Multiple endocrine neoplasia type 2 (ORPHA:653)
A rare multiple endocrine neoplasia (MEN) syndrome that is principally characterized by the association of medullary thyroid carcinoma (MTC) with other endocrine tumors. The variant MEN 2A is defined by MTC associated with pheochromocytoma and/or primary hyperparathyroidism (MEN2A); the variant MEN 2B is defined as an aggressive form of MTC in association with pheochromocytoma but without primary hyperparathyroidism.
Epidemiology
The total prevalence of all variants of multiple endocrine neoplasia type 2 (MEN2) is approximately 1/35,000. MEN2A, accounts for 95% of MEN2 cases.
Clinical description
MEN2 can affect all age groups, with manifestations beginning in infancy to early childhood (MEN2B) or adulthood (MEN2A). Clinical manifestations are related to the tumors associated. MTC affects all forms of MEN2, is usually the first manifestation of the disease, and arises in the parafollicular cells of the thyroid. In MEN2A, MTC is associated in 50% of cases with pheochromocytoma (PCC) and in 20-30% with primary hyperparathyroidism (PHPT). PCC is almost always benign and is usually multicentric, bilateral, and confined to the adrenal gland. In classical MEN2A, PHPT is usually mild and between one to four parathyroid glands may be enlarged. MEN2A can also be associated with cutaneous lichen amyloidosis or Hirschsprung's disease (HD). In 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), ophthalmologic abnormalities (alacrima in infancy, thickened and everted eyelids, mild ptosis, and prominent corneal nerves), skeletal anomalies (marfanoid body habitus, narrow long facies, pes cavus, pectus excavatum, high-arched palate, scoliosis, hyperextensible joints and slipped capital femoral epiphyses), and a generalized ganglioneuromatosis throughout the aerodigestive tract.
Etiology
MEN2 is caused by a heterozygote germline activating mutation in the RET proto-oncogene (10q11.2), encoding a membrane tyrosine kinase receptor. The clinical subtypes depend on which functional domain the mutations affect.
Diagnostic methods
Clinical diagnosis involves identification of MTC, PCC, and eventually PHPT. MTC is diagnosed by ultrasound (US) of the neck and serum levels of calcitonic (Ctn) and carcinoembryonic antigen (CEA). Screening of PCC consists of measuring metanephrines and normetanephrines from either free plasma or a 24-hour urine test. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. A positive genetic test of RET confirms the clinical diagnosis in affected patients.
Differential diagnosis
Differential diagnoses include MTC, Hirschsprung disease and familial medullary thyroid carcinoma (FMTC). FMTC is also associated with germline RET variants but patients only manifest MTC.
Antenatal diagnosis
Prenatal diagnosis is possible where the mutation has previously been identified in a family member.
Genetic counseling
MEN2 is an autosomal-dominant syndrome and individuals carrying the pathogenic variant have a 50% risk of transmitting the variant to each offspring, independent of sex. Approximately 75% of MEN2B cases are sporadic (with the RET mutation arising de novo), while 25% are familial.
Management and treatment
RET mutation predicts the clinical phenotype and guides treatment. As recommended by the American thyroid association, management and treatment is stratified according to risk of aggressive MTC: highest risk (HST); high risk (H); moderate risk (MOD). All patients require evaluation of serum Ctn every 6 months for the first year, then annually if serum Ctn remains normal or undetectable. Annual US of the neck is indicated for both H and HST categories. Total thyroidectomy (TTX) should be performed when the serum Ctn level becomes elevated in MOD, and at or before 5 years of age (based on serum Ctn levels) for H and HST risk groups. Life-long thyroid hormone supplementation is needed after thyroid removal. The tyrosine kinase inhibitors, vandetanib and cabozantinib, are approved (in the USA and Europe) for the treatment of patients with advanced progressive MTC. MEN2A patients in the H and MOD risk groups should be simultaneously screened for PHPT and PCC. Only visibly enlarged parathyroids should be resected.
Prognosis
The prognosis depends on the stage at which MTC is diagnosed and efficacy of initial surgical treatment. Early diagnosis and complete initial resection of tumors increases life expectancy.

                            Last update: 
                            June 2021


                            - Expert reviewer(s): 
                            Pr Maria Luisa BRANDI  - Dr Francesca GIUSTI  - Dr Francesca MARINI