Endocrine Abstracts

Introduction: Pathogenic RET mutations cause Multiple Endocrine Neoplasia type 2 (MEN2) and sixty-one have been classified according to their penetrance of MTC. However, this distinct pattern of genotype-phenotype presentations is not always precisely predictable. P.Val804Met, the most frequent mutation in RET, is currently thought to confer a low lifetime risk with later onset of MTC.

Methodology: We present demographical, clinical, biochemical, genetic and histopathological data of three generations of patients from a family diagnosed with MEN2. The index case was a 7 year old girl who presented with advanced MTC with lymph node metastases, calcitonin of 3600 mg/l, CEA 204 ng/l and was found to have p.Val804Met RET mutation. Subsequent genetic testing identified twelve family members with the same mutation.

Results: Three generations of patients (3M, 9F, age ranges 1-72yrs) included two grandparents, three daughters and seven grandchildren. Biochemical assessment showed abnormal calcitonin in two grandparents, one of the daughters and two grandchildren. CEA levels were normal apart from index case. All patients underwent total thyroidectomies, five central and two lateral lymphadenectomies. Histology showed MTC with no LN involvement in two grandparents, MTC with LN involvement in one daughter and two grandchildren. One grandchild had microMTC and four C-cell hyperplasia. Additional pathology included papillary microcarcinoma and follicular cancer. Nine family members were cured (undetectable post-op calcitonin) but three have persistent disease with elevated calcitonin (3) and CEA (1), two of them receiving treatment with Selpercatinib. Analysis showed no second variant of RET mutation in blood and tumour DNA was negative for somatic RET, KRAS, HRAS and NRAS mutations in index case.

Conclusion: Our study showed that carriers of p.Val804Met have varying phenotypic presentation and not always a late onset or mild disease. Prophylactic thyroidectomy should be considered in these carriers if there is family history of early-onset MTC.