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PubMed2006

Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.

Adenoma↗
PubMed2007

The multiple endocrine neoplasia syndromes.

Multiple endocrine neoplasia (MEN) type 1 and type 2 exhibit an autosomal dominant pattern of inheritance. In the past two decades the germline mutations that cause these inherited syndromes have been identified. The large majority of patients with MEN1 have mutations in the menin gene. Mutations in the REarranged during Transfection (RET) gene cause MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Specific codon mutations within RET correlate with disease phenotype and severity. Also, children from families with MEN2A, MEN2B, or FMTC, who are found to have inherited a mutated RET allele, can be managed by prophylactic thyroidectomy, thus preventing the development of medullary thyroid carcinoma (MTC), the dominant endocrinopathy in patients with these hereditary syndromes. New insights into the molecular pathway of RET signal transduction are leading to novel targeted therapies in patients with locally advanced or metastatic hereditary MTC.

Humans↗
PubMed1991

Application of MEN 203 as a polymorphic DNA probe in screening multiple endocrine neoplasia 2a.

Multiple endocrine neoplasia 2a (MEN 2a) is known to be genetically linked to a locus on chromosome 10. The application of polymorphic DNA probes for the region has made it possible to identify carriers of the disease susceptible gene. We performed DNA analysis for a newly found non-Caucasian MEN 2a family using MEN 203 as a probe. Data from DNA analysis of the family members were concordant with the results of conventional endocrinological tests. Furthermore, DNA analysis discriminated four individuals out of fifteen as non-carriers of the gene with a high degree of certainty. The results relieved these people from taking screening tests for years. DNA analysis employing suitable markers such as MEN 203 appears to be useful for a screening program of MEN 2a in Japanese as well as Caucasians.

Aged↗
PubMed2006

Molecular implications of RET mutations for pheochromocytoma risk in multiple endocrine neoplasia 2.

Multiple endocrine neoplasia Type 2 (MEN 2) is an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC). The disease has three subtypes, which are distinguished by the presence of additional phenotypes. In particular, pheochromocytoma occurs in approximately 50% of patients with the MEN 2A or MEN 2B subtypes, but is not found in patients with the milder disease subtype, familial MTC (FMTC). All subtypes of MEN 2 are caused by activating mutations of the RET (REarranged in Transfection) proto-oncogene. RET encodes a transmembrane receptor tyrosine kinase, required for development of neuroendocrine cell types and the kidneys. All MEN 2 subtypes are associated with single amino acid substitution mutations that are found in either the extracellular domain or in the kinase domain of RET. There are strong genotype-phenotype correlations in MEN 2 between patient phenotype and the specific residue that is mutated. MEN 2A is primarily associated with substitutions at five extracellular cysteine residues, while 95% of MEN 2B is associated with a single methionine to threonine mutation in the kinase domain (M918T). In FMTC, RET mutations are more broadly distributed, with both extracellular cysteines and intracellular sites implicated. In all cases, MEN 2-RET mutations result in constitutive activation of the receptor, although the mechanism and relative functional effects of the mutations vary. Recent advances in functional characterization and development of molecular models of RET and of various MEN 2-RET mutants are helping us understand tissue-specific differences in oncogenic potential conferred by the different RET mutations. Here, we discuss and compare several well-characterized mutations of the extracellular and kinase domains, which have quite varied functional implications.

Adrenal Gland Neoplasms↗
PubMed1983

The Multiple Endocrine Neoplasia syndromes.

The Multiple Endocrine Neoplasia syndromes are familial disorders in which neoplastic changes develop in multiple endocrine tissues. Almost all of these diseases are inherited as autosomal dominant traits with complete penetrance but variable expressivity. Classification of the Multiple Endocrine Neoplasias is based on the pattern of endocrine organ involvement. Multiple Endocrine Neoplasia Type I (MEN-I) is characterized by the concurrence of pituitary adenomas, parathyroid hyperplasia and pancreatic islet cell neoplasms. Multiple Endocrine Neoplasia Type II (MEN-II or IIa) consists of medullary thyroid carcinoma (MTC), parathyroid hyperplasia and pheochromocytomas. Multiple Endocrine Neoplasia Type IIb (MEN-IIb) is similar to MEN-IIa in that affected patients have MTC and pheochromocytomas. Multiple mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract are also present in patients with MEN-IIb, but these individuals rarely manifest hyperparathyroidism. The Multiple Endocrine Neoplasia syndromes have attracted a great deal of attention because of their characteristic clinical features and familial pattern of occurrence. By utilizing recently developed "provocative tests" it is possible through aggressive screening of kindred members at risk to detect certain of these diseases (particularly MTC and pancreatic islet cell neoplasia) at an early stage. Therapeutic intervention in selected patients is associated with a high cure rate.

Adenoma, Islet Cell↗
PubMed2001

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene.

Adenoma↗
PubMed1998

[Multiple endocrine neoplasia associated with multiple lipomas].

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN-1) is characterized by tumors of the parathyroids, the neuroendocrine pancreas-duodenum and the anterior pituitary, but shows also a wide clinical variety of other symptoms. CASE REPORT: We present a case of a 68-year-old woman with a 18 year history of MEN-1 consisting of gastrinoma and primary hyperparathyroidism. Beside these typical symptoms, the patient suffered from thyroid adenoma, malignant kidney tumor and multiple subcutaneous lipomas. RESULT: While the number of autopsies declined from 113 in 1977 to 66 in 1984, the number of diagnostic techniques used increased continuously (94, 107, 118 and 140, amounting to 0.83, 1.34, 1.76 and 2.12 per patient). The premortal detection of abdominal abnormalities increased globally from 16.8 to 32.5%. This increase was largely due to better diagnosis of liver and gallbladder abnormalities which were in most cases of little relevance. CONCLUSION: Whether these non-endocrine tumors are associated to MEN-1 is unclear and has to be tested by examining the chromosomal regions 11q13 and 11q24/25 of the tumors sample, in which the possible MEN-1 involved tumor suppressor genes are located.

Aged↗
PubMed1995

[Screening of multiple endocrine neoplasias type 1. Reflexions of the Study Group on Multiple Endocrine Neoplasias type 1].

The "Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1 (GENEM 1)" is a French group involved in a comprehensive multicentre study of Multiple Endocrine Neoplasia type 1 syndrome (NEM 1). The objectives of this group are to define diagnostic and therapeutic protocols and to carry out genetic research on NEM1. The first aim of physicians is to recognize the syndrome and to determine the appropriate screening especially into two circumstances: 1 degree In case of isolated and sporadic glandular disease -i-e-parathyroid glands, endocrine pancreas, antehypophysis, adrenal glands and neuroendocrine tumors? 2 degrees In case of very high probability of NEM 1 syndrome? This paper answers these two questions, based on the analysis of the first 150 cases collected by the GENEM 1.

Adenoma↗
PubMedDate not supplied

Genetic testing in multiple endocrine neoplasia and related syndromes.

Multiple Endocrine Neoplasia (MEN) syndromes are inherited diseases characterised by endocrine tumours occuring as autosomal dominant genetic diseases with high penetrance. In MEN1, most tumours affect the parathyroids, endocrine pancreas, anterior pituitary, and adrenal glands. The MEN1 gene has been cloned recently and encodes a nuclear protein without known function so far. More than 200 germline mutations have been identified in MEN1 patients throughout the entire coding sequence and no genotype-phenotype correlation has been found. Now, MEN1 gene screening is a powerful tool in pre-symptomatic diagnosis for MEN1 patients and those with inherited MEN1 related syndromes. MEN2 refers to the inherited forms of medullary thyroid carcinoma (MTC) which is associated with phaechromocytoma and parathyroid tumours in MEN2A, phaechromocytoma and mucosal neuromas in MEN2B. Familial isolated MTC is characterised by MTC only, and the three variants of MEN2 are related to germline missense mutations of the RET proto-oncogene, which encodes a tyrosine-kinase receptor. Germline RET mutations in MEN2 patients are related to the two main functionnal domains in the RET protein, the extracellular ligand binding domain (MEN2A and FMTC) and the intracellular catalytic domain (MEN2A, MEN2B and FMTC). Genotype-phenotype correlations have been established but must be used carefully in clinical practice. RET mutation analysis is now available for patients and prophylactic thyroidectomy in gene-carriers could be the most reliable way to cure the patients. Mechanisms of tumourigenesis induced by MEN2-related RET germline mutations have been analysed by in vitro studies and the generation of transgenic mice which develop true bilateral MTC. Recent insights on MEN syndrome pathogenesis and related inherited endocrine disorders have a major clinical impact and fundamental studies are now in progress in order to identify all genetic events leading from a normal endocrine tissue towards a fully malignant phenotype.

Adult↗
PubMed1994

[Multiple endocrine neoplasia type I. Review and presentation of the study group of multiple endocrine neoplasia type I (GENEM I)].

Multiple endocrine neoplasia type I, also known as Wermer's syndrome, is characterized by the presence of functioning or nonfunctioning tumors or hyperplasia of the parathyroid glands, pancreatic islet cells and pituitary gland. MEN I syndrome may be either familial or sporadic. MEN I locus has recently been mapped to chromosome 11, and further characterization of the abnormal gene appears imminent. The GENEM I, a multidisciplinary study group is in the process of formation. Pathologists have to specify the morphological criteria of hyperplasia vs tumor. Further characterization of the gene and its product requires the application of molecular biology methods to the pathologic tissues of these patients.

Adrenal Gland Neoplasms↗
PubMed1997

Pulmonary lymphangioleiomyoma in a patient with multiple endocrine neoplasia type I.

The multiple endocrine neoplasia (M.E.N.) syndromes consist of a group of proliferative disorders that selectively target specific sets of endocrine and soft tissue cells. Here we report a case of lymphangioleiomyoma of the lung in a patient with multiple endocrine neoplasia Type I (M.E.N. I). This is the first time such an association has been reported. In our opinion it could possibly be ascribed to the genetic predisposition to proliferative disorders of patients with M.E.N. syndromes.

Female↗
PubMed2006

Impact of RET proto-oncogene analysis on the clinical management of multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, primary hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia type 2 is still an underdiagnosed, or late-diagnosed condition in many areas of the world. Since 1993, when the first missense RET proto-oncogene (RET) mutations were reported in MEN2, up to 46 different RET-causing disease mutations have been described. Since a strong genotype-phenotype correlation exists for MEN2, the detection of RET mutations has produced a major impact in early recognition and treatment of MTC and MEN2. Presently, RET mutation analysis should be performed for all MEN2 cases and their at-risk familial relatives. Further, prophylactic total thyroidectomy is indicated in all cases harboring activating gametic RET mutations. In most RET mutation carriers, prophylactic total thyroidectomy is indicated at ages as early as a few months to 4 years of age, promoting longer survival and improvement of quality of life or even definitive cure. We discuss the large impact of RET proto-oncogene analysis on the clinical management of MEN2 and the role of early RET molecular DNA diagnosis in providing clinicians and surgeons with valuable information that enables them to indicate early total thyroidectomy.

Carcinoma, Medullary↗
PubMed1994

Molecular mechanisms of neoplasia in multiple endocrine neoplasia type 1-related and sporadic tumors of the pancreatic islet cells.

Pancreatic islet tumors are relatively rare in the general population but occur frequently in patients with MEN 1. Delineation of the genetic events leading to neoplastic transformation of islet cells is at an early stage; but based on tumor deletion studies, it appears that inactivation of the MEN 1 gene is an early step in carcinogenesis for both sporadic and MEN 1-related tumors. Limited data also suggested a role for other tumor suppressors including the retinoblastoma, adenomatous polyposis coli, and Gorlin syndrome genes. Activation of oncogenes has not been identified in pancreatic islet tumors.

Adenoma, Islet Cell↗
PubMed2005

Multiple endocrine neoplasia--introduction.

Each multiple endocrine neoplasia (MEN) syndrome expresses striking features of hormone oversecretion from its own characteristic group of tissues. Additional expressions include non-hormonal tumours in each MEN syndrome and selected cancers in some syndromes. The complexity of its stereotyped features results in difficult management issues that often justify cooperation across multiple specialties. MEN syndromes, though rare, have long received intense study as models for more common diseases. The syndromal nature often with a large pedigree has promoted recent discovery of the main gene that differs for each of the six MEN syndromes. Each mutant gene has been introduced into clinical decision-making and into further clarification of tumorigenesis. This mini-symposium is related to the 9th International Workshop on Multiple Endocrine Neoplasia in June 2004; it consists of six manuscripts. They report new developments in clinical practices and in basic understandings about this rapidly advancing field.

Genotype↗
PubMed2004

[Multiple endocrine neoplasia syndroms. Type 1].

Multiple endocrine neoplasia (MEN) type 1 syndrome or Wermer syndrome is a classical malignant neoplasia syndrome, inherited in the autosomal dominant pattern, when hyperplastic and/or neoplastic injury develops synchronously or metachronously in the cells of the parathyroid gland, pancreas islets, hypophysis, and rarer in other neuroendocrine organs. The syndrome develops when germinative MEN 1--neoplasia suppression gene inactivation mutations occurs. More than 95 percent of patients have this MEN 1 gene mutation, when the penetration of mutation is almost 100 percent. An early stage of this syndrome is hyperfunction in organs, with the syndromes of hormone excess, later benign and/or malign neoplasia develops, this mostly determines the prognosis for the patient. The risk of this syndrome developing should be estimated for all the patients diagnosed with endocrine organ hyperplasia, which determines hyperfunction, or endocrine organs neoplasia. For patients with multiple endocrine neoplasia type 1 syndrome, endocrine neoplasia develops earlier than in sporadic cases; multifocality is typical for them. Multifocality of neoplasia, typical combinations of injuries and anamnesis of the family helps to diagnose the syndrome. Diagnosis is confirmed through genetical analysis, which is also important in determining the inheritors of mutations, potential patients. After genetically diagnosing multiple endocrine neoplasia type 1 syndrome, it is not enough to analyze and look after patients with malignant neoplasia, or to make early diagnosis on pre-neoplasic disease and neoplasia, or to apply means of prevention and start well-timed treatment, but also to diagnose this syndrome for the patient's relatives, and to determine their risk of getting cancer. This opens new possibilities in early diagnostics and prevention of malignant neoplasia. The main purpose of this literature review is to introduce medical-practitioners to the newest theories of type 1 multiple endocrine neoplasia syndrome pathogenesis, clinical peculiarities, methods of diagnostics and treatment.

Adult↗
PubMed2025

Approach to the Patient With Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disorder in which patients develop multiple endocrine tumors simultaneously. Among these, primary hyperparathyroidism is the most common and often the earliest manifestation. All patients with MEN1 and hypercalcemia should have surgery, with most patients requiring surgical treatment before the age of 50 years. The timing of parathyroid surgery mainly depends on hypercalcemia and the presence of renal or skeletal complications. The goals of treatment are to correct hypercalcemia, prevent target organ damage, and minimize the risk of postoperative hypoparathyroidism as much as possible. Currently, the most widely recommended surgical approach is subtotal parathyroidectomy via the cervical approach (removal of 3 or 3.5 glands). With advances in imaging technology, patients with clearly localized lesions-particularly younger patients-may be candidates for individualized unilateral resection (ie, removal of both glands on the affected side). In addition, recurrent hypercalcemia after surgery is relatively common in patients with MEN1. The management of the remaining glands remains challenging, such patients usually need reoperation, calcimimetic therapy, or clinical observation. For patients requiring repeated parathyroid surgeries, in addition to searching for multifocal lesions, the possibility of ectopic parathyroid glands should also be taken into account. Ectopic parathyroid adenoma, caused by abnormal embryonic migration, complicates surgery in both sporadic and MEN1-related primary hyperparathyroidism. However, in MEN1, their higher frequency and multiglandular distribution make localization even more challenging, often leading to incomplete resection and recurrence.

Humans↗
PubMed2005

Lessons from genes mutated in multiple endocrine neoplasia (MEN) syndromes.

Multiple endocrine neoplasia (MEN) types 1 and 2 syndromes are rare hereditary cancer syndromes expressing a variety of endocrine and non-endocrine neoplasias and lesions. The improving of both molecular and clinical genetics knowledge helps health care providers in the whole spectrum of the clinical managements of MEN patients. The MEN1 gene, a tumour suppressor gene, is responsible of MEN1 syndrome, and is probably involved in the regulation of several cell functions, including DNA replication and repair and transcriptional machinery. RET proto-oncogene encodes for a receptor tyrosine kinase protein whose expression is fundamental for appropriate migration, development and differentiation of neuroendocrine cells originating from neural crest. Currently, DNA testing makes possible the early identification of germline mutation in asymptomatic mutant gene carriers in both MEN syndromes. Consequently, the combination of new genetic and diagnostic tools could permit a precocious detection of MEN-associated neoplasms, and in particular the identification of a strong genotype-phenotype correlations in MEN2 syndrome demonstrates an improving outcome and quality of life for affected subjects.

Humans↗
PubMed2003

Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by the occurrence of multiple endocrine tumors of the parathyroid, pancreas, and anterior pituitary in patients. To study tumorigenesis related to the MEN1 syndrome, we have generated Men1 knockout mice using the gene targeting approach. Heterozygous Men1 mutant mice developed the same range of major endocrine tumors as is seen in MEN1 patients, affecting the parathyroid, pancreatic islets, pituitary and adrenal glands, as well as the thyroid, and exhibiting multistage tumor progression with metastatic potential. In particular, extrapancreatic gastrinoma, pancreatic glucagonoma, and mixed hormone-producing tumors in islets were observed. In addition, there was a high incidence of gonadal tumors of endocrine origin, i.e. Leydig cell tumors, and ovary sex-cord stromal cell tumors in heterozygous Men1 mutant mice. Hormonal disturbance, such as abnormal PTH and insulin levels, was also observed in these mice. These tumors were associated with loss of heterozygosity of the wild-type Men1 allele, suggesting that menin is involved in suppressing the development of these endocrine tumors. All of these features are reminiscent of MEN1 symptoms in humans and establish heterozygous Men1 mutant mice as a suitable model for this disease.

Animals↗