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Multiple Endocrine Neoplasia Type 2A, MEN 2A - RET

Familial Medullary Thyroid Carcinoma, FMTC

Clinical Features

The multiple endocrine neoplasia type 2A is an autosomal dominant tumor disease which is characterized by C-cell tumors of the thyroid gland (medullary thyroid carcinoma, MTC) often combined with tumors of the adrenal medulla (pheochromocytoma in about 50% of cases) and hyperplasia or adenomas of the parathyroid. The risk for thyroid carcinoma is as high as 100% in adulthood. Therefore, gene carriers undergo early prophylactic thyroidectomy which is known to significantly improve the prognosis of this tumor syndrome.

Although principally non-malignant, pheochromocytomas may lead to hypertensive crises due to increased secretion of adrenaline and noradrenaline during anesthesia or delivery. Involvement of the parathyroid may be without clinical features or may lead to symptomatic hyperparathyroidism (about 15-20% of cases with hypercalcemia or renal stones). Itching skin lesions between shoulder blades are present in some patients (histologically amyloidosis).

Genetic Information

The multiple endocrine neoplasia type 2A is autosomal dominant, in around 6-9% of cases a mutation in the RET gene arises de novo. In around 98% of the patients affected by MEN2A, one of five common mutations in exons 10 and 11 is found in the ret-proto-oncogene (re-arranged-during-transfection). The mutations tend to affect cysteine codons which are important for intramolecular stabilization of the receptor. A mutation in one of these codons leads to intermolecular dimerization of the receptor and thus to a constitutive activity, independent of the ligand. Also in individuals with familial medullary thyroid carcinomas (FMTC), one of these five mutations is found at high rate. A molecular genetic examination in a patient or in a suspect case may allow for an elaborate prophylaxis of the index patient and for an identification of gene carriers within a family. Preventive management should be started early since thyroid carcinomas may manifest as early as in the second decade of life.

Prevalence

Around 1 : 30 000

Diagnostic