Endocrine Abstracts

JOINT1908

The Y791F mutation of the RET proto-oncogene is a well-documented genetic alteration associated with familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia type 2A (MEN2A), and familial pheochromocytoma. This mutation activates the RET receptor in its monomeric form. Here, we present an analysis of 15 unrelated families carrying the Y791F mutation, exhibiting diverse phenotypic expressions.

Patients and Methods: Over the past 35 years, we have evaluated 406 patients with medullary thyroid carcinoma (MTC) (age range: 2–80 years, mean age: 49 years). Genetic testing for RET proto-oncogene mutations was performed using direct double-strand sequencing of PCR-amplified genomic DNA.

Results: Of the 406 MTC cases, 128 (32%) were familial. Germline Y791F mutations (C791) were identified in eight patients with MTC (age at diagnosis: 33–62 years, mean: 48 years), all of whom were index cases within their families. Among these, four patients were diagnosed, surgically treated, and cured at ages 33, 42, 54, and 55, while four others presented with metastatic MTC at ages 47, 53, 54, and 62. One patient diagnosed at 53 years of age succumbed to the disease at 63. None exhibited associated disorders. The same mutation was identified in 33 family members. Prophylactic thyroidectomy was performed in five individuals, with histopathological confirmation of C-cell hyperplasia in three cases (ages 13, 16, and 29). One patient had concurrent kidney hypoplasia and primary hyperparathyroidism (PHPT), though MEN1 mutations were not detected. Two mutation carriers showed no clinical or histological evidence of thyroid disease. Additionally, six patients exhibited congenital urogenital anomalies without other associated conditions. The L769L polymorphism was detected in five individuals, including four with MTC.

Conclusion: The prevalence of inherited MTC in our cohort aligns with previous reports; however, the frequency of the Y791F mutation appears higher than in other studies. Phenotypic expression varies widely, ranging from asymptomatic carriers to overt malignancy. Notably, a more aggressive disease course was observed in patients harboring the coexistent L769L polymorphism. The presence of renal malformations suggests that despite its oncogenic potential, insufficient RET protein expression during embryogenesis may contribute to developmental anomalies or indicate the involvement of additional genetic factors.