Multiple endocrine neoplasia(MEN): Pathogenesis, Symptoms & Treatments
Multiple endocrine neoplasia (MEN) is a tumor that occurs in two or more endocrine organs, and can be classified into four types: MEN 1,2,3,4. Each MEN can be inherited dominantly or sporadically without family history. The diagnosis of MEN is based on the following: (1) two or more clinical features according to the associated tumor, (2) family history, (3) genetic mutation associated with MEN, . In particular, genetic testing is crucial for the clinical diagnosis of MEN, and it is also very important for screening people who have genetic mutations in their families and for early treatment.
Men type 1 (Wermer's syndrome) is characterized by the presence of parathyroids, pancreatic islets, and anterior pituitary tumors, and adrenal cortical tumors, carcinoid tumors of the foregut, meningiomas, facial angiofibromas, collagenomas, and lipomas . The prevalence of MEN1 is approximately 0.25%, ranging from 1-18% in primary hyperparathyroidism, 16-38% in pancreatic islet tumors, and less than 3% in pituitary tumor patients. MEN are present in all ages, and most clinical and biochemical aspects associated with MEN tumors are known to occur at ages 40-49. Untreated patients can prematurely die and the probability of dying before age 50 reaches 50%. Tumors that cause death include pancreatic neuroendocrine tumor (NET), foregut carcinoid, and others.
MEN 2 (Sipple's syndrome) is characterized by the occurrence of medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors, again divided into three clinical variants: MEN 2A, MEN 2B, and MTC only. MEN2A is the most common form of MEN2, and MTC is known to be associated in 50% of patients with pheochromocytomas and 20% of patients with parathyroid tumors. It is known that MEN2B is known as MEN type 3, and the occurrence of MTC and pheochoromocytoma is associated with the Marfanoid habitus (mucosal neuromas of the lips, tongue, eyelids, medullated corneal fibers, intestinal autonomic ganglion dysfunction leading to multiple diverticulae and megacolon) . These variants of MEN type 2 are all caused by a mutation of the RET protooncogene. In the case of MEN2A, mutations in the cysteine-rich extracellular domain (95%) and codon 634 (85%) are common. In MEN 2B / MEN 3 patients, the codon 918 mutation (~ 95%) appears predominantly in the intracellular tyrosine kinase domain.
Patients with MEN 1-associated tumors (parathyroid adenomas, pituitary adenomas, pancreatic NETs) associated with gonadal, adrenal, renal, and thyroid tumors were classified as MEN type 4 with mutations in the CDNKIB gene.
MEN type 2 is a dominant genetic disorder caused by a mutation in the RET protooncogene on chromosome 10, occurring at approximately 1 / 30,000 of the general population. MEN2A and MEN2B belonging to MEN type 2 show high penetrance to the dominant genetics and may appear as multicentric tumor formation depending on the organs in which RET protooncogene is expressed. Especially in the thyroid, parathyroid, and adrenal glands, which may lead to a decrease in the patient's life expectancy and quality of life. Therefore, early diagnosis and treatment of disease is very important for the prognosis of patients, and this can be confirmed by the change of prognosis of patients according to early diagnosis of MTC.
In the case of MEN2A, it is classified again into four variants: Classical MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HD), and Familial MTC (FMTC). The clinical features of MEN2A may vary depending on the area of expression of the RET protooncogene, and the penetrance of MTC reaches 100%.
MTC is a neuroendocrine tumor that occurs in the parafollicular C cell of the thyroid gland. MTC occurs in almost all cases of MEN type 2 patients. In the case of MEN2A-associated MTC, it is known to occur mainly at 20-29 years earlier than MEN2B. In the absence of clinical manifestations of MTC, prophylactic total thyroidectomy with a systematic central neck dissection and life-long thyroxine replacement before 1 to 5 years of age may be helpful in improving the prognosis of patients with MEN type 2, Total thyroidectomy with bilateral central resection is recommended.
Pheochromocytoma occurs in more than 50% of MEN2A patients and is a major cause of mortality and morbidity. Patients may present with symptoms of cathecholamine secretion (headache, throbbing, sweating), and in the absence of symptoms, they are found through bio-chemical screening based on the family history of MEN. In both cases, surgical removal is recommended.
Parathyroid tumors occur in 10-25% of MEN2A patients, but more than half of the patients do not show hypocalcemia. In these normocalcemic patients, abnormally enlarged parathyroid findings may be observed when thyroidectomy for MTC is performed.
To date, about 50 mutants of the RET protooncogene have been reported to be present in exons 5, 8, 10, 11, 13, 14, 15, and 16 of GEN2. RET germline mutations are observed in more than 95% of MEN2A patients, of which Cys634Arg mutations are the most common.
Men type 1 (Wermer's syndrome) is characterized by the presence of parathyroids, pancreatic islets, and anterior pituitary tumors, and adrenal cortical tumors, carcinoid tumors of the foregut, meningiomas, facial angiofibromas, collagenomas, and lipomas . The prevalence of MEN1 is approximately 0.25%, ranging from 1-18% in primary hyperparathyroidism, 16-38% in pancreatic islet tumors, and less than 3% in pituitary tumor patients. MEN are present in all ages, and most clinical and biochemical aspects associated with MEN tumors are known to occur at ages 40-49. Untreated patients can prematurely die and the probability of dying before age 50 reaches 50%. Tumors that cause death include pancreatic neuroendocrine tumor (NET), foregut carcinoid, and others.
MEN 2 (Sipple's syndrome) is characterized by the occurrence of medullary thyroid carcinoma (MTC), pheochromocytomas, and parathyroid tumors, again divided into three clinical variants: MEN 2A, MEN 2B, and MTC only. MEN2A is the most common form of MEN2, and MTC is known to be associated in 50% of patients with pheochromocytomas and 20% of patients with parathyroid tumors. It is known that MEN2B is known as MEN type 3, and the occurrence of MTC and pheochoromocytoma is associated with the Marfanoid habitus (mucosal neuromas of the lips, tongue, eyelids, medullated corneal fibers, intestinal autonomic ganglion dysfunction leading to multiple diverticulae and megacolon) . These variants of MEN type 2 are all caused by a mutation of the RET protooncogene. In the case of MEN2A, mutations in the cysteine-rich extracellular domain (95%) and codon 634 (85%) are common. In MEN 2B / MEN 3 patients, the codon 918 mutation (~ 95%) appears predominantly in the intracellular tyrosine kinase domain.
Patients with MEN 1-associated tumors (parathyroid adenomas, pituitary adenomas, pancreatic NETs) associated with gonadal, adrenal, renal, and thyroid tumors were classified as MEN type 4 with mutations in the CDNKIB gene.
MEN type 2 is a dominant genetic disorder caused by a mutation in the RET protooncogene on chromosome 10, occurring at approximately 1 / 30,000 of the general population. MEN2A and MEN2B belonging to MEN type 2 show high penetrance to the dominant genetics and may appear as multicentric tumor formation depending on the organs in which RET protooncogene is expressed. Especially in the thyroid, parathyroid, and adrenal glands, which may lead to a decrease in the patient's life expectancy and quality of life. Therefore, early diagnosis and treatment of disease is very important for the prognosis of patients, and this can be confirmed by the change of prognosis of patients according to early diagnosis of MTC.
In the case of MEN2A, it is classified again into four variants: Classical MEN2A, MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HD), and Familial MTC (FMTC). The clinical features of MEN2A may vary depending on the area of expression of the RET protooncogene, and the penetrance of MTC reaches 100%.
MTC is a neuroendocrine tumor that occurs in the parafollicular C cell of the thyroid gland. MTC occurs in almost all cases of MEN type 2 patients. In the case of MEN2A-associated MTC, it is known to occur mainly at 20-29 years earlier than MEN2B. In the absence of clinical manifestations of MTC, prophylactic total thyroidectomy with a systematic central neck dissection and life-long thyroxine replacement before 1 to 5 years of age may be helpful in improving the prognosis of patients with MEN type 2, Total thyroidectomy with bilateral central resection is recommended.
Pheochromocytoma occurs in more than 50% of MEN2A patients and is a major cause of mortality and morbidity. Patients may present with symptoms of cathecholamine secretion (headache, throbbing, sweating), and in the absence of symptoms, they are found through bio-chemical screening based on the family history of MEN. In both cases, surgical removal is recommended.
Parathyroid tumors occur in 10-25% of MEN2A patients, but more than half of the patients do not show hypocalcemia. In these normocalcemic patients, abnormally enlarged parathyroid findings may be observed when thyroidectomy for MTC is performed.
To date, about 50 mutants of the RET protooncogene have been reported to be present in exons 5, 8, 10, 11, 13, 14, 15, and 16 of GEN2. RET germline mutations are observed in more than 95% of MEN2A patients, of which Cys634Arg mutations are the most common.
