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Multiple endocrine neoplasia type 2
A multiple endocrine neoplasia, a polyglandular cancer syndrome. There are two forms of MEN2: MEN2A and MEN2B.
ORPHA:653Classification level: Disorder
Multiple endocrine neoplasia type 2 (MEN2) total prevalence of all variants is approximately 1/35,000. MEN2A, accounts for 95% of MEN2 cases.
The clinical manifestations of MEN2 are related to the syndrome subtypes and depend on the specific mutation in the RET gene. There are two forms of MEN2: MEN2A and MEN2B. MEN2A comprises four subvariants: 1) classical MEN2A (represented by the uniform presence of medullary thyroid carcinoma (MTC) and the less frequent occurrence of pheochromocytoma (PCC) or primary hyperparathyroidism (PHPT) or both; 2) MEN2A with Cutaneous lichen amyloidosis (CLA); 3) MEN2A with Hirschsprung's disease (HD); 4) familial medullary thyroid carcinoma (FMTC) consisting in families or individuals with RET germline mutations who manifest only MTC. MEN2B variant is characterised by the occurrence of MTC and PCC but not PHPT. Other features of MEN2B include multiple neuromas of the gastro-enteric mucosa, bumps on the lips, eyelids, and tongue, hyperextensible joints and marphanoid habitus. MEN2 can affect all age groups, with manifestations beginning in infancy to early childhood (MEN2B) or adulthood (MEN2A). MTC affects all forms of MEN2, is usually the first manifestation of the disease, and arises in the lateral thyroid lobes. In MEN2A, MTC is associated in 50% of cases with PCC and in 20-30% with PHPT. The PCC are almost always benign and are usually multicentric, bilateral, and conﬁned to the adrenal gland. Patients with PCC have additional symptoms of headache, palpitations, nervousness, hypertension and tachycardia. PHPT in patients with classical MEN2A is usually mild and it can be associated with symptoms such as depression, muscle weakness and fatigue. From one to four parathyroid glands may be enlarged. The CLA in MEN2A is characterized by dermatological lesions that are particularly evident in the scapular region of the back corresponding to dermatomes T2-T6. MEN2B: MTC often presents in infancy and is highly aggressive, metastasizing early to regional lymph nodes and beyond. Approximately 50% of patients with MEN2B develop PCC. They also have a unique physical appearance characterized by a typical facies (mucosal neuromas of the lips and tongue, bumpy lips ), ophthalmologic abnormalities (inability to make tears in infancy, thickened and everted eyelids, mild ptosis, and prominent corneal nerves), skeletal malformations (marfanoid body habitus, narrow long facies, pes cavus, pectus excavatum, high-arched palate, scoliosis, and slipped capital femoral epiphyses), and a generalized ganglioneuromatosis throughout the aerodigestive tract.
MEN2 is caused by a heterozygote germline activating mutation in the RET proto-oncogene (10q11.2), encoding the membrane tyrosine kinase receptor RET. Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B.
Clinical diagnosis involves identification of MTC, PCC, and eventually PHPT. The diagnosis of MTCis performed byultrasound (US) of the neck and dosage of serum levels of calcitonic (Ctn) and carcinoembryonic antigen (CEA). Ctn >10pg/ml is indicative of MTC. Screening of PCC consists of measuring free plasma metanephrines and normetanephrines or 24-hour urinary metanephrines and normetanephrines. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. A positive genetic testing of RET gene confirms the clinical diagnosis in affected patients.
Differential diagnoses include MTC and Hirschsprung disease.
Prenatal diagnosis is possible and can identify mutations in the offspring of RET mutation carriers.
MEN2 is an autosomal-dominant syndrome and parents have a 50% chance of passing on the RET gene mutation to their offspring independently by sex.
Management and treatment
RET mutations predict MEN2 clinical phenotype and guide treatment plans. The American Thyroid Association (ATA) stratified three risk categories for aggressive MTC and defined their specific tumor management guidelines:1) highest risk (HST); 2) high risk (H); 3) moderate risk (MOD). All the three categories requires evaluation of serum Ctn every 6 months for the first year, then annually if serum Ctn remains undetectable or within normal range. Annual US of the neck is indicated for both H and HST categories. For MOD category total thyroidectomy (TTX) should be performed when the serum Ctn level becomes elevated. For H and HST categories TTX should be performed at or before 5 years of age, based on serum Ctn levels. Life-long thyroid hormone supplementation is needed after thyroid removal. Two, orally administered, thyrosin kinase inhibitors, vandetanib and cabozantinib, have been approved by FDA and EMA for the treatment of patients with advanced progressive MTC. MEN2A patients in the H and MOD categories should be screened also for PHPT, at the time of screening for PCC. Only visibly enlarged parathyroids should be resected.
The prognosis depends on the stage at which MTC is diagnosed and quality of initial surgical treatment. Early diagnosis and complete initial resection of tumors increases life expectancy.