Multiple endocrine neoplasias
Multiple endocrine neoplasia (MEN) refers to a rare group of inherited disorders characterized by the development of tumors in multiple endocrine glands. It primarily consists of two main types: MEN1 and MEN2, both of which follow an autosomal dominant inheritance pattern. MEN1 is associated with tumors in the parathyroid glands, anterior pituitary, and pancreas, while MEN2 is subcategorized into MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC). MEN2A is linked to medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism, whereas MEN2B features similar cancers but also includes neuromas, with FMTC primarily involving medullary thyroid cancer.
The risk of inheriting these conditions is significant, as children of affected parents have a 50% chance of inheriting the defective gene. Symptoms vary widely depending on the tumors present, with MEN1 often presenting hyperparathyroidism and MEN2 commonly showing medullary thyroid cancer. Genetic testing is available for both types, particularly beneficial for MEN2 to enable early intervention and treatment. Overall, individuals with MEN syndromes typically face a lower life expectancy due to tumor-related complications and associated hormonal disturbances.
Multiple endocrine neoplasias
ALSO KNOWN AS: MEN; Wermer syndrome; Sipple syndrome
DEFINITION Multiple endocrine neoplasia (MEN) is a syndrome of rare, inherited endocrine disorders characterized by the development of tumors involving multiple endocrine organs. It is classified into two main types, MEN1 and MEN2, which are primarily autosomal dominant disorders. MEN1 was first described by Paul Wermer in 1954 and is characterized by tumors of the parathyroid gland, anterior thyroid gland, and pancreas. MEN2 is subcategorized into MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC). MEN2A was described by John Sipple in 1961 and is characterized by medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. MEN2B is characterized by medullary thyroid cancer, pheochromocytoma, and neuromas. FMTC is a variant of MEN2A in which there is a strong predilection for medullary thyroid cancer only.
Risk Factors
Because of the mode of transmission, each child of an affected parent has a 50 percent probability of acquiring the defective gene, and males and females are affected equally. Of the different types of MEN syndromes, MEN1 was the most common, with a of about 1 in 30,000 people, according to 2022 data from the Cleveland Clinic. MEN2 had a prevalence of about 1 in 35,000. Hyperparathyroidism is the most common manifestation in MEN1 and almost invariably presents before the age of fifty. Medullary thyroid cancer is the most common tumor in MEN2 and usually presents before the age of twenty.
Etiology and Genetics
MEN1 follows an autosomal dominant pattern of inheritance. In 1997, scientists discovered the culprit mutation, which involves inactivations of the tumor-suppressor gene MEN1 on the long arm of chromosome 11 (11q13). The gene product is a nuclear protein named Menin, which is a tumor-suppressor protein. It interacts with and normally suppresses JunD-dependent transcriptional activation. However, it is unclear why mutation of the gene would lead to unregulated cell growth, since JunD itself is associated with inhibition of cell growth. The actual phenotypic expression of tumors in MEN1 is also thought to be due to additional deletions of the normal copy of the gene. MEN2 also follows an autosomal dominant pattern of inheritance but involves genetic defects in the RET on chromosome 10. The RET protein is a receptor tyrosine expressed in cells of the thyroid gland, the adrenal gland, neurons, and other tissues, and appears to be involved in tissue growth and differentiation. MEN2A and FMTC share many similarities in the mutations affecting the RET gene, while MEN2B is due to an altogether different set of RET mutations. RET mutations in MEN2A/FMTC typically involve cysteine residues in the cysteine-rich region of the RET protein’s extracellular domain, while MEN2B is associated with a single Met to Thr mutation in the intracellular TK2 domain of the protein. Normally, the RET protein is activated by binding of one of its ligands with subsequent intracellular signal activation. However, the mutations in MEN2 leads to an ligand-independent activation of the signaling pathway. The mutations in MEN2 are unique because they lead to a gain of function, which is different from that of MEN1 and many other heritable predispositions for cancer, which are due to loss of function mutations involving inactivation of tumor-suppressor genes.
Symptoms
Because of the different tumors expressed in the different types of MEN syndromes, clinical symptoms and signs are variable and depend on the type of existing tumor, the amount of hormone produced, and individual responses to these changes. For example, patients with parathyroid gland involvement typically will have elevated parathyroid hormone, leading to elevated calcium levels, which can lead to bone pain, kidney stones, or confusion. Those with medullary thyroid cancer typically present with a thyroid mass or lymph node enlargement in the neck.
Screening and Diagnosis
It is unclear whether screening family members of those with MEN1 mutation actually leads to any overall benefits in the long term. Genetic testing is available, but the actual yield and cost-effectiveness of testing should be considered on an individual basis. Contrarily, screening and early diagnosis of family members with MEN2 kindreds has shown to be beneficial because medullary thyroid cancer is a life-threatening disease and can be cured or prevented with early surgery. Traditional biochemical testing has now been replaced by the more accurate DNA testing for the RET gene mutation.
Treatment and Therapy
General therapy for those with MEN syndromes include medical management of hormonal disturbances along with surgical treatment of underlying tumors if specific criteria are met and medical management is insufficient. Those with medullary thyroid cancer should have the thyroid gland removed, and pheochromocytomas should also be removed. Family members found to have a RET mutation should undergo preventive total thyroid gland removal, usually at an early age.
Prevention and Outcomes
Patients with MEN syndromes will usually have a lower life expectancy, usually from a combination of tumor burden, tumor spread, or complications from hormonal disturbances. In addition to high-risk family members being screened for common presentations such as hyperparathyroidism and medullary thyroid cancer, they should also be screened for the less common presentations such as pheochromocytomas.
Bibliography
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Giusti, Francesca, Francesca Marini, and Maria Luisa Brandi. "Multiple Endocrine Neoplasia Type 1." GeneReviews, 10 Mar. 2022, www.ncbi.nlm.nih.gov/books/NBK1538/. Accessed 10 Sept. 2024.
Kronenberg, Henry, et al. Williams Textbook of Endocrinology. 11th ed. Philadelphia: Saunders/Elsevier, 2007. Print.
Moline, Jessica, and Charis Eng. "Multiple Endocrine Neoplasia Type 2: An Overview." Genetics in Medicine, vol. 13, no. 9, September 2011, pp. 755-764, doi.org/10.1097/GIM.0b013e318216cc6d. Accessed 10 Sept. 2024.
"Multiple Endocrine Neoplasia (MEN)." Cleveland Clinic, 23 May 2022, my.clevelandclinic.org/health/diseases/23088-multiple-endocrine-neoplasia-men. Accessed 10 Sept. 2024.
Stratakis, C. A., ed. Endocrine Tumor Syndromes and Their Genetics. Basel: Karger, 2013. Print.
Wermer, Paul. “Genetic Aspect of Adenomatosis of Endocrine Glands.” American Journal of Medicine 16 (1954): 363–71. Print.