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Multiple endocrine neoplasia type 2A(MEN2A)

MedGen UID:
9958
Concept ID:
C0025268
Neoplastic Process
Synonyms: MEN 2A; MEN-2A syndrome; MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; Pheochromocytoma and amyloid producing medullary thyroid carcinoma; PTC syndrome; Sipple syndrome
SNOMED CT: Multiple endocrine neoplasia type 2A (721188000); MEN (multiple endocrine neoplasia) type 2A (721188000); MEN2A - multiple endocrine neoplasia type 2A (721188000)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: 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.
 
Gene (location): RET (10q11.21)
 
Monarch Initiative: MONDO:0008234
OMIM®: 171400
Orphanet: ORPHA247698

Disease characteristics

Excerpted from the GeneReview: Multiple Endocrine Neoplasia Type 2
Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, familial medullary thyroid carcinoma (FMTC, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features of MEN2B 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 MEN2B, early adulthood in MEN2A, and middle age in FMTC. [from GeneReviews]
Authors:
Charis Eng  |  Gilman Plitt   view full author information

Additional descriptions

From OMIM
Multiple endocrine neoplasia type IIA is an autosomal dominant syndrome of multiple endocrine neoplasms, including medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas. MEN2B (162300), characterized by MTC with or without pheochromocytoma and with characteristic clinical abnormalities such as ganglioneuromas of the lips, tongue and colon, but without hyperparathyroidism, is also caused by mutation in the RET gene (summary by Lore et al., 2001). For a discussion of genetic heterogeneity of multiple endocrine neoplasia, see MEN1 (131100).  http://www.omim.org/entry/171400
From MedlinePlus Genetics
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.

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 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.

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.  https://medlineplus.gov/genetics/condition/multiple-endocrine-neoplasia

Clinical features

From HPO
Chest pain
MedGen UID:
2992
Concept ID:
C0008031
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to the chest.
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 distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; 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 lead to catecholamine excess. Symptoms of PGL/PCC result from either 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 developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Medullary thyroid carcinoma
MedGen UID:
66772
Concept ID:
C0238462
Neoplastic Process
The presence of a medullary carcinoma of the thyroid gland.
Parathyroid gland adenoma
MedGen UID:
75502
Concept ID:
C0262587
Neoplastic Process
A benign tumor of the parathyroid gland that can cause hyperparathyroidism.
Elevated urinary epinephrine level
MedGen UID:
358197
Concept ID:
C1868393
Finding
The concentration of epinephrine in the urine, normalized for urine concentration, is above the upper limit of normal.
Elevated urinary vanillylmandelic acid
MedGen UID:
866485
Concept ID:
C4020735
Finding
An increased concentration of vanillylmandelic acid in the urine.
Elevated urinary dopamine level
MedGen UID:
868696
Concept ID:
C4023099
Finding
The concentration of dopamine in the urine, normalized for urine concentration, is above the upper limit of normal.
Elevated urinary norepinephrine level
MedGen UID:
1841548
Concept ID:
C5826344
Finding
The concentration of noradrenaline in the urine, normalized for urine concentration, is above the upper limit of normal.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Hypertensive crisis
MedGen UID:
5701
Concept ID:
C0020546
Finding
A severe, acute increase in blood pressure that may result in stroke or myocardial ischemia.
Palpitations
MedGen UID:
14579
Concept ID:
C0030252
Finding
A sensation that the heart is pounding or racing, which is a non-specific sign but may be a manifestation of arrhythmia.
Aganglionic megacolon
MedGen UID:
5559
Concept ID:
C0019569
Disease or Syndrome
The disorder described by Hirschsprung (1888) and known as Hirschsprung disease or aganglionic megacolon is characterized by congenital absence of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the gastrointestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR) when aganglionosis extends proximal to the sigmoid (Amiel et al., 2008). Total colonic aganglionosis and total intestinal HSCR also occur. Genetic Heterogeneity of Hirschsprung Disease Several additional loci for isolated Hirschsprung disease have been mapped. HSCR2 (600155) is associated with variation in the EDNRB gene (131244) on 13q22; HSCR3 (613711) is associated with variation in the GDNF gene (600837) on 5p13; HSCR4 (613712) is associated with variation in the EDN3 gene (131242) on 20q13; HSCR5 (600156) maps to 9q31; HSCR6 (606874) maps to 3p21; HSCR7 (606875) maps to 19q12; HSCR8 (608462) maps to 16q23; and HSCR9 (611644) maps to 4q31-q32. HSCR also occurs as a feature of several syndromes including the Waardenburg-Shah syndrome (277580), Mowat-Wilson syndrome (235730), Goldberg-Shprintzen syndrome (609460), and congenital central hypoventilation syndrome (CCHS; 209880). Whereas mendelian modes of inheritance have been described for syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. The development of surgical procedures decreased mortality and morbidity, which allowed the emergence of familial cases. HSCR occurs as an isolated trait in 70% of patients, is associated with chromosomal anomaly in 12% of cases, and occurs with additional congenital anomalies in 18% of cases (summary by Amiel et al., 2008).
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Elevated circulating calcitonin concentration
MedGen UID:
401432
Concept ID:
C1868394
Finding
Concentration of calcitonin, a 32-amino acid polypeptide hormone that is produced primarily by the parafollicular cells of the thyroid, in the blood circulation above the upper limit of normal.
Cutaneous lichen amyloidosis
MedGen UID:
812175
Concept ID:
C3805845
Disease or Syndrome
Lichen amyloidosis presents with multiple localized or rarely generalized, hyperpigmented grouped papules with a predilection for the shins, calves, ankles, and dorsa of the feet and thighs.
Hyperparathyroidism
MedGen UID:
6967
Concept ID:
C0020502
Disease or Syndrome
Excessive production of parathyroid hormone (PTH) by the parathyroid glands.
Thyroid nodule
MedGen UID:
21547
Concept ID:
C0040137
Neoplastic Process
A nodular lesion that develops in the thyroid gland. The term "thyroid nodule" refers to any abnormal growth that forms a lump in the thyroid gland.
Thyroid C cell hyperplasia
MedGen UID:
90975
Concept ID:
C0342190
Disease or Syndrome
An abnormal growth of parafollicular (C-cells) cells.
Increased circulating cortisol level
MedGen UID:
871175
Concept ID:
C4025651
Finding
Overproduction of the hormone of cortisol by the adrenal cortex, resulting in a characteristic combination of clinical symptoms termed Cushing syndrome, with truncal obesity, a round, full face, striae atrophicae and acne, muscle weakness, and other features.

Term Hierarchy

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

Professional guidelines

PubMed

Elisei R, Bottici V, Cappagli V, Ramone T, Tacito A, Ciampi R, Romei C
Ann Endocrinol (Paris) 2019 Jun;80(3):187-190. Epub 2019 Apr 11 doi: 10.1016/j.ando.2019.04.014. PMID: 31053251
Tang KL, Lin Y, Li LM
World J Surg Oncol 2014 Jan 9;12:8. doi: 10.1186/1477-7819-12-8. PMID: 24400812Free PMC Article
Raue F, Frank-Raue K
Clinics (Sao Paulo) 2012;67 Suppl 1(Suppl 1):69-75. doi: 10.6061/clinics/2012(sup01)13. PMID: 22584709Free PMC Article

Curated

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

Recent clinical studies

Etiology

Mathiesen JS, Effraimidis G, Rossing M, Rasmussen ÅK, Hoejberg L, Bastholt L, Godballe C, Oturai P, Feldt-Rasmussen U
Semin Cancer Biol 2022 Feb;79:163-179. Epub 2021 Apr 1 doi: 10.1016/j.semcancer.2021.03.035. PMID: 33812987
Fallahi P, Ferrari SM, Galdiero MR, Varricchi G, Elia G, Ragusa F, Paparo SR, Benvenga S, Antonelli A
Semin Cancer Biol 2022 Feb;79:180-196. Epub 2020 Nov 26 doi: 10.1016/j.semcancer.2020.11.013. PMID: 33249201
Fishbein L
Curr Cardiol Rep 2019 Jul 31;21(9):104. doi: 10.1007/s11886-019-1184-y. PMID: 31367972
Griebeler ML, Gharib H, Thompson GB
Endocr Pract 2013 Jul-Aug;19(4):703-11. doi: 10.4158/EP12430.RA. PMID: 23512389
Raygada M, Pasini B, Stratakis CA
Adv Otorhinolaryngol 2011;70:99-106. Epub 2011 Feb 24 doi: 10.1159/000322484. PMID: 21358191Free PMC Article

Diagnosis

Jayasinghe R, Basnayake O, Jayarajah U, Seneviratne S
J Int Med Res 2022 Jul;50(7):3000605221110698. doi: 10.1177/03000605221110698. PMID: 35822284Free PMC Article
Fallahi P, Ferrari SM, Galdiero MR, Varricchi G, Elia G, Ragusa F, Paparo SR, Benvenga S, Antonelli A
Semin Cancer Biol 2022 Feb;79:180-196. Epub 2020 Nov 26 doi: 10.1016/j.semcancer.2020.11.013. PMID: 33249201
Castinetti F
Aging (Albany NY) 2019 Jun 12;11(11):3416-3417. doi: 10.18632/aging.102030. PMID: 31188782Free PMC Article
Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma
Thyroid 2015 Jun;25(6):567-610. doi: 10.1089/thy.2014.0335. PMID: 25810047Free PMC Article
White ML, Doherty GM
Surg Oncol Clin N Am 2008 Apr;17(2):439-59, x. doi: 10.1016/j.soc.2007.12.002. PMID: 18375361

Therapy

Fallahi P, Ferrari SM, Galdiero MR, Varricchi G, Elia G, Ragusa F, Paparo SR, Benvenga S, Antonelli A
Semin Cancer Biol 2022 Feb;79:180-196. Epub 2020 Nov 26 doi: 10.1016/j.semcancer.2020.11.013. PMID: 33249201
Redaelli S, Plaza-Menacho I, Mologni L
Endocr Relat Cancer 2018 Feb;25(2):T53-T68. doi: 10.1530/ERC-17-0297. PMID: 29348306
Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma
Thyroid 2015 Jun;25(6):567-610. doi: 10.1089/thy.2014.0335. PMID: 25810047Free PMC Article
White ML, Doherty GM
Surg Oncol Clin N Am 2008 Apr;17(2):439-59, x. doi: 10.1016/j.soc.2007.12.002. PMID: 18375361
Macdonald JS
Curr Opin Oncol 1991 Feb;3(1):139-41. doi: 10.1097/00001622-199102000-00019. PMID: 1675125

Prognosis

Mathiesen JS, Effraimidis G, Rossing M, Rasmussen ÅK, Hoejberg L, Bastholt L, Godballe C, Oturai P, Feldt-Rasmussen U
Semin Cancer Biol 2022 Feb;79:163-179. Epub 2021 Apr 1 doi: 10.1016/j.semcancer.2021.03.035. PMID: 33812987
Fallahi P, Ferrari SM, Galdiero MR, Varricchi G, Elia G, Ragusa F, Paparo SR, Benvenga S, Antonelli A
Semin Cancer Biol 2022 Feb;79:180-196. Epub 2020 Nov 26 doi: 10.1016/j.semcancer.2020.11.013. PMID: 33249201
Castinetti F
Aging (Albany NY) 2019 Jun 12;11(11):3416-3417. doi: 10.18632/aging.102030. PMID: 31188782Free PMC Article
Griebeler ML, Gharib H, Thompson GB
Endocr Pract 2013 Jul-Aug;19(4):703-11. doi: 10.4158/EP12430.RA. PMID: 23512389
Raygada M, Pasini B, Stratakis CA
Adv Otorhinolaryngol 2011;70:99-106. Epub 2011 Feb 24 doi: 10.1159/000322484. PMID: 21358191Free PMC Article

Clinical prediction guides

Al-Salameh A, Baudry C, Cohen R
Presse Med 2018 Sep;47(9):722-731. Epub 2018 Jun 13 doi: 10.1016/j.lpm.2018.03.005. PMID: 29909163
Grey J, Winter K
Endocr Relat Cancer 2018 Feb;25(2):T69-T77. Epub 2017 Oct 24 doi: 10.1530/ERC-17-0335. PMID: 29066504
Tsang VH, Tacon LJ, Learoyd DL, Robinson BG
Recent Results Cancer Res 2015;204:157-78. doi: 10.1007/978-3-319-22542-5_7. PMID: 26494388
Delorme S, Raue F
Recent Results Cancer Res 2015;204:91-116. doi: 10.1007/978-3-319-22542-5_4. PMID: 26494385
Viola D, Romei C, Elisei R
Endocr Dev 2014;26:202-13. Epub 2014 Aug 29 doi: 10.1159/000363165. PMID: 25231454

Recent systematic reviews

Scapineli JO, Ceolin L, Puñales MK, Dora JM, Maia AL
Fam Cancer 2016 Oct;15(4):625-33. doi: 10.1007/s10689-016-9892-6. PMID: 26920351
Coyle D, Friedmacher F, Puri P
Pediatr Surg Int 2014 Aug;30(8):751-6. Epub 2014 Jun 28 doi: 10.1007/s00383-014-3538-2. PMID: 24972642
Scholten A, Schreinemakers JM, Pieterman CR, Valk GD, Vriens MR, Borel Rinkes IH
Endocr Pract 2011 Jan-Feb;17(1):7-15. doi: 10.4158/EP10050.OR. PMID: 20570815

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