Multiple endocrine neoplasia 2B

It is a pathology that predisposes to the development of medullary thyroid cancer and tumors, generally benign, in the adrenal glands. It is caused by germline and somatic mutations in the RET proto-oncogene.

Endocrine neoplasia type 2 (MEN2) is an inherited disorder that affects the endocrine system, including the thyroid, parathyroid and adrenal glands. The type of inheritance is autosomal dominant. MEN2 is divided into two subtypes: MEN2A and MEN2B. The prevalence is 13-24 and 1-2 per million individuals in MEN2A and MEN2B, respectively. MEN2B is the more aggressive form of the disease, therefore, patients with this subtype have a poorer prognosis than those with MEN2A.

Symptoms

MEN2A: This subtype occurs in 90% of MEN2 patients. It is associated with medullary thyroid carcinoma (MTC), pheochromocytoma (adrenal gland tumor), primary hyperparathyroidism, MEN2A associated with cutaneous lichenoid amyloidosis, MEN2A associated with Hirschsprung's disease and familial MTC.

MEN2B: The onset of symptoms often occurs at a very early age. Subtype 2B is also associated with CMT and pheochromocytoma like subtype 2A, but does not manifest hyperparathyroidism and may also develop ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Thus, the initial signs in this subtype are usually chronic constipation, abdominal distension, diarrhea or megacolon at birth. Patients also show developmental abnormalities such as mucosal neuromas of the lips and tongue, lip lumps and marfanoid habitus (with skeletal abnormalities and joint laxity).

Common symptoms associated with medullary thyroid carcinoma include difficulty breathing and swallowing, hoarseness, voice changes, and enlarged lymph nodes in the neck. The clinical features associated with pheochromocytomas are high blood pressure, headache, tremors, palpitations, excessive sweating, anxiety and nervousness. In hyperparathyroidism, fatigue, weakness, joint and muscle pain, kidney stones, nausea and vomiting, constipation and abdominal pain are common.

Disease management

Treatment of MEN2 depends on the subtype and symptoms of the individual. Thyroidectomy (surgical removal of the thyroid gland) is one of the main treatments for MEN2. Removal of the glands associated with these disorders is also recommended to treat CMT and pheochromocytoma. The FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) have approved two tyrosine kinase inhibitor drugs, vandetanib and cabozantinib, for the treatment of patients with advanced progressive CMT.

Genes analyzed

RET

Bibliography

Carlson, K. M., Bracamontes, J., Jackson, C. E., et al . Parent-of-origin effects in multiple endocrine neoplasia type 2B. American journal of human genetics. 1994 Dec;55(6):1076-82.

Carlson, K. M., Dou, S., Chi, D., et al . Single missense mutation in the tyrosine kinase catalytic domain of the RET proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proceedings of the National Academy of Sciences of the United States of America. 1994 Feb 15;91(4):1579-83.

Eng C. Multiple Endocrine Neoplasia Type 2. GeneReviews®. University of Washington, Seattle; 1993-2023.

Eng, C., Mulligan, L. M., Smith, D. P., et al . Mutation of the RET proto-oncogene in sporadic medullary thyroid carcinoma. Genes, chromosomes & cancer. 1995 Mar;12(3):209-12.

Eng, C., Smith, D. P., Mulligan, L. M., et al . A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995 Feb 2;10(3):509-13.

Mathiesen, J. S., Effraimidis, G., Rossing, M., et al . Multiple endocrine neoplasia type 2: A review. Seminars in cancer biology. 2022 Feb;79:163-179.

Puñales, M. K., Graf, H., Gross, J. L., et al . RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. The Journal of clinical endocrinology and metabolism. 2003 Jun;88(6):2644-9.