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Multiple endocrine neoplasia, type 2b(MEN2B)

MedGen UID:
9959
Concept ID:
C0025269
Neoplastic Process
Synonyms: MEN 2B; MEN IIB; MEN2B; Mucosal neuroma syndrome; Multiple endocrine neoplasia, type 3; Multiple endocrine neoplasia, type 3 (formerly); MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MULTIPLE ENDOCRINE NEOPLASIA, TYPE III; NEUROMATA, MUCOSAL, WITH ENDOCRINE TUMORS; Wagenmann-froboese syndrome
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Multiple endocrine neoplasia, type 3 (61530001); MEN, type 3 (61530001); Mucosal neuroma syndrome (61530001); Multiple endocrine neoplasia, type 2b (61530001); MEN 2B syndrome (61530001); MEN 3 - Multiple endocrine neoplasia type 3 (61530001); MEN 2B - Multiple endocrine neoplasia type 2B (61530001); Multiple endocrine neoplasia type 2B (61530001); MEN 3 syndrome (61530001); Multiple endocrine neoplasia type 3 (61530001)
 
Gene (location): RET (10q11.21)
OMIM®: 162300
Orphanet: ORPHA247709

Disease characteristics

Excerpted from the GeneReview: Multiple Endocrine Neoplasia Type 2
Multiple endocrine neoplasia type 2 (MEN 2) is classified into three subtypes: MEN 2A, FMTC (familial medullary thyroid carcinoma), and MEN 2B. All three subtypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B have an increased risk for pheochromocytoma; MEN 2A has an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a "marfanoid" habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC. [from GeneReviews]
Authors:
Jessica Marquard  |  Charis Eng   view full author information

Additional descriptions

From OMIM
Multiple endocrine neoplasia type IIB (MEN2B) is an autosomal dominant hamartoneoplastic syndrome characterized by aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and thickened corneal nerves. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus. Other more variable features include skeletal anomalies and gastrointestinal problems (review by Morrison and Nevin, 1996). For a discussion of genetic heterogeneity of multiple endocrine neoplasia (MEN), see MEN1 (131100).  http://www.omim.org/entry/162300
From GHR
Multiple endocrine neoplasia is a group of disorders that affect the body's network of hormone-producing glands called the endocrine system. Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia typically involves tumors (neoplasia) in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, the condition can be life-threatening.The major forms of multiple endocrine neoplasia are called type 1, type 2, and type 4. These types are distinguished by the genes involved, the types of hormones made, and the characteristic signs and symptoms.Many different types of tumors are associated with multiple endocrine neoplasia. Type 1 frequently involves tumors of the parathyroid glands, the pituitary gland, and the pancreas. Tumors in these glands can lead to the overproduction of hormones. The most common sign of multiple endocrine neoplasia type 1 is overactivity of the parathyroid glands (hyperparathyroidism). Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue.The most common sign of multiple endocrine neoplasia type 2 is a form of thyroid cancer called medullary thyroid carcinoma. Some people with this disorder also develop a pheochromocytoma, which is an adrenal gland tumor that can cause dangerously high blood pressure. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and familial medullary thyroid carcinoma (FMTC). These subtypes differ in their characteristic signs and symptoms and risk of specific tumors; for example, hyperparathyroidism occurs only in type 2A, and medullary thyroid carcinoma is the only feature of FMTC. The signs and symptoms of multiple endocrine neoplasia type 2 are relatively consistent within any one family.Multiple endocrine neoplasia type 4 appears to have signs and symptoms similar to those of type 1, although it is caused by mutations in a different gene. Hyperparathyroidism is the most common feature, followed by tumors of the pituitary gland, additional endocrine glands, and other organs.  https://ghr.nlm.nih.gov/condition/multiple-endocrine-neoplasia

Clinical features

Ganglioneuroma
MedGen UID:
6545
Concept ID:
C0017075
Neoplastic Process
A benign neoplasm that usually arises from the sympathetic trunk in the mediastinum, representing a tumor of the sympathetic nerve fibers arising from neural crest cells.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.
Medullary thyroid carcinoma
MedGen UID:
66772
Concept ID:
C0238462
Neoplastic Process
A neuroendocrine carcinoma arising from the C-cells of the thyroid gland. It is closely associated with multiple endocrine neoplasia syndromes. Approximately 10% to 20% of medullary thyroid carcinomas are familial. Patients usually present with a thyroid nodule that is painless and firm. In the majority of cases nodal involvement is present at diagnosis. Surgery is the preferred treatment for both primary lesions and recurrences. This carcinoma is generally not very sensitive to radiation and almost unresponsive to chemotherapy.
Proximal femoral epiphysiolysis
MedGen UID:
57704
Concept ID:
C0149887
Disease or Syndrome
A developmental deformity in which the metaphysis of the FEMUR moves proximally and anteriorly away from FEMUR HEAD (epiphysis) at the upper GROWTH PLATE. It is most common in male adolescents and is associated with a greater risk of early OSTEOARTHRITIS of the hip.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.
Disproportionate tall stature
MedGen UID:
323048
Concept ID:
C1836996
Finding
A tall and slim body build with increased arm span to height ratio (>1.05) and a reduced upper-to-lower segment ratio (<0.85), i.e., unusually long arms and legs. The extremities as well as the hands and feet are unusually slim.
Failure to thrive in infancy
MedGen UID:
358083
Concept ID:
C1867873
Finding
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of FECES. These symptoms are associated with a variety of causes, including low DIETARY FIBER intake, emotional or nervous disturbances, systemic and structural disorders, drug-induced aggravation, and infections.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency of loose or watery bowel movements.
Colonic diverticula
MedGen UID:
41628
Concept ID:
C0012811
Anatomical Abnormality
A pouch or sac opening from the COLON.
Aganglionic megacolon
MedGen UID:
6285
Concept ID:
C0025160
Pathologic Function
An abnormal dilation of the colon not due to obstruction.
Ganglioneuroma
MedGen UID:
6545
Concept ID:
C0017075
Neoplastic Process
A benign neoplasm that usually arises from the sympathetic trunk in the mediastinum, representing a tumor of the sympathetic nerve fibers arising from neural crest cells.
Aganglionic megacolon
MedGen UID:
6285
Concept ID:
C0025160
Pathologic Function
An abnormal dilation of the colon not due to obstruction.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.
Global developmental delay
MedGen UID:
892935
Concept ID:
C4020875
Pathologic Function
Elevated urinary epinephrine
MedGen UID:
358197
Concept ID:
C1868393
Finding
An increased concentration of adrenaline in the urine.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Muscular Diseases
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Elevated urinary epinephrine
MedGen UID:
358197
Concept ID:
C1868393
Finding
An increased concentration of adrenaline in the urine.
Elevated calcitonin
MedGen UID:
401432
Concept ID:
C1868394
Finding
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Abnormally increased curvature of the thoracic portion of the spine.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature of the lumbar portion of the spinal column.
Scoliosis
MedGen UID:
21278
Concept ID:
C0037932
Finding
Deformities of the SPINE characterized by abnormal bending or flexure in the vertebral column. They may be bending forward (KYPHOSIS), backward (LORDOSIS), or sideway (SCOLIOSIS).
Joint laxity
MedGen UID:
39439
Concept ID:
C0086437
Pathologic Function
Lack of stability of a joint.
Proximal femoral epiphysiolysis
MedGen UID:
57704
Concept ID:
C0149887
Disease or Syndrome
A developmental deformity in which the metaphysis of the FEMUR moves proximally and anteriorly away from FEMUR HEAD (epiphysis) at the upper GROWTH PLATE. It is most common in male adolescents and is associated with a greater risk of early OSTEOARTHRITIS of the hip.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
High, narrow palate
MedGen UID:
324787
Concept ID:
C1837404
Finding
The presence of a high and narrow palate.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Thick lower lip vermilion
MedGen UID:
473520
Concept ID:
C2053437
Finding
Abnormality of the skin
MedGen UID:
11449
Concept ID:
C0037268
Congenital Abnormality
A skin abnormality that is present at birth or detected in the neonatal period.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Nodular goiter
MedGen UID:
42271
Concept ID:
C0018023
Disease or Syndrome
An enlarged THYROID GLAND containing multiple nodules (THYROID NODULE), usually resulting from recurrent thyroid HYPERPLASIA and involution over many years to produce the irregular enlargement. Multinodular goiters may be nontoxic or may induce THYROTOXICOSIS.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.
Medullary thyroid carcinoma
MedGen UID:
66772
Concept ID:
C0238462
Neoplastic Process
A neuroendocrine carcinoma arising from the C-cells of the thyroid gland. It is closely associated with multiple endocrine neoplasia syndromes. Approximately 10% to 20% of medullary thyroid carcinomas are familial. Patients usually present with a thyroid nodule that is painless and firm. In the majority of cases nodal involvement is present at diagnosis. Surgery is the preferred treatment for both primary lesions and recurrences. This carcinoma is generally not very sensitive to radiation and almost unresponsive to chemotherapy.
Parathyroid hyperplasia
MedGen UID:
75767
Concept ID:
C0271844
Disease or Syndrome
Hyperplasia of the parathyroid gland.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Multiple endocrine neoplasia, type 2b in Orphanet.

Professional guidelines

PubMed

ACMG Board of Directors.
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. PMID: 25356965
Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society.
J Clin Endocrinol Metab 2014 Jun;99(6):1915-42. doi: 10.1210/jc.2014-1498. PMID: 24893135
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics.
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. PMID: 23788249Free PMC Article
Raue F, Rondot S, Schulze E, Szpak-Ulczok S, Jarzab B, Frank-Raue K
Eur J Hum Genet 2012 Jan;20(1) Epub 2011 Aug 24 doi: 10.1038/ejhg.2011.142. PMID: 21863057Free PMC Article
Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS).
Pancreas 2010 Aug;39(6):775-83. doi: 10.1097/MPA.0b013e3181ebb4f0. PMID: 20664475Free PMC Article
American Thyroid Association Guidelines Task Force., Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr
Thyroid 2009 Jun;19(6):565-612. doi: 10.1089/thy.2008.0403. PMID: 19469690
Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ
J Clin Endocrinol Metab 2001 Dec;86(12):5658-71. doi: 10.1210/jcem.86.12.8070. PMID: 11739416
Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjöld M, Komminoth P, Hendy GN, Mulligan LM
JAMA 1996 Nov 20;276(19):1575-9. PMID: 8918855

External

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Recent clinical studies

Etiology

Jones BA, Sisson JC
J Pediatr 1983 Feb;102(2):219-23. PMID: 6130134
Carney JA, Sizemore GW, Hayles AB
Pathobiol Annu 1978;8:105-53. PMID: 364372
Carney JA, Sizemore GW, Lovestedt SA
Oral Surg Oral Med Oral Pathol 1976 Jun;41(6):739-52. PMID: 1063979
Carney JA, Go VL, Sizemore GW, Hayles AB
N Engl J Med 1976 Dec 2;295(23):1287-91. doi: 10.1056/NEJM197612022952304. PMID: 980061

Diagnosis

Damm DD
Gen Dent 2010 Sep-Oct;58(5):457, 459. PMID: 20829172
Jones BA, Sisson JC
J Pediatr 1983 Feb;102(2):219-23. PMID: 6130134
Carney JA, Sizemore GW, Hayles AV
Cancer 1979 Dec;44(6):2173-83. PMID: 389410
Cuthbert JA, Gallagher ND, Turtle JR
Aust N Z J Med 1978 Oct;8(5):518-20. PMID: 33647
Carney JA, Hayles AB
Mayo Clin Proc 1977 Sep;52(9):543-8. PMID: 895196

Prognosis

Carney JA, Go VL, Sizemore GW, Hayles AB
N Engl J Med 1976 Dec 2;295(23):1287-91. doi: 10.1056/NEJM197612022952304. PMID: 980061

Clinical prediction guides

Winkelmann RK, Carney JA
J Invest Dermatol 1982 Nov;79(5):307-12. PMID: 6127365

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