Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant disorder characterized by medullary thyroid cancer (MTC) and pheochromocytoma. The disorder can also include mucosal neuromas, which are often located on the lips and tongue. Patients with MEN2B frequently suffer from disturbances of colonic motility, including intestinal pseudo-obstruction. The underlying defect in patients with MEN2B is a germline mutation in the RET proto-oncogene.
Case Report
A 3-month-old boy presented with chronic constipation. Family history was unremarkable, and his symptoms did not resolve with oral laxatives. A barium enema showed colonic distension, without the presence of a transition zone. Rectal manometry demonstrated normal relaxation of the internal anal sphincter, and rectal suction biopsy confirmed the presence of ganglion cells.
The patient was followed regularly. Colonic manometry at the age of 3 years revealed nonpropagating high-amplitude contractions consistent with neuropathic dysmotility, a form of intestinal pseudo-obstruction. The patient was placed on cisapride, which resulted in decreased abdominal distension and an increased frequency of bowel movements.
At the age of 7 years, the patient's abdominal radiograph revealed continued colonic distension (Figure 1). During a routine dental visit, multiple small protrusions suggestive of mucosal neuromas were noticed on the tongue and buccal mucosa (Figure 2). Screening blood tests for MEN2B revealed a markedly elevated calcitonin level of 1,282 pg/mL (normal <100 pg/mL). Urinary catecholamines were normal, and a magnetic resonance image of the patient's abdomen was negative for adrenal tumors. Genetic testing revealed a missense mutation in the RET proto-oncogene.
Figure 1.
Abdominal radiograph revealing distended loops of large bowel, consistent with the diagnosis of intestinal pseudo-obstruction.
Figure 2.
Arrows pointing to mucosal neuromas on buccal mucosa.
Subsequently, the patient underwent total thyroidectomy and reimplantation of the left inferior parathyroid gland. Medullary carcinoma was found in the right and left lobes of the thyroid (Figure 3), and lymph nodes were negative for metastases. Since surgery, serum calcitonin and urinary catecholamines have been normal.
Figure 3.
Medullary carcinoma tumor nests composed of spindled- to oval-shaped cells with a low-to-moderate nuclear/cytoplasmic ratio (A). Strongly positive immunohistochemical calcitonin stain (red) in area of medullary carcinoma (B).
Approximately 18 months after surgery, the patient developed dysphonia. Direct laryngoscopy revealed a left vocal cord tumor, and the true left vocal cord was excised. Histologic staining confirmed the presence of a benign neurofibroma (Figure 4). Since its removal, the patient has not had problems with phonation.
Figure 4.
Vocal cord neurofibroma composed of numerous bundles of elongated cells with wavy dark nuclei identified beneath the squamous epithelium.
Discussion
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder that is subclassified into MEN2A, MEN2B, and familial medullary thyroid cancer (FMTG). MEN2A predisposes patients to the development of MTG, pheochromocytoma, and primary parathyroid hyperplasia.1 Whereas patients with MEN2B are also likely to develop MTG and pheochromocytoma, parathyroid hyperplasia is not associated with MEN2B. MEN2B may also be associated with ganglioneuromas of the digestive tract, mucosal neuromas, and skeletal and ophthalmic abnormalities.2 Patients with FMTC are predisposed to develop MTC but not the other manifestations of MEN2A and MEN2B (Table 1).1
Table 1.
Clinical Findings Associated With MEN2 Syndromes
| Syndrome | MTC | Pheochromocytoma | Parathyroid hyperplasia | Intestinal ganglioneuromas | Mucosal neuromas |
|---|---|---|---|---|---|
| MEN2A | Yes | Yes | Yes | No | No |
| MEN2B | Yes | Yes | No | Yes | Yes |
| FMTC | Yes | No | No | No | No |
- MEN2
multiple endocrine neoplasia
- MTC
medullary thyroid cancer
- FMTC
familial medullary thyroid cancer.
The underlying defect in patients with MEN2 disorders is a germline mutation in the RET proto-oncogene on chromosome 10. RET is expressed from the neural crest, including C cells of the thyroid, adrenal medulla, and enteric ganglia, and encodes a member of the receptor tyrosine kinase family of transmembrane receptors. The RET mutations seen in MEN2 are thought to be activating, with different mutations causing tissue-specific effects.3 Specifically, altered RET alleles function as transforming genes, leading to organ-specific growth advantages.4
Greater than 95% of the mutations in patients with MEN2A and FMTC are located in exon 10 or 11. More than 90% of MEN2B cases are secondary to a mutation from methionine to threonine in exon 16 at codon 918.3 This occurs as a de novo mutation in more than 50% of affected individuals.2 Another mutation known to result from MEN2B occurs at codon 883 in exon 15 and involves a substitution of alanine by phenylalanine.1
The gastrointestinal (GI) symptoms of MEN2B may occur early in life. Most commonly, patients experience either chronic constipation or diarrhea. Feeding difficulties, dysphagia, vomiting, borborygmus, and intermittent abdominal pain may also be present. Patients frequently suffer from disturbances of colonic motility, including intestinal pseudo-obstruction. This is secondary to ganglioneuromatosis of the GI tract, which involves increased numbers of ganglion cells, supportive cells, and nerve fibers in every layer of the bowel wall, especially the myenteric plexus. Radiographic abnormalities include segmental dilation of the small bowel, abnormal haustral pattern of the colon, and, most commonly, megacolon. Hirschsprung disease is frequently suspected in these patients, so they often undergo manometric studies and/or rectal suction biopsy.5
Anorectal manometry performed in patients with MEN2B can reveal the disarrangement of the internal sphincter rhythmic wave and a complete absence of the rectoanal inhibitory reflex.6 Patients with MEN2B can also have completely normal anorectal manometric findings, as was the case with our patient.
Colonic mucosal biopsies can help us differentiate between Hirschsprung disease and ganglioneuromatosis. In the former, a variable length segment of bowel is aganglionic, and cholinergic nerve fibers increase. Ganglioneuromatosis, as discussed above, is associated with MEN2B. Patients with intestinal neuronal dysplasia type B can also have hyperplastic ganglia, but these are limited to the submucosa.5,7
Patients with MEN2B tend to have mucosal neuromas, which are often located on the lips, tongue, and buccal mucosa. Other manifestations include various skeletal and ophthalmologic anomalies. Marfanoid habitus, congenital dislocation of the hip, pes planus, pes cavus, pectus excavatum, and kyphosis can all be seen. Patients may also have high-arched palate, broad forehead, or hypertelorism. Eye findings often include prominent corneal nerves and multiple submucosal neuromas of the conjunctivae and eyelids.8
Early diagnosis of MEN2B is essential, because MTC is a life-threatening disease that can be cured or prevented by total thyroidectomy. When evaluating patients suspected of having a MEN2 disorder, obtaining a serum calcitonin level can help in the evaluation for medullary thyroid carcinoma. If the serum calcitonin level is elevated, as it was in this case, urgent thyroidectomy is indicated.
Patients with MEN2 syndromes should undergo DNA testing in order to identify the specific RET mutation. Once this mutation is known, first-degree relatives should be genotyped. Relatives who do not carry the genetic mutation are not at risk for developing the disease and do not need to be subjected to further testing. Affected relatives should undergo prophylactic thyroidectomy, because MTC develops at an early age in patients.8 Because metastatic disease has occurred in children as young as 1 year, thyroidectomy during the first year of life is advised.9 Even in patients with normal serum calcitonin levels, MTG can be found in resected thyroid tissue, further supporting the need for early resection.8
Total thyroidectomy with central lymph node dissection is recommended for patients with RET mutations associated with MEN2 syndromes.10 Radiotherapy and chemotherapy have both been shown to be less effective than surgery. Elevated immunoreactive serum calcitonin levels after treatment may suggest residual or recurrent disease. Therefore, serial measurement of calcitonin is advised.11
Conclusion
Gastroenterologists should consider the diagnosis of MEN2B when evaluating patients with pseudo-obstruction of unknown etiology. Elevated calcitonin levels suggest the presence of MTG. Because the MTG associated with MEN2B can be life-threatening, thyroidectomy is advised at the time of diagnosis. First-degree relatives of patients with MEN2B should undergo genetic testing for identical RET mutations. Any relative carrying such a mutation can be diagnosed with the disease.
References
- 1.Gimm O, Marsh DJ, Andrew SD, 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;82:3902–3904. doi: 10.1210/jcem.82.11.4508. [DOI] [PubMed] [Google Scholar]
- 2.Carlson KM, Bracamontes J, Jackson GE, et al. Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet. 1994;55:1076–1082. [PMC free article] [PubMed] [Google Scholar]
- 3.Mulligan LM, Ponder BAJ. Genetic basis of endocrine disease: multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 1995;80:1989–1995. doi: 10.1210/jcem.80.7.7608246. [DOI] [PubMed] [Google Scholar]
- 4.Santoro M, Garlomagno F, Romano A, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267:381–383. doi: 10.1126/science.7824936. [DOI] [PubMed] [Google Scholar]
- 5.Krijger R, Brooks A, van der Harst E, et al. Gonstipation as the presenting symptom in de novo multiple endocrine neoplasia type 2B. Pediatrics. 1998;102:405–407. doi: 10.1542/peds.102.2.405. [DOI] [PubMed] [Google Scholar]
- 6.Shimotake T, Kubota Y, Inoue K, et al. Absence of rectoanal inhibitory reflex in a child with multiple endocrine neoplasia type 2B. J Pediatr Surg. 1998;33:1268–1271. doi: 10.1016/s0022-3468(98)90166-x. [DOI] [PubMed] [Google Scholar]
- 7.Gariepy G. Developmental disorders of the enteric nervous system: genetic and molecular bases. J Pediatr Gastroenterol Nutr. 2004;39:5–11. doi: 10.1097/00005176-200407000-00003. [DOI] [PubMed] [Google Scholar]
- 8.Jacobs J, Hawes M. From eyelid bumps to thyroid lumps: report of a MEN type IIb family and review of the literature. Ophthal Plast Reconstr Surg. 2001;17:195–201. doi: 10.1097/00002341-200105000-00009. [DOI] [PubMed] [Google Scholar]
- 9.O'Riordain DS, O'Brien T, Grotty TB, et al. Multiple endocrine neoplasia type 2: more than an endocrine disorder. Surgery. 1995;118:936–942. doi: 10.1016/s0039-6060(05)80097-2. [DOI] [PubMed] [Google Scholar]
- 10.Gagel RF, Robinson MF, Donovan DT, et al. Glinical review 44. Medullary thyroid carcinoma: recent progress. J Clin Endocrinol Metab. 1993;76:809–814. doi: 10.1210/jcem.76.4.8473386. [DOI] [PubMed] [Google Scholar]
- 11.Stepanas AV, Samaan NA, Hill GSJ, et al. Medullary thyroid carcinoma. Importance of serial serum calcitonin measurements. Cancer. 1979;43:825–837. doi: 10.1002/1097-0142(197903)43:3<825::aid-cncr2820430308>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]