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Multiple Endocrine Neoplasia Type 2: an Overview Jessica Moline, MS1, and Charis Eng, MD, Phd1,2,3,4

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GENETEST REVIEW Genetics in Medicine Multiple endocrine neoplasia type 2: An overview Jessica Moline, MS1, and Charis Eng, MD, PhD1,2,3,4 TABLE OF CONTENTS Clinical Description of MEN 2 .......................................................................755 Surveillance...................................................................................................760 Multiple endocrine neoplasia type 2A (OMIM# 171400) ....................756 Medullary thyroid carcinoma ................................................................760 Familial medullary thyroid carcinoma (OMIM# 155240).....................756 Pheochromocytoma ................................................................................760 Multiple endocrine neoplasia type 2B (OMIM# 162300) ....................756 Parathyroid adenoma or hyperplasia ...................................................761 Diagnosis and testing......................................................................................756 Hypoparathyroidism................................................................................761 Clinical diagnosis: MEN 2A........................................................................756 Agents/circumstances to avoid .................................................................761 Clinical diagnosis: FMTC ............................................................................756 Testing of relatives at risk...........................................................................761 Clinical diagnosis: MEN 2B ........................................................................756 Therapies under investigation ...............................................................761 Histological, biochemical, and imaging studies .....................................756 Other..........................................................................................................761 MTC and C-cell hyperplasia...................................................................756 Genetic counseling......................................................................................761 Pheochromocytoma ................................................................................757 Mode of inheritance................................................................................761 Parathyroid abnormalities.......................................................................757 Risk to family members ..........................................................................761 Molecular genetic testing...........................................................................757 Related genetic counseling issues.........................................................761 Genetically related (allelic) disorders........................................................758 Testing of at-risk individuals ..............................................................761 Hirschsprung disease...............................................................................758 Considerations in families with de novo mutations ......................762 Papillary thyroid carcinoma ...................................................................758 Genetic cancer risk assessment and counseling.............................762 Genotype-phenotype correlations ................................................................758 Family planning ...................................................................................762 Differential diagnosis.......................................................................................759 Prenatal testing ........................................................................................762 Apparently sporadic MTC ..........................................................................759 Preimplantation genetic diagnosis........................................................762 Pheochromoctyoma ....................................................................................759 Molecular genetics ..........................................................................................762 Hyperparathryoidism...................................................................................760 Molecular genetic pathogenesis ...............................................................762 Intestinal ganglioneuromatosis..................................................................760 Normal allelic variants.................................................................................762 Disease management......................................................................................760 Pathologic allelic variants ...........................................................................762 Treatment of manifestations......................................................................760 Normal gene product .................................................................................762 Prevention of primary manifestations ......................................................760 Abnormal gene product .............................................................................762 Prevention of secondary manifestations ..................................................760 References .........................................................................................................762 Abstract: Multiple endocrine neoplasia type 2 is historically composed germline RET mutation is critical for the prevention and management of of three clinical subtypes, all of which are associated with germline potentially life-threatening neoplasms. This overview summarizes the mutations in the RET proto-oncogene. Multiple endocrine neoplasia clinical description of multiple endocrine neoplasia type 2, diagnosis type 2A, familial medullary thyroid carcinoma, and multiple endocrine and testing strategies, management and surveillance, and differential neoplasia type 2B are collectively associated with a 70–100% risk of diagnosis for other related syndromes. Genet Med 2011:13(9):755–764. medullary thyroid carcinoma by age 70 years. Pheochromocytomas are Key Words: multiple endocrine neoplasia type 2, MEN 2A, MEN 2B, identified in 50% of individuals with multiple endocrine neoplasia type FMTC, medullary thyroid carcinoma 2A and multiple endocrine neoplasia type 2B. Furthermore, those with multiple endocrine neoplasia type 2A have a 20–30% risk for primary hyperparathyroidism. Individuals with multiple endocrine neoplasia he identification and phenotypic characterization of germ- type 2B often have distinct physical features including mucosal neuro- Tline high-penetrance gain-of-function mutations in the RET mas of the lips and tongue, medullated corneal nerve fibers, ganglion- proto-oncogene, encoding a receptor tyrosine kinase, as causing euromatosis of the gastrointestinal tract, distinctive facies with enlarged the great majority of multiple endocrine neoplasia (MEN) type lips, and a “Marfanoid” body habitus. Clinical recognition and accurate 2 (MEN 2) heralded the era of accurate, evidence-based molec- diagnosis of individuals and families who are at risk of harboring a ular diagnosis, predictive testing, genetic counseling, gene- informed cancer risk assessment, and preventative medicine. MEN 2, occurring in 1:200,000 live births, is an autosomal From the 1Genomic Medicine Institute, Lerner Research Institute, Cleveland dominant neuroendocrine neoplasia predisposition syndrome Clinic; 2Taussig Cancer Institute, Cleveland Clinic; 3Department of Genet- characterized by variable penetrance of medullary thyroid car- 4 ics, Case Western Reserve University School of Medicine; and Case Com- cinoma (MTC), pheochromocytoma, and hyperparathyroidism prehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. (HPT). Age at presentation, frequency, and age-related pen- etrances of component neoplasias vary between each subtype of Charis Eng, MD, PhD, Cleveland Clinic, Genomic Medicine Institute, 9500 MEN 2 and most likely are genotype dependent. Euclid Avenue, NE-50, Cleveland, OH 44195. E-mail: [email protected]. Disclosure: The authors declare no conflict of interest. Submitted for publication December 29, 2010. CLINICAL DESCRIPTION OF MEN 2 Accepted for publication February 18, 2011. Historically, MEN 2 has been divided into three subtypes Published online ahead of print May 5, 2011. depending on clinical features. With the identification and char- DOI: 10.1097/GIM.0b013e318216cc6d acterization of RET and genotype-associated phenotypes, it Genetics IN Medicine • Volume 13, Number 9, September 2011 755 Moline and Eng Genetics IN Medicine • Volume 13, Number 9, September 2011 became obvious that all three subtypes are allelic and that MEN Multiple endocrine neoplasia type 2B (OMIM# 2A and familial MTC (FMTC) are merely manifestations of 162300) different penetrances of RET mutations.1,2 The MEN 2B subtype comprises approximately 5% of cases of MEN 2. MEN 2B is characterized by the early development of an aggressive form of MTC in all affected individuals.21 Multiple endocrine neoplasia type 2A (OMIM# Individuals with MEN 2B who do not undergo thyroidectomy at 171400) an early age (Ͻ1 year) are likely to develop metastatic MTC at MEN 2A makes up approximately 70–80% of cases of MEN 2. an early age. Before intervention with early prophylactic thy- As genetic testing for RET mutations has become available, it has roidectomy, the average age of death in individuals with MEN become apparent that 70–95% of individuals with MEN 2A de- 2B was 21 years.
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