Multiple endocrine neoplasia, type 2B (MEN 2B) is an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus and other skeletal abnormalities. Symptoms depend on the glandular elements present. Diagnosis and treatment are the same as for MEN 2A.

Ninety-five percent of MEN 2B cases result from a single amino acid substitution in the RET protein. As in MEN 2A and familial medullary thyroid carcinoma, this mutation results in activation of RET proto-oncogene–mediated cellular processes. More than 50% are de novo mutations and thus may be sporadic rather than familial.

Symptoms and Signs

Symptoms and signs reflect the glandular abnormalities present (see Table 1: Multiple Endocrine Neoplasia (MEN) Syndromes: Conditions Associated With MEN Syndromes). About 50% of patients have the complete syndrome with mucosal neuromas, pheochromocytomas, and medullary thyroid carcinoma (MTC). Fewer than 10% have neuromas and pheochromocytomas alone, whereas the remaining patients have neuromas and MTC without pheochromocytoma.

Often, mucosal neuromas are the earliest sign, and they occur in most or all patients. Neuromas appear as small glistening bumps on the lips, tongue, and buccal mucosae. The eyelids, conjunctivae, and corneas also commonly develop neuromas; infants are often unable to make tears. Thickened eyelids and diffusely hypertrophied lips are characteristic. GI abnormalities related to altered motility (constipation, diarrhea, and, occasionally, megacolon) are common and thought to result from diffuse intestinal ganglioneuromatosis. Patients almost always have a marfanoid habitus. Skeletal abnormalities are common, including deformities of the spine (lordosis, kyphosis, scoliosis), slipped capital femoral epiphyses, pes cavus, and talipes equinovarus.

MTC and pheochromocytoma resemble the corresponding disorders in MEN 2A syndrome; both tend to be bilateral and multicentric. MTC, however, tends to be particularly aggressive in MEN 2B and may be present in very young children.

Although the neuromas, facial characteristics, and GI disorders are present at an early age, the syndrome may not be recognized until MTC or pheochromocytoma manifests in later life.

Diagnosis

• Clinical suspicion
• Genetic testing
• Plasma free metanephrine or urinary catecholamine levels
• Pheochromocytoma localization with MRI or CT

MEN 2B is suspected in patients with a family history of MEN 2B, pheochromocytoma, multiple mucosal neuromas, or MTC. Genetic testing is highly accurate and is done to confirm the disorder. Genetic testing also is done to screen 1st-degree relatives and any symptomatic family members of patients with MEN 2B as in MEN 2A (see Multiple Endocrine Neoplasia (MEN) Syndromes: Screening).

Pheochromocytoma may be suspected clinically and is confirmed by measuring plasma free metanephrines or urinary catecholamines (see Adrenal Disorders: Diagnosis). Laboratory testing for MTC may be done (see Thyroid Disorders: Diagnosis). MRI or CT is used to search for pheochromocytomas and MTC.

Treatment

• Surgical excision of identified tumors
• Prophylactic thyroidectomy

Affected patients should have total thyroidectomy as soon as the diagnosis is established. Pheochromocytoma, if present, should be removed before thyroidectomy is done. Gene carriers should undergo prophylactic thyroidectomy before age 1 yr.

Key Points

• MEN 2B has a mutation of the same gene as in MEN 2A and manifests similarly except for the absence of hyperparathyroidism and the presence of multiple mucosal neuromas and a marfanoid habitus.
• Patients should have genetic testing for the RET proto-oncogene and blood or urine tests for pheochromocytoma.
• Pheochromocytoma is excised and prophylactic thyroidectomy is done.

Last full review/revision September 2012 by Patricia A. Daly, MD; Lewis Landsberg, MD