Multiple endocrine neoplasia
Encyclopedia
The term multiple endocrine neoplasia
(MEN) encompasses several distinct syndrome
s featuring tumors of endocrine gland
s, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.
MEN syndromes are inherited as autosomal dominant disorders.
The term multiple endocrine neoplasia is used when two or more endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or more tumor types in a single patient does not automatically designate that individual as having MEN because there is a small statistical chance that development of two "sporadic" tumors that occur in one of the MEN syndromes could occur by chance.
The term "multiple endocrine neoplasia" was introduced in 1968, but descriptions of the condition date back to 1903.
and Carney complex
are two other autosomal dominant endocrine tumor syndromes with features that overlap the clinical features of the MEN syndromes. Although not transmitted in the germline, McCune-Albright syndrome
is a genetic syndrome characterized by endocrine neoplastic features involving endocrine glands that overlap with those involved in MEN1 or MEN2.
In 1953 Underdahl et al. reported a case series of 8 patients with a syndrome of pituitary, parathyroid, and pancreatic islet adenomas.
In 1954 Wermer noted that this syndrome was transmitted as a dominant trait.
In 1959 Hazard et al. described medullary (solid) thyroid carcinoma.
In 1961 Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma.
In 1966 Williams et al. described the combination of mucosal neuromas, pheochromocytoma and medullary thyroid carcinoma.
In 1968 Steiner et al. introduced the term "multiple endocrine neoplasia" (MEN) to describe disorders featuring combinations of endocrine tumors and proposed the terms 'Wermer syndrome' for MEN 1 and 'Sipple syndrome' for MEN 2.
In 1974 Sizemore et al. showed that the MEN 2 category included two groups of patients with MTC and pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B).
In 1988 the MEN1 locus was assigned to Chromosome 11 (11q13).
In 1993 the MEN2 gene (RET) was cloned.
In 1998 the MEN1 gene was cloned
MEN 2B
is sometimes known as MEN 3 and the designation varies by institution (c.f. www.ClinicalReview.com).
Although a variety of additional eponyms have been proposed for MEN2B (e.g. Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann–Froboese syndrome), none ever gained sufficient traction to merit continued use and, indeed, are all but abandoned in the medical literature. Another early report was Schimke et al. in 1968.
OMIM also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B
. The presentation is believed to overlap that of MEN1 and MEN2.
gene consists of ten exons, spanning about 10 kb, and encodes a 610 amino acid protein named menin. The first exon and the last part of exon 10 are not translated. A main transcript of 2.8 kb has been described in a large variety of human tissues (pancreas, thymus, adrenal glands, thyroid, testis, leukocytes, heart, brain, lung, muscle, small intestine, liver, and kidney); an additional transcript of approximately 4 kb has been detected in pancreas and thymus, suggesting a tissue-specific alternative splicing.
Fifty percent of patients develop signs and symptoms by 20 years of age and more than 95% have symptoms by 40 years of age. There is significant intra- and inter-familial variability in the age of onset, severity of disease, and tumor types. Despite numerous studies, no genotype-phenotype correlations have been established, suggesting that unknown genetic and environmental modifiers are involved in the expression of the MEN1 phenotype.
MEN1 patients usually have a family history of MEN1. Inheritance is autosomal dominant; any affected parent has a 50% chance to transmit the disease to his or her progeny. MEN1 gene mutations can be identified in 70-95% of MEN1 patients.
Many endocrine tumors in MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other MEN1 tumors are associated with an elevated risk for malignancy. About one third of patients affected with MEN1 will die early from an MEN1-related cancer or associated malignancy. Entero-pancreatic gastrinomas and thymic and bronchial carcinoids are the leading cause of morbidity and mortality. Consequently, the average age of death in individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.
Neoplasia
Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
(MEN) encompasses several distinct syndrome
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
s featuring tumors of endocrine gland
Endocrine gland neoplasm
An endocrine gland neoplasm is a neoplasm affecting one or more glands of the endocrine system.Examples include:* Adrenal tumor* Pituitary adenomaThe most common form is thyroid cancer....
s, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.
MEN syndromes are inherited as autosomal dominant disorders.
Terminology
The older names, "multiple endocrine adenomas" and "multiple endocrine adenomatosis" (MEA), have been replaced by the current terminology.The term multiple endocrine neoplasia is used when two or more endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or more tumor types in a single patient does not automatically designate that individual as having MEN because there is a small statistical chance that development of two "sporadic" tumors that occur in one of the MEN syndromes could occur by chance.
The term "multiple endocrine neoplasia" was introduced in 1968, but descriptions of the condition date back to 1903.
Related conditions
Although not officially categorized as multiple endocrine neoplasia syndromes, Von Hippel-Lindau diseaseVon Hippel-Lindau disease
Von Hippel–Lindau is a rare, autosomal dominant genetic condition in which hemangioblastomas are found in the cerebellum, spinal cord, kidney and retina. These are associated with several pathologies including renal angioma, renal cell carcinoma and pheochromocytoma...
and Carney complex
Carney complex
Carney complex, also known as LAMB syndrome and NAME syndrome is an autosomal dominant condition comprising myxomas of the heart and skin, hyperpigmentation of the skin , and endocrine overactivity It is distinct from Carney's triad...
are two other autosomal dominant endocrine tumor syndromes with features that overlap the clinical features of the MEN syndromes. Although not transmitted in the germline, McCune-Albright syndrome
McCune-Albright syndrome
McCune–Albright syndrome, described in 1937 by Donovan James McCune and Fuller Albright, is a genetic disorder of bones, skin pigmentation and hormonal problems along with premature puberty.-Symptoms:...
is a genetic syndrome characterized by endocrine neoplastic features involving endocrine glands that overlap with those involved in MEN1 or MEN2.
History
In 1903 Erdheim described the case of an acromegalic patient with a pituitary adenoma and three enlarged parathyroid glands.In 1953 Underdahl et al. reported a case series of 8 patients with a syndrome of pituitary, parathyroid, and pancreatic islet adenomas.
In 1954 Wermer noted that this syndrome was transmitted as a dominant trait.
In 1959 Hazard et al. described medullary (solid) thyroid carcinoma.
In 1961 Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma.
In 1966 Williams et al. described the combination of mucosal neuromas, pheochromocytoma and medullary thyroid carcinoma.
In 1968 Steiner et al. introduced the term "multiple endocrine neoplasia" (MEN) to describe disorders featuring combinations of endocrine tumors and proposed the terms 'Wermer syndrome' for MEN 1 and 'Sipple syndrome' for MEN 2.
In 1974 Sizemore et al. showed that the MEN 2 category included two groups of patients with MTC and pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B).
In 1988 the MEN1 locus was assigned to Chromosome 11 (11q13).
In 1993 the MEN2 gene (RET) was cloned.
In 1998 the MEN1 gene was cloned
Comparison
Percentages refer to how large fraction of people with the MEN type develop the neoplasia type.| Feature | MEN 1 Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:... |
MEN 2 Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant . They generally occur in endocrine organs Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary... |
||
|---|---|---|---|---|
| MEN 2A Multiple endocrine neoplasia type 2 Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant . They generally occur in endocrine organs Multiple endocrine neoplasia type 2 (also known as "Pheochromocytoma and amyloid producing medullary... |
MEN 2B Multiple endocrine neoplasia type 2b Multiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands... |
FMTC | ||
| Eponym Eponym An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named... |
Wermer syndrome | Sipple syndrome | (multiple) | (none) |
| OMIM | ||||
| Pancreatic tumors | gastrinoma Gastrinoma A gastrinoma is a tumor in the pancreas or duodenum that secretes excess of gastrin leading to ulceration in the duodenum, stomach and the small intestine. There is hypersecretion of the HCl in the duodenum which causes the ulcers... (50%), insulinoma Insulinoma An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin.Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is... (20%), vipoma VIPoma A VIPoma is a rare endocrine tumor, usually originating in the pancreas, that produces vasoactive intestinal peptide .... , glucagonoma Glucagonoma A glucagonoma is a rare tumor of the alpha cells of the pancreas that results in up to a 1000-fold overproduction of the hormone glucagon. Alpha cell tumors are commonly associated with glucagonoma syndrome, though similar symptoms are present in cases of pseudoglucagonoma syndrome in the absence... , PPoma |
- | - | - |
| Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland, and account for about 15% of intracranial neoplasms. Tumors which exceed 10 mm in size are defined as macroadenomas, and those smaller than 10 mm are referred to as microadenomas... |
66% | - | - | - |
| Parathyroid hyperplasia | 90% | 50% | - | - |
| Medullary thyroid carcinoma | - | 100% | 85% | 100% |
| Pheochromocytoma Pheochromocytoma A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent... |
- | >33% | 50% | - |
| Marfanoid Marfan syndrome Marfan syndrome is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers.... body habitus |
- | - | 80% | - |
| Mucosal neuroma Neuroma A neuroma is a growth or tumor of nerve tissue. Just as the Latin word for swelling is now restricted to neoplasias, the equivalent Greek suffix -oma has shared in that fate. Thus, the typical modern usage of neuroma is for nerve tumors... |
- | - | 100% | - |
| Gene Gene A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains... (s) |
MEN1 MEN1 Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1.... |
RET RET proto-oncogene The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules.... |
RET RET proto-oncogene The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules.... |
RET RET proto-oncogene The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor family of extracellular signalling molecules.... , NTRK1 |
| Approx. prevalence Prevalence In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population... |
1 in 35,000 (1 in 20,000 to 1 in 40,000) |
1 in 40,000 | 1 in 40,000 | |
| Initial description (year) | 1954 | 1961 | 1965 | |
MEN 2B
Multiple endocrine neoplasia type 2b
Multiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands...
is sometimes known as MEN 3 and the designation varies by institution (c.f. www.ClinicalReview.com).
Although a variety of additional eponyms have been proposed for MEN2B (e.g. Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann–Froboese syndrome), none ever gained sufficient traction to merit continued use and, indeed, are all but abandoned in the medical literature. Another early report was Schimke et al. in 1968.
OMIM also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B
CDKN1B
Cyclin-dependent kinase inhibitor 1B is an enzyme that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4...
. The presentation is believed to overlap that of MEN1 and MEN2.
The MEN1 gene
The MEN1MEN1
Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1....
gene consists of ten exons, spanning about 10 kb, and encodes a 610 amino acid protein named menin. The first exon and the last part of exon 10 are not translated. A main transcript of 2.8 kb has been described in a large variety of human tissues (pancreas, thymus, adrenal glands, thyroid, testis, leukocytes, heart, brain, lung, muscle, small intestine, liver, and kidney); an additional transcript of approximately 4 kb has been detected in pancreas and thymus, suggesting a tissue-specific alternative splicing.
The Menin Protein
Menin is a 610 amino acid (67Kda) nuclear protein, highly conserved from mouse (98%), rat (97%) and, more distantly, zebrafish (75%) and Drosophila (47%) (47-51). Human and mouse MEN1 amino acid sequences share 95.8% identity and 98.4% similarity. Analysis of menin amino acid sequence did not reveal homologies to any other known human or mammalian protein, sequence motif, or signal peptide. The absence of significant homology to any other protein complicates efforts to elucidate the functions of menin.Pathophysiology
MEN1 follows Knudson’s “two-hit” model for tumor suppressor gene carcinogenesis (30). The first hit is a heterozygous MEN1 germline mutation, inherited from one parent (familial cases) or developed in an early embryonic stage (sporadic cases) and present in all cells at birth. The second hit is a MEN1 somatic mutation, usually a large deletion, that occurs in the predisposed endocrine cell as loss of the remaining wild-type allele and gives cells the survival advantage needed for tumor development.MEN1 mutations in multiple endocrine neoplasia patients and clinical genetics
MEN1 gene mutations can be identified in 70-95% of MEN1 patients and in about 20% of familial isolated hyperparathyroidism cases. Almost all patients are heterozygous for mutations. One affected family has been identified with individuals both homozygous and heterozygous for MEN1 mutations. In this family, there was no difference in disease history between the homozygous and heterozygous mutation carriers.Fifty percent of patients develop signs and symptoms by 20 years of age and more than 95% have symptoms by 40 years of age. There is significant intra- and inter-familial variability in the age of onset, severity of disease, and tumor types. Despite numerous studies, no genotype-phenotype correlations have been established, suggesting that unknown genetic and environmental modifiers are involved in the expression of the MEN1 phenotype.
Manifestations
Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract (30-80% of cases), and anterior pituitary (15-90% of cases). Other endocrine and non-endocrine neoplasms including adrenocortical and thyroid tumors, visceral and cutaneous lipomas, meningiomas, facial angiofibromas and collagenomas, and thymic, gastric, and bronchial carcinoids also occur. The phenotype of MEN1 is broad, and over 20 different combinations of endocrine and non-endocrine manifestations have been described. MEN1 should be suspected in patients with an endocrinopathy of two of the three characteristic affected organs, or with an endocrinopathy of one of these organs plus a first-degree relative affected by MEN1 syndrome.MEN1 patients usually have a family history of MEN1. Inheritance is autosomal dominant; any affected parent has a 50% chance to transmit the disease to his or her progeny. MEN1 gene mutations can be identified in 70-95% of MEN1 patients.
Many endocrine tumors in MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other MEN1 tumors are associated with an elevated risk for malignancy. About one third of patients affected with MEN1 will die early from an MEN1-related cancer or associated malignancy. Entero-pancreatic gastrinomas and thymic and bronchial carcinoids are the leading cause of morbidity and mortality. Consequently, the average age of death in individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.
Recommended cancer surveillance
A recommend surveillance program for Multiple Endocrine Neoplasia Type 1 has been suggested by the International Guidelines for Diagnosis and Therapy of MEN syndromes group.See also
- Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1Multiple endocrine neoplasia type 1 or Wermer's syndrome is part of a group of disorders that affect the endocrine system.-Explanation:...
- Multiple endocrine neoplasia type 2a
- Multiple endocrine neoplasia type 2bMultiple endocrine neoplasia type 2bMultiple endocrine neoplasia type 3 is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands...
External links
- Endocrine and Metabolic Diseases Information Service
- The Association for Multiple Endocrine Neoplasia Disorders (AMEND)
- A Personal Blog (Thyroid Cancer and Pheochromocytoma, MEN 2B)
- Multiple Endocrine Neoplasia type 2 (MEN2 RET database)