multiple endocrine neoplasia type 2b

Summary

Summary: Similar to MEN2A, it is also caused by mutations of the MEN2 gene, also known as the RET proto-oncogene. Its clinical symptoms include medullary carcinoma (CARCINOMA, MEDULLARY) of THYROID GLAND and PHEOCHROMOCYTOMA of ADRENAL MEDULLA (50%). Unlike MEN2a, MEN2b does not involve PARATHYROID NEOPLASMS. It can be distinguished from MEN2A by its neural abnormalities such as mucosal NEUROMAS on EYELIDS; LIP; and TONGUE, and ganglioneuromatosis of GASTROINTESTINAL TRACT leading to MEGACOLON. It is an autosomal dominant inherited disease.

Top Publications

  1. Torre M, Martucciello G, Ceccherini I, Lerone M, Aicardi M, Gambini C, et al. Diagnostic and therapeutic approach to multiple endocrine neoplasia type 2B in pediatric patients. Pediatr Surg Int. 2002;18:378-83 pubmed
    ..The surgical treatment of MEN 2B is total thyroidectomy with cervical lymphadenectomy of the central compartment of the neck. When possible, this intervention should be performed prophylactically before 1 year of age...
  2. Donckier J, Rosiere A, Heureux E, Michel L. Diabetes mellitus as a primary manifestation of multiple endocrine neoplasia type 2B. Acta Chir Belg. 2008;108:732-7 pubmed
    A 22-year-old-man presenting with diabetes mellitus was found to suffer from multiple endocrine neoplasia type 2B (MEN B)...
  3. Gimm O, Marsh D, Andrew S, Frilling A, Dahia P, Mulligan L, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997;82:3902-4 pubmed
    ..Our data demonstrate a novel etiologic event which may have roles in predisposition to MEN 2B when present in the germline and in the pathogenesis of sporadic MTC when somatic...
  4. Jasim S, Ying A, Waguespack S, Rich T, Grubbs E, Jimenez C, et al. Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid. 2011;21:189-92 pubmed publisher
    Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at ..
  5. Choi S, Yoon S, Calabrese P, Arnheim N. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. PLoS Genet. 2012;8:e1002420 pubmed publisher
    b>Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome...
  6. Santoro M, Carlomagno F, Romano A, Bottaro D, Dathan N, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267:381-3 pubmed
    ..Oncogenic conversion of RET in these neoplastic syndromes establishes germline transmission of dominant transforming genes in human cancer...
  7. Shimotake T, Tsuda T, Aoi S, Fumino S, Iwai N. Iodine 123 metaiodobenzylguanidine radio-guided navigation surgery for recurrent medullary thyroid carcinoma in a girl with multiple endocrine neoplasia type 2B. J Pediatr Surg. 2005;40:1643-6 pubmed
    b>Multiple endocrine neoplasia type 2B (MEN 2B) is an inherited cancerous syndrome characterized by medullary thyroid carcinoma (MTC), adrenal pheochromocytoma, marfanoid habitus, and enteric ganglioneuromatosis...
  8. Spyer G, Ellard S, Turnpenny P, Hattersley A, Vaidya B. Phenotypic multiple endocrine neoplasia type 2B, without endocrinopathy or RET gene mutation: implications for management. Thyroid. 2006;16:605-8 pubmed
    ..We suggest that prophylactic thyroidectomy is unnecessary in these patients although they should still be screened for endocrinopathy on a regular basis...
  9. Cranston A, Carniti C, Oakhill K, Radzio Andzelm E, Stone E, McCallion A, et al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res. 2006;66:10179-87 pubmed
    ..Our findings have implications both in the clinic and in the successful development of novel kinase-targeted anticancer drugs...

More Information

Publications62

  1. Camacho C, Hoff A, Lindsey S, Signorini P, Valente F, Oliveira M, et al. Early diagnosis of multiple endocrine neoplasia type 2B: a challenge for physicians. Arq Bras Endocrinol Metabol. 2008;52:1393-8 pubmed
    ..Here we report four cases of MEN2B in which the late diagnosis had a significant impact in clinical evolution and, potentially, in overall survival...
  2. Leboulleux S, Travagli J, Caillou B, Laplanche A, Bidart J, Schlumberger M, et al. Medullary thyroid carcinoma as part of a multiple endocrine neoplasia type 2B syndrome: influence of the stage on the clinical course. Cancer. 2002;94:44-50 pubmed
    b>Multiple endocrine neoplasia type 2B (MEN 2B) is an exceptional syndrome, for which the optimal age of thyroidectomy is poorly established and the course of medullary thyroid carcinoma (MTC) is ill-defined.
  3. Menko F, van der Luijt R, de Valk I, Toorians A, Sepers J, van Diest P, et al. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab. 2002;87:393-7 pubmed
    ..Mutation analysis revealed a double RET germline mutation, Val804Met and Ser904Cys, in affected individuals. The clinical phenotype, the functional effect of the mutations, and the clinical implications of our findings are discussed...
  4. Fink A, Lapidot M, Spierer A. Ocular manifestations in multiple endocrine neoplasia type 2b. Am J Ophthalmol. 1998;126:305-7 pubmed
    To describe the clinical and laboratory findings in a patient with multiple endocrine neoplasia type 2b.
  5. Smith D, Houghton C, Ponder B. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997;15:1213-7 pubmed
    ..Identification of this new mutation will contribute to understanding the molecular basis of MEN 2B, and will assist in the clinical management of families harbouring this mutation...
  6. Fox E, Widemann B, Chuk M, Marcus L, Aikin A, Whitcomb P, et al. Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res. 2013;19:4239-48 pubmed publisher
  7. Sotos J. Abraham Lincoln's marfanoid mother: the earliest known case of multiple endocrine neoplasia type 2B?. Clin Dysmorphol. 2012;21:131-6 pubmed publisher
    ..directed at two monogenic disorders of the transforming growth factor ? system: Marfan syndrome and multiple endocrine neoplasia type 2B. The present report examines newly discovered phenotypic information about Lincoln's biological ..
  8. Brauckhoff M, Gimm O, Weiss C, Ukkat J, Sekulla C, Brauckhoff K, et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg. 2004;28:1305-11 pubmed
  9. Kitamura Y, Scavarda N, Wells S, Jackson C, Goodfellow P. Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet. 1995;4:1987-8 pubmed
  10. Wray C, Rich T, Waguespack S, Lee J, Perrier N, Evans D. Failure to recognize multiple endocrine neoplasia 2B: more common than we think?. Ann Surg Oncol. 2008;15:293-301 pubmed
    ..However, the diagnosis of MEN2B is often delayed beyond childhood, at which time medullary thyroid carcinoma (MTC) may be regionally advanced or metastatic. We examined the extent of this delay and its impact on the treatment of MTC...
  11. Jain S, Watson M, DeBenedetti M, Hiraki Y, Moley J, Milbrandt J. Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors. Cancer Res. 2004;64:3907-13 pubmed
    ..These findings provide molecular evidence that associate the previously unexplained skeletal abnormalities and early malignancy in MEN 2B compared with MEN 2A syndrome...
  12. Charfi S, Ayadi L, Ellouze S, Ghorbel R, Khabir A, Gouiaa N, et al. [Composite pheochromocytoma associated with multiple endocrine neoplasia type 2B]. Ann Pathol. 2008;28:225-8 pubmed publisher
  13. Iwashita T, Kato M, Murakami H, Asai N, Ishiguro Y, Ito S, et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene. 1999;18:3919-22 pubmed
  14. Rizzo C, Califano D, Colucci D Amato G, De Vita G, D Alessio A, Dathan N, et al. Ligand stimulation of a Ret chimeric receptor carrying the activating mutation responsible for the multiple endocrine neoplasia type 2B. J Biol Chem. 1996;271:29497-501 pubmed
    ..Moreover, we introduced the dominant mutation, responsible for the multiple endocrine neoplasia type 2B, in the catalytic domain of the Ret chimera...
  15. Romeo G, Ceccherini I, Celli J, Priolo M, Betsos N, Bonardi G, et al. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. 1998;243:515-20 pubmed
  16. Salvatore D, Melillo R, Monaco C, Visconti R, Fenzi G, Vecchio G, et al. Increased in vivo phosphorylation of ret tyrosine 1062 is a potential pathogenetic mechanism of multiple endocrine neoplasia type 2B. Cancer Res. 2001;61:1426-31 pubmed
    ..The more efficient triggering of these pathways may account for the difference between MEN2A and MEN2B syndromes...
  17. Brauckhoff M, Machens A, Hess S, Lorenz K, Gimm O, Brauckhoff K, et al. Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis. Surgery. 2008;144:1044-50; discussion 1050-3 pubmed publisher
    More than 90% of M918T carriers with multiple endocrine neoplasia type 2B (MEN 2B) harbor de novo mutations in the REarranged during Transfection (RET) protooncogene...
  18. Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, Aoki N, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999;90:1-5 pubmed
    ..Combinations of mutations of the RET proto-oncogene may cause oncogenic activities different from those of single mutations...
  19. Eter N, Klingmuller D, Hoppner W, Spitznas M. Typical ocular findings in a patient with multiple endocrine neoplasia type 2b syndrome. Graefes Arch Clin Exp Ophthalmol. 2001;239:391-4 pubmed
    ..Therefore, the importance of ophthalmic assessment in making the diagnosis has to be stressed...
  20. Nakata S, Okugi H, Saitoh Y, Takahashi H, Shimizu K. Multiple endocrine neoplasia type 2B. Int J Urol. 2001;8:398-400 pubmed
    We report a case of multiple endocrine neoplasia type 2B (MEN 2B) in a 30-year-old woman. There was no family history of MEN 2B in her family...
  21. Carlson K, Bracamontes J, Jackson C, Clark R, Lacroix A, Wells S, et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet. 1994;55:1076-82 pubmed
    b>Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities...
  22. Yin M, King S, Hutson J, Chow C. Multiple endocrine neoplasia type 2B diagnosed on suction rectal biopsy in infancy: a report of 2 cases. Pediatr Dev Pathol. 2006;9:56-60 pubmed
    ..showed a de novo germline Met918Thr mutation in both patients, confirming the diagnosis of multiple endocrine neoplasia type 2B (MEN 2B)...
  23. Fernández R, Navarro E, Antinolo G, Ruiz Ferrer M, Borrego S. Evaluation of the role of RET polymorphisms/haplotypes as modifier loci for MEN 2, and analysis of the correlation with the type of RET mutation in a series of Spanish patients. Int J Mol Med. 2006;17:575-81 pubmed
    ..Nevertheless, these observations do not permit us to exclude the possible role of other variants in RET or other related genes, in the final presentation of the disease...
  24. Blaugrund J, Johns M, Eby Y, Ball D, Baylin S, Hruban R, et al. RET proto-oncogene mutations in inherited and sporadic medullary thyroid cancer. Hum Mol Genet. 1994;3:1895-7 pubmed
  25. Murakumo Y, Jijiwa M, Asai N, Ichihara M, Takahashi M. RET and neuroendocrine tumors. Pituitary. 2006;9:179-92 pubmed
    ..In this review, we summarize progress in the study of RET from bench to bedside, focusing on pathophysiology of neuroendocrine tumors...
  26. Zhang X, Wang J, Zhang Y, Wan H, Zhang B, Yan D, et al. [Genotype-phenotype correlations in multiple endocrine neoplasia type 2]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2016;51:538-41 pubmed publisher
    ..To evaluate the relationship between different RET mutations and the aggressiveness of hereditary medullary thyroid cancer (HMTC) or the presentation of other endocrine disorders in patients with multiple endocrine neoplasia type 2 (MEN2)...
  27. Truchot F, Grezard P, Wolf F, Balme B, Perrot H. Multiple idiopathic mucocutaneous neuromas: a new entity?. Br J Dermatol. 2001;145:826-9 pubmed
    ..Biological, morphological and genetic investigations were negative and excluded the diagnosis of multiple endocrine neoplasia type 2b. After reviewing the literature, we concluded that our patient has an extremely unusual acquired ..
  28. Ellard S. Multiple endocrine neoplasia types 1 and 2. Methods Mol Med. 2004;92:267-83 pubmed
  29. Kambouris M, Jackson C, Feldman G. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat. 1996;8:64-70 pubmed
    ..Confirmation of the specific mutation can be achieved by restriction enzymatic digestion (if feasible) or by DNA sequencing...
  30. Tumer N, Brown J, Carballeira A, Fishman L. Tyrosine hydroxylase gene expression in varying forms of human pheochromocytoma. Life Sci. 1996;59:1659-65 pubmed
    ..benign intra-adrenal chromaffin tumors and other non-malignant intra-adrenal tumors associated with multiple endocrine neoplasia type 2B (MEN 2B) and von Hippel-Lindau disease along with one extra-adrenal malignant pheochromocytoma...
  31. Tomida I, Rohrbach J, Zierhut M, Dralle H. [Conjunctival neuromas and prominent corneal nerve fibers as diagnostic indication of multiple endocrine disease]. Klin Monbl Augenheilkd. 2001;218:463-5 pubmed
    ..Multiple endocrine neoplasias (MEN-syndromes) represent diverse, mostly autosomal-dominant inherited, seldom sporadic diseases. MEN 2B-syndrome comprises medullary thyroid carcinoma, pheochromocytoma and mucosal neuromas...
  32. de Bonilla Damiá Á, Calvo Morón C, De la Riva Pérez P, Iglesias Jerez R, Molina Mora M, Castro Montaño J. [Detection by SPECT-CT scan with (99m)Tc-(V) DMSA of bone metastases in patient with medullary thyroid cancer]. Rev Esp Med Nucl. 2011;30:365-7 pubmed publisher
    ..We analyze the role of DMSA-V and the new hybrid SPECT-CT scan systems in the extension study and monitoring of medullary thyroid cancer...
  33. Søndergaard Pedersen J, Schaffalitzky De Muckadell O. Choroidal metastases in multiple endocrine neoplasia type 2B. Acta Ophthalmol Scand. 2007;85:120-1 pubmed
  34. Frank Raue K, Rondot S, Raue F. Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC. Mol Cell Endocrinol. 2010;322:2-7 pubmed publisher
    ..MEN 2 provides a unique model for early prevention and cure of cancer and for the roles of stratified mutation-based diagnosis and therapy of carriers...
  35. Hutson J, Catto Smith T, Gibb S, Chase J, Shin Y, Stanton M, et al. Chronic constipation: no longer stuck! Characterization of colonic dysmotility as a new disorder in children. J Pediatr Surg. 2004;39:795-9 pubmed
  36. Margraf R, Mao R, Wittwer C. Rapid diagnosis of MEN2B using unlabeled probe melting analysis and the LightCycler 480 instrument. J Mol Diagn. 2008;10:123-8 pubmed publisher
    b>Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant, inherited cancer syndrome. MEN2B patients have a high risk of developing medullary thyroid carcinoma, and prophylactic thyroidectomy is recommended by 6 months of age...
  37. Engelmann D, Koczan D, Ricken P, Rimpler U, Pahnke J, Li Z, et al. Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance. Endocr Relat Cancer. 2009;16:211-24 pubmed publisher
  38. Milman S, Whitney K, Fleischer N. Metastatic medullary thyroid cancer presenting with elevated levels of CA 19-9 and CA 125. Thyroid. 2011;21:913-6 pubmed publisher
    ..We report a novel finding of metastatic MTC presenting with elevated CA 19-9 and CA 125 serum levels, with concurrent tissue staining for these antigens...
  39. Katai M, Sakurai A, Fukushima Y. [Genetic testing and counseling for familial tumor syndromes]. Gan To Kagaku Ryoho. 2002;29:502-7 pubmed
    ..Genetic medicine is not sufficiently available at present in Japan. Establishment of genetic services that deal with genetic counseling, family support and ethical, social and legal issues is strongly desired...
  40. Handa S, Saraswat A, Radotra B, Kumar B. Chronic macrocheilia: a clinico-pathological study of 28 patients. Clin Exp Dermatol. 2003;28:245-50 pubmed
    ..More such studies from other centres will help physicians to make an accurate aetiological diagnosis and treat this uncommon but disfiguring condition with confidence...
  41. Costamagna D, Spinelli A, Sandru R, Mioli P, Pintor M, Bona R. Differential diagnosis and surgical management of megacolon in a woman with multiple endocrine neoplasia type 2. Tech Coloproctol. 2007;11:284-5 pubmed
  42. Hwang E, Kim D, Hwang J, Jung H, Suh J, Park Y, et al. Regulation of signal transducer and activator of transcription 1 (STAT1) and STAT1-dependent genes by RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncogenic tyrosine kinases. Mol Endocrinol. 2004;18:2672-84 pubmed
    ..Such immune response-promoting activity of RET/PTC may also relate to the development of Hashimoto's thyroiditis...
  43. Jindrichova S, Vcelak J, Vlcek P, Neradilova M, Nemec J, Bendlova B. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004;183:257-65 pubmed
    ..The genotype/phenotype correlations are given. Genetic testing revealed germ-line mutations in 23 index patients, 24 family members and excluded them in 53 relatives...
  44. Karges W, Adler G. [Clinical genetics of neuroendocrine tumors]. Med Klin (Munich). 2003;98:712-6 pubmed
    ..NETs thus represent a paradigmatic example of the successful link between basic genetic science and clinical care in molecular medicine...
  45. Montoya Martínez G, Moreno Palacios J, Serrano Brambila E. [Lumboscopic adrenalectomy for pheochromocytoma in a patient with multiple endocrine neoplasia type 2B]. Cir Cir. 2009;77:131-3 pubmed
    b>Multiple endocrine neoplasia type 2B (MEN 2B) is an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, a marfanoid habitus and mucosal ganglioneuromatosis...
  46. Unruh A, Fitze G, Jänig U, Bielack S, Lochbühler H, Coerdt W. Medullary thyroid carcinoma in a 2-month-old male with multiple endocrine neoplasia 2B and symptoms of pseudo-Hirschsprung disease: a case report. J Pediatr Surg. 2007;42:1623-6 pubmed
  47. Ledwidge S, Moorghen M, Longman R, Thomas M. Adult transmural intestinal ganglioneuromatosis is not always associated with multiple endocrine neoplasia or neurofibromatosis: a case report. J Clin Pathol. 2007;60:222-3 pubmed
  48. Gestblom C, Sweetser D, Doggett B, Kapur R. Sympathoadrenal hyperplasia causes renal malformations in Ret(MEN2B)-transgenic mice. Am J Pathol. 1999;155:2167-79 pubmed
    ..Our observations illustrate a novel pathogenic mechanism for renal dysgenesis that may explain how putative activating mutations of the RET gene can produce a phenotype usually associated with RET deficiency...
  49. Paris J, McCandlish I, Schwarz T, Simpson J, Smith S. Small intestinal ganglioneuromatosis in a dog. J Comp Pathol. 2013;148:323-8 pubmed publisher
    ..This is the first report of small intestinal GN affecting a mature dog, in which pathology was localized to the mucosal lamina propria and surgical treatment resulted in a successful outcome...
  50. Frank Raue K, Rondot S, Hoeppner W, Goretzki P, Raue F, Meng W. Coincidence of multiple endocrine neoplasia types 1 and 2: mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism. J Clin Endocrinol Metab. 2005;90:4063-7 pubmed
    ..In patients with MEN1, parathyroid hyperplasia or multiple adenomas occur in approximately 90-95%. MEN2A-related HPT is characterized by a mild hypercalcemia, which is mostly asymptomatic...
  51. King S, Southwell B, Hutson J. An association of multiple endocrine neoplasia 2B, a RET mutation; constipation; and low substance P-nerve fiber density in colonic circular muscle. J Pediatr Surg. 2006;41:437-42 pubmed
    ..A deficiency of the neurotransmitter substance P (SP) has been identified in both pediatric and adult patients with chronic constipation...
  52. Mass E, Lapidot M, Gadoth N. Case report: multiple endocrine neoplasia type 2B misdiagnosed as familial dysautonomia. Eur J Paediatr Dent. 2005;6:48-50 pubmed
    ..Oro-dental features include a lack of tongue fungiform papillae, impairment of taste, oro-dental self-mutilation, dental crowding, excessive plaque and calculus accumulation, salivary over production and low caries experience...
  53. Mise N, Drosten M, Racek T, Tannapfel A, Pützer B. Evaluation of potential mechanisms underlying genotype-phenotype correlations in multiple endocrine neoplasia type 2. Oncogene. 2006;25:6637-47 pubmed
    ..Whereas MEN 2A mutants resulted in accelerated cell proliferation, MEN 2B-RET mutants significantly enhanced suppression of apoptosis, which may account, at least partially, for some of the clinical differences in MEN 2 patients...