FaCD Online Syndrome Fact Sheet

Last updated: 06 Jun 2008

Name: Multiple Endocrine Neoplasia, type 2B

Synonym: MEN2B, Wagenmann-Froboese s.

Mode of Inheritance: AD/ de novo

Genes

RET, mapped to 10q11.2

Tumor features

alimentary tract neuromas
C-cell hyperplasia
conjunctival neuromas
eyelid neuromas
ganglioneuroma(tosis)
ganglioneuromatosis, intestinal
laryngeal neuromas
lips, neuromas of
nasal neuromas
pheochromocytoma
thyroid cancer, medullary

Tumor features (possible)

colorectal hamartomatous polyps
gastrointestinal polyps, juvenile type

Non-tumor features

café au lait spots
cornea, prominent nerves
mandible, prominent
Marfanoid habitus
myopathy
palate, high arched
pes cavus
scoliosis

Comment

This disorder is characterized by an aggressive type of medullary thyroid carcinoma (which may develop as early as below the age of 1 year), pheochromocytomas (50 % of cases, often bilateral), Marfanoid habitus (in 75 % of cases) often with proximal muscle wasting, skeletal anomalies (including lordosis, scoliosis, pectus excavatum, pes cavus and slipped capital femoral epiphysis) and mucosal neuromas. These neuromas may develop in the digestive tract (including lips, bucosal mucosa and the tongue) as well as part of the respiratory tract (pharynx, larynx), conjunctivae and eyelids. Extensive enteric gangliomatosis may be present, which may lead to the development of a megacolon, or several degrees of constipation. Obstipation in newborns is one of the ways MEN2B may present itself[7]. Disorders of esophageal motility may develop as well. Corneal nerves are prominent. Occasionally cafe au lait spots are noted. The jaw may be prominent and the palate high-arched.[1-3]. Despite the typical phenotype, MEN2B may go unrecognized for years[6,8].

Approximately 50 % of cases are caused by a de novo RET gene germline mutation. The RET gene mutations in MEN 2B are typical, the vast majority of cases being a point mutation in codon 918, encoding part of the intracellular tyrosine kinase domain: the substrate recognition site[4;5].

Occasionally mucosal/intestinal neuromas have been observed in the absence of germline RET mutations, a condition referred to as mucosal neuroma syndrome. A boy with juvenile polyposis, intestinal ganglioneuromatosis and a missense RET mutation has been reported[9]

Links

eMedicine info on MEN 23 1 08

References

[1] Morrison PJ, Nevin NC. Multiple endocrine neoplasia type 2B (Mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genet 33[9], 779-782. 1996.
[2] Vasen HFA, van der Feltz M, Raue F, Kruseman AN, Koppeschaar HP, Pieters G, Seif FJ, Blum WF, Lips CJ. The natural course of multiple endocrine neoplasia type IIb. A study of 18 cases. Arch Intern Med 1992; 152(6):1250-1252.
[3] O'Riordain DS, O'Brien T, Crotty TB, Gharib H, Grant CS, van Heerden JA. Multiple endocrine neoplasia type 2B: More than an endocrine disorder. Surgery 1995; 118(6):936-942.
[4] Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and Hirschsprung disease. Hum Mutat 9[2], 97-109. 1997.
[5] Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, Ploos van Amstel HK, Lips CJM, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue FY, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M, Komminoth P, Hendy GN, Gharib H, Thibodeau SN, Lacroix A, Frilling A, Ponder BAJ, Mulligan LM. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET mutation consortium analysis. JAMA 276[19], 1575-1579. 1996.
[6] Wray CJ, Rich TA, Waguespack SG, Lee JE, Perrier ND, Evans DB. Failure to recognize multiple endocrine neoplasia 2B: more common than we think?. Annals of surgical oncology 2008; 15(1):293-301.
[7] 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. Journal of pediatric surgery 2007; 42(9):1623-6.
[8] Ohyama T, Sato M, Murao K, Kittaka K, Namihira H, Matsubara S, Imachi H, Yamauchi K, Takahara J. A case of multiple endocrine neoplasia type 2B undiagnosed for many years despite its typical phenotype. Endocrine 2001; 15(2):143-6.
[9] Nguyen AT, Zacharin MR, Smith M, Hardikar W. Isolated intestinal ganglioneuromatosis with a new mutation of RET proto-oncogene. European journal of gastroenterology & hepatology 2006; 18(7):803-5.