Endocrine Abstracts

Background: Multiple endocrine neoplasia type 2 (MEN2) is a group of pleomorphic syndromes which infer a susceptibility to several endocrine conditions. The RET Val804Met mutation is classified as a moderate-risk mutation for familial medullary thyroid cancer (MTC), without the other components of MEN2 syndromes. However, here we describe a rare case of a gentleman with RET p.V804M, presenting with primary hyperparathyroidism (PHPT) and no evidence of MTC.

Summary: A 31 year old man presented with recurrent bilateral renal stones. Investigations revealed normocalcaemic primary hyperparathyroidism (parathyroid hormone of 8.2 pmo/l and adjusted calcium of 2.60 mmol/l). Further tests indicated a low 24 hour urinary calcium-creatinine clearance ratio (0.0078). Three modalities of imaging (US, Sestamibi and 4DCT) suggested a right superior parathyroid adenoma. Genetic analysis revealed a mutation in codon 804 of the RET proto-oncogene, leading to a Valine-Methionine (Val804Met) substitution. Interestingly, thyroid function and calcitonin levels were normal and imaging showed no signs of MTC. Familial hypercalcaemic hypercalciuria (FHH) was also considered given the low 24-hour urinary calcium-creatinine clearance ratio. Genetic analysis for FHH was negative, as well as for MEN1, CDC73, GNA11 and CDKN1B. Currently, the patient remains under regular surveillance with yearly biochemistry and regular thyroid ultrasound. Familial genetic testing demonstrated that the patient’s father also carries this mutation, with no evidence of MTC or PHPT, despite being >75years of age.

Conclusion: Typically, the RET Val804Met mutation has a high penetrance, with up to 80% of individuals presenting with MTC by the age of 70 years. Although there are reported associations of the Val804Met mutation with other MEN2 features, it is very rare for primary hyperparathyroidism to be the index presentation as here. We recommend investigating for other associated presentations with MEN2.