients with germline GCM2 variants and primary hyperparathyroidism. J Endocr Soc. 2017; 1(5): 488–499.