Presentation of a kindred with familial medullary thyroid carcinoma and Cys61 1Phe mutation of the RET proto-oncogene demonstrating low grade malignancy

Objective: Booth multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are caused by germline mutations of the RET proto-oncogene. A broad spectrum of malignancy within and between fami lies has been described with no clear genotype-phenotype correlation due to a scarcity of available data of large kindreds. Design: Here we present the only known family with a germline mutation of c odon 611 TGC to TTC (exon 10) in the RET proto-oncogene leading to a replac ement of cysteine by phenylalanine (Cys611Phe or C611F). Results: Twenty family members of this large kindred are gene carriers (GCs ) and seven (5-13 years old) are potential carriers but have yet to be anal ysed, The clinical course of medullary thyroid carcinoma (MTC) in this fami ly is characterized by a very slow evolution and progression of the tumour with no MTC-related death to date. Of 11 patients (30-69 years old) having undergone thyroidectomy six were classified as pT(1), four as pT(2) and one as C-cell hyperplasia according to the TNM system of the International Uni on Against Cancer. Due to cervical and mediastinal lymph node metastasis on e patient (44 years old) had to be operated on a second time. The seven non -operated GCs of the fourth and fifth generation (17-26 years old) are year ly monitored with pentagastrin stimulation tests; one non-operated GC (43 y ears old) has refused any further investigations. Screening for primary hyp erparathyroidism and phaeochromocytoma was negative in all cases. Conclusion: We suggest from these experiences that the general advice for t hyroidectomy in early childhood should be modified in certain families, dep ending on genotype.