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PubMed2005

Multiple endocrine neoplasia type 2B and Hirschsprung's disease.

Multiple endocrine neoplasia type 2B and Hirschsprung's disease are genetic disorders characterized by gross and/or microscopic pathology of the enteric nervous system and associated dysmotility. A specific missense mutation in the RET proto-oncogene is the etiology of multiple endocrine neoplasia type B, in contrast to very complex multigenetic defects that underlie Hirschsprung's disease, which include overt mutations and more subtle changes in the RET locus. In this review, the molecular genetics of the 2 conditions are discussed, and the clinical implications of existing data and future studies are summarized.

Genetic Predisposition to Disease↗

PubMed1997

Multiple idiopathic mucosal neuromas: a minor form of multiple endocrine neoplasia type 2B or a new entity?

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare autosomal dominant process characterized by medullary thyroid carcinoma, pheochromocytoma, and mucosal neuromas. A point mutation at codon 918 of the RET protooncogene has been observed in approximately 90% of patients and families with MEN 2B. Mucosal neuromas are the most consistent and distinctive feature (100% of patients) of MEN 2B and are considered pathognomonic. We describe a 35-year-old woman with mucosal neuromas of the lower lip and tongue that appeared in early childhood. Examination did not reveal other abnormalities. After a follow-up of more than 22 years with periodic clinical, biochemical, and radiologic studies, no evidence of MEN 2B has been detected. Analysis of the RET protooncogene exons 10, 11, and 16 did not demonstrate point mutation in the MEN 2B region (M918T).

Adult↗

PubMed1976

Alimentary-tract ganglioneuromatosis. A major component of the syndrome of multiple endocrine neoplasia, type 2b.

Although the syndrome of multiple endocrine neoplasia, type 2b, is known to comprise mucosal ganglioneuromatosis, medullary thyroid carcinoma, pheochromocytoma and skeletal anomalies, we wish to document the importance of the alimentary-tract components. In nine patients with this syndrome, we found diffuse ganglioneurmatosis extending from the lips to the rectum. Alimentary symptoms, constipation or diarrhea or both were present in six of these patients. Similar symptoms were present in six of seven other affected patients from whom alimentary-tract tissue was not obtained. Five of the 16 patients had megacolon, which led to operation in four, and a sixth patient had colectomy for diverticulitis complicating diffuse diverticulosis. The alimentary manifestations warrant greater emphasis, not only because they were prominent in the patients whom we studied but also because in 14, these manifestations were present before the endocrine neoplasms were detected.

Adolescent↗

PubMed1999

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.

Multiple endocrine neoplasia (MEN) type 2B is a clinically distinct entity among the autosomal dominant MEN 2 syndromes. Most patients with MEN 2B carry a germline mutation (M918T) of the RET proto-oncogene, while a few carry A883F. We examined a patient with MEN 2B, but without M918T or A883F, and her relatives. Here, we report the presence in this patient of 2 germline mutations, V804M and Y806C in the same allele. While the novel Y806C was inherited from her father, its carriers (her father and brother) was not affected by MEN 2. In contrast, V804M was a de novo mutation, that has been reported in patients with familial medullary thyroid carcinoma. Combinations of mutations of the RET proto-oncogene may cause oncogenic activities different from those of single mutations.

Base Sequence↗

PubMed2002

Diagnostic and therapeutic approach to multiple endocrine neoplasia type 2B in pediatric patients.

Multiple endocrine neoplasia (MEN) 2B is a hereditary syndrome including medullary thyroid carcinoma (MTC), pheochromocytoma, gastrointestinal (GI) disorders, marfanoid facies, and multiple ganglioneuromas. MTC is the major cause of mortality, and often appears during the 1st decade of life. RET proto-oncogene mutations are responsible for MEN 2B. Other RET mutations cause MEN 2A syndrome, familial MTC, or Hirschsprung's disease. We studied three MEN 2B patients with the aim of delineating the best diagnostic and therapeutic protocol. The gold standards for diagnosis are histochemical study of the rectal mucosa and molecular analysis of RET, which in familial cases detects MEN 2B at a preclinical stage so that early total prophylactic thyroidectomy can be performed. In non-familial cases, the diagnosis can be suggested by the presence of GI symptoms, ganglioneuromas, and/or the typical facies. The intestinal innervation pattern, analyzed with the acetylcholinesterase technique, is pathognomonic for MEN 2B. In our protocol a rectal biopsy is, therefore, the first measure. 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.

Adolescent↗

PubMed2001

Multiple endocrine neoplasia type 2B.

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. DNA testing was carried out and a point mutation was found in exon 16, codon 918 (ATG to ACG) in the RET proto-oncogene. The woman died of medullary thyroid carcinoma, 13 years after a total thyroidectomy.

Adrenal Gland Neoplasms↗

PubMed1999

De novo RET proto-oncogene mutation in a patient with multiple endocrine neoplasia type 2B.

We report a case of multiple endocrine neoplasia type 2B (MEN 2B) with de novo RET proto-oncogene mutation. The patient, a 23-year-old Taiwanese woman, was admitted for treatment of recurrent medullary thyroid cancer (MTC) 7 years after a total thyroidectomy. Mucosal neuromas and marfanoid appearance were also noted. Because MEN 2B was suspected, the patient and her family members underwent genetic analysis. A heterozygous germline mutation at codon 918 (ATG-->ACG) of the proto-oncogene RET was detected in the patient. This mutation was considered de novo, as it was not detected in either of her parents or her siblings. The patient underwent surgery for removal of the recurrent tumor. Although no pheochromocytoma was noted, regular follow-up is necessary because of persistent hypercalcitoninemia.

Adult↗

PubMed1991

Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A.

Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple endocrine neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple endocrine neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic "marfanoid" habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1(2). Sixty-one members of two well-characterized kindreds segregating MTC1 and 34 [corrected] members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroendocrine tissue development.

Adrenal Gland Neoplasms↗

PubMed1984

[Multiple endocrine neoplasia type 2b. Clinical, diagnostic and therapeutic aspects].

Multiple Endocrine Neoplasia type 2b (MEN 2b) is a rare syndrome. The principal features are: medullary thyroid carcinoma (MTC), dysmorphism, a ganglioneuromatosis and pheochromocytomas. Eight cases of MEN 2b have been observed at the Institute Gustave Roussy, between 1968 and 1983. Seven involved children under 15 years of age. Eight had a bilateral MTC; six had dysmorphism; six had mucosal tongue neuromas. Six were troubled with visceral ganglioneuromatosis of whom two had intestinal obstruction and one urinary chronic retention. One patient had pheochromocytoma with hypertension. From this experience and other data it appears that: the dysmorphism is frequently poorly interpreted; the visceral ganglioneuromatosis is an early and severe feature; it is important to examine the patient for pheochromocytoma; the MTC must be detected by calcitonin dosage after stimulation, and requires total thyroidectomy; familial screening must be done. To improve the poor prognosis of MEN 2b, early diagnosis and aggressive treatment are necessary.

Adolescent↗

PubMed1996

[Multiple endocrine neoplasia type 2a and 2b].

Multiple endocrine neoplasia type 2a and 2b (MEN 2a and 2b) are rare diseases, inherited as autosomal dominant traits. The neoplasias in MEN 2a are medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. In MEN 2b a characteristic phenotype is seen in combination with medullary thyroid carcinoma and pheochromocytoma. Through screening the diseases can be detected at an early stage, hereby improving prognosis. This is important as the diseases are inherited and occur in young individuals. In this review, epidemiology, clinical features, diagnosis and treatment are discussed.

Carcinoma, Medullary↗

PubMed2000

Multiple endocrine neoplasia type 2B--genetic basis and clinical expression.

Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.

Adrenal Gland Neoplasms↗

PubMed2003

[A case report and pedigree study of a single point mutation in RET proto-oncogene and type 2B multiple endocrine neoplasia].

OBJECTIVE: To determine the relationship between a single point mutation in RET proto-oncogene and the occurrence of multiple endocrine neoplasia type 2B (MEN-2B) in a Chinese pedigree. METHODS: We used the methods of polymerase chain reaction (PCR), reverse transcriptase polymerase chain reaction (RT-PCR) and direct gene sequencing of PCR products by an automated DNA sequencer to scan the entire exon 16 of RET proto-oncogene in the tumor (c)DNA from one patient with MEN-2B and the leukocyte DNA from this patient and both of his parents. RESULTS: We found the same mutation Met(ATG)-->Thr(ACG) at codon 918 in exon 16 of RET proto-oncogene in both the tumor (c)DNA and leukocyte DNA of the MEN-2B patient in the form of homozygous missense mutation, but there was no corresponding mutation in leukocytes DNA of his parents. CONCLUSION: We propose that in Chinese population, the point mutation M918T is also associated with the onset of MEN-2B and this case of MEN-2B is sporadic. Thus it may provide a genetic basis for the early diagnosis and treatment of patients suffering from MEN-2B and their at-risk family members in Chinese population.

Adolescent↗

PubMed1996

Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome).

Multiple endocrine neoplasia type 2B (MEN 2B), or the mucosal neuroma syndrome, is an autosomal dominant hamartoneoplastic syndrome. Features include multiple mucosal neuromas, phaeochromocytoma, medullary thyroid carcinoma, and Marfanoid body habitus with a characteristic dysmorphic facies. The gene responsible is the receptor tyrosine kinase (RET) proto-oncogene on chromosome 10. The mutational spectrum of MEN 2B is remarkably narrow, with over 95% of cases being caused by a single methionine to threonine substitution in the intracellular tyrosine kinase domain. Recent biochemical evidence suggests that this mutation alters the substrate specificity of intracellular signal transduction.

Adrenal Gland Neoplasms↗

PubMed1995

Multiple endocrine neoplasia type 2B: more than an endocrine disorder.

BACKGROUND: Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disorder differentiated from MEN 2A primarily by its extraendocrine features. This report describes the clinical spectrum and outcome of MEN 2B. METHODS: Twenty-one patients underwent operation for manifestations of MEN 2B between 1970 and 1993. Median follow-up was 16.9 years. Diagnosis was made through family screening in nine, the development of medullary thyroid carcinoma (MTC) in seven, phenotypic features in four, and constipation in one. Median age at presentation of colonic dysfunction, MTC, and pheochromocytoma was 0.1, 16, and 28 years, respectively. RESULTS: Every patient had MTC. Fifteen (94%) of 16 patients undergoing primary thyroidectomies had multicentric disease, and seven (44%) had nodal metastases. Seven patients (33%) had pheochromocytoma, six bilateral and one malignant. Adrenalectomy was curative in every patient. Nineteen patients (90%) had colonic disturbances, typically chronic constipation from birth. Megacolon developed in 14 patients, and eight required colonic surgery. Every patient had the characteristic phenotype. Dominant features included neuromas of the tongue, buccal mucosa, lips, conjunctivae, and eyelids and a marfanoid habitus. Other features included high arched palate, corneal nerve thickening, and dental and skeletal abnormalities. Four patients died, two of metastatic MTC, one after operation for metastatic MTC, and one as a consequence of colonic perforation. Of 17 survivors, three have hepatic metastases from MTC, eight have nodal metastases, and six are well with normal or mildly elevated calcitonin levels. CONCLUSIONS: MEN 2B is characterized by a relatively aggressive form of MTC, bilateral pheochromocytoma, severe colonic dysfunction, and a multitude of other extraendocrine abnormalities. Early recognition of MEN 2B and early prophylactic thyroidectomy are essential. Colonic dysfunction has previously received little attention, and further investigation of the pathogenesis and treatment of this disorder is warranted.

Adolescent↗

PubMed2004

External ophthalmic findings in multiple endocrine neoplasia type 2B.

PURPOSE: To identify external ophthalmic abnormalities in multiple endocrine neoplasia type 2B (MEN2B), which may facilitate early detection and prophylactic thyroidectomy to prevent medullary thyroid carcinoma. METHODS: Three patients with MEN2B were examined by an oculoplastic surgeon and external ophthalmic findings were recorded. RESULTS: All patients had prominent corneal nerves, thickened eyelids, mild ptosis and eversion of the upper eyelids. Two patients displayed eyelid nodules and one exhibited lower lid margin eversion. CONCLUSION: Ptosis and lower lid margin eversion are previously unreported findings in patients with MEN2B. Medullary thyroid carcinoma is the most serious consequence of MEN2B and has a high mortality if untreated. Early diagnosis and prophylactic thyroidectomy may be lifesaving. Gene mutations can be identified but the sporadic tendency of the syndrome emphasizes the importance of early clinical detection. MEN2B is one of a number of systemic malignancies with ophthalmic manifestations. Ophthalmologists should be aware of the external features of this rare but lethal malignancy.

Blepharoptosis↗

PubMed1994

A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.

Multiple endocrine neoplasia type 2 (MEN 2) comprises three clinically distinct, dominantly inherited cancer syndromes. MEN 2A patients develop medullary thyroid carcinoma (MTC) and phaeochromocytoma. MEN 2B patients show in addition ganglioneuromas of the gastrointestinal tract and skeletal abnormalities. In familial MTC, only the thyroid is affected. Germ-line mutations of the RET proto-oncogene have recently been reported in association with MEN 2A and familial MTC. All mutations occurred within codons specifying cysteine residues in the transition point between the RET protein extracellular and transmembrane domains. We now show that MEN 2B is also associated with mutation of the RET proto-oncogene. A mutation in codon 664, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein, was found in all nine unrelated MEN 2B patients studied. The same mutation was found in six out of 18 sporadic tumours.

Base Sequence↗

PubMed1982

Multiple endocrine neoplasia type 2b in twins.

The syndrome of multiple endocrine neoplasia (MEN or MEA) type 2b is characterized by the association of medullary carcinoma of the thyroid, phaeochromocytoma, ganglioneuromatosis and Marfan-like features. Though this disorder usually shows a familial distribution, it may also appear spontaneously as the result of a genetic mutation. This paper describes the second case of MEA type 2 in twins, and appears to be the first description in twins of the association of medullary carcinoma of the thyroid, Marfan-like features and multiple neuromas.

Adolescent↗

PubMed1983

Early diagnosis and thyroidectomy in multiple endocrine neoplasia, type 2b.

Medullary thyroid carcinoma is a feature of multiple endocrine neoplasia, type 2b (MEN 2b). The cancer frequently gives rise to metastases in early life and is therefore often incurable by age 4 years. Because MEN 2b frequently appears as a spontaneous mutation, and because the characteristic phenotypic features are absent in the early life of most affected patients, both MEN 2b and its medullary thyroid cancer may elude diagnosis for years. Total thyroidectomy is the only established treatment for medullary thyroid carcinoma. The timing of thyroidectomy must take into account risks and benefits in small children, but the operation may well not cure after age 4 years. Thyroidectomies in two of our patients were accomplished at ages 2 and 2 1/2 years; no complications were encountered, and no metastatic disease was found in either child. Feeding difficulties--poor suck to the point of failure to thrive--were present in the neonatal periods of seven of our nine patients who had MEN 2b. Infants with feeding difficulties should be examined periodically for the onset of pathognomonic features of MEN 2b, particularly the ganglioneuromas, which usually appear before age three years.

Adolescent↗