Endocrine Abstracts

Background: Medullary thyroid carcinoma (MTC) can result from an inherited predisposition related to variants in the RET gene. The insTTCTdelG variant in codon 666 has been previously associated with MTC in one family, but larger studies are not available. We aim to describe biochemical and clinical characteristics associated with this genetic variant in sixteen Belgian families.

Methods: Retrospective study of sixteen families in Belgium, evaluating biochemical and clinical characteristics of index patients (IPs) and their carrier-relatives (CPs).

Results: Familial genetic cascade screening of sixteen IPs identified 108 additional family members carrying the variant (total cohort n = 124, 55% females, 45% males), with age ranging from 6y to 83y (mean 42+/-18y) at first clinical evaluation. Twenty-six (22%) CPs had elevated baseline calcitonin at screening. In the total cohort, 39 (31%) patients underwent thyroidectomy, resulting in 34 patients with histological diagnosis of MTC, 2 with C-cell hyperplasia (CCH), 3 with negative histology. The age at diagnosis ranged from 8y to 83y (mean 48+/-17y, with 30 (76%) females affected compared to 10 (24%) males. Five IPs and 14 CPs were diagnosed in stage I, 3 IPs and 1 CPs in stage II, 2 IPs and 1 CP in stage III, 3 IPs and 2 CPs in stage IVa, 2 IPs and 1 CP were diagnosed with MTC without available staging data. Thyroidectomy was combined with prophylactic lymph node resection in 23 (59%) patients, with therapeutic lymph node resection in 8 (21%) patients, and without lymph node resection in 8 (21%) patients. Postoperatively, 28 (71%) patients were in remission, 7 (18%) were diagnosed with biochemical recurrent disease, 3 (7%) with structural locoregional recurrent disease. One patient with MTC was also diagnosed with pheochromocytoma, 1 patient with MTC with primary hyperparathyroidism, and 1 patient with pheochromocytoma and primary hyperparathyroidism. One IP and 2 CPs had clinical disease without thyroidectomy (1 due to fear, 2 because of stable very low risk clinical disease based on calcitonin+/-imaging and shared clinical decision). In the CP subgroup, MTC or CCH was diagnosed in 22 (20%) patients (mean age 49+/-17y) for a total follow up time of 446 patient y (diagnostic risk of 0.04% per y follow-up per patient).

Conclusion: This retrospective study on the insTTCTdelG-RET666 variant, which is the largest to date, suggests that this variant is pathogenic and associated with low risk MTC/CCH and rarer other MEN2-A manifestations.