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PubMed1994

Parent-of-origin effects in multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases arising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in order to determine the parental origin of the mutated RET allele. In all cases the new mutation was of paternal origin. We observe a distortion of the sex ratio in both de novo MEN 2B patients and the affected offspring of MEN 2B transmitting males. These results suggests a differential susceptibility of RET to mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development.

Chromosomes, Human, Pair 10↗

PubMed1995

No mutation at codon 918 of the RET gene in a family with multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare cancer syndrome which is inherited in an autosomal dominant manner. The molecular basis of this condition has recently been defined as a mutation of codon 918 of exon 16 of the RET proto-oncogene. The mutation in codon 918 has been described in 69 out of 72 families with MEN 2B. We have studied a brother and sister who undoubtedly have the features of MEN 2B as evidenced by medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas and skeletal abnormalities. Neither of these patients has the classic gene mutation at codon 918 of exon 16 of the RET proto-oncogene, and although exons 2-20 have also been sequenced, no abnormality has been found. DNA analysis is a sensitive method of screening families for the MEN 2 syndromes. The absence of the mutation at codon 918 in a phenotypically normal individual would refute the diagnosis of MEN 2B, but in an individual with some of the features of MEN 2B would make the clinician reconsider the diagnosis. This family demonstrates that, although it is rare, the absence of the mutation in codon 918 of exon 16 of the RET proto-oncogene does not always exclude the diagnosis of MEN 2B. In such families routine biochemical screening for medullary thyroid carcinoma and phaeochromocytoma must be maintained for all individuals at genetic risk.

Adolescent↗

PubMed1994

Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG-->ACG) results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.

Alleles↗

PubMed1979

C-cell disease of the thyroid gland in multiple endocrine neoplasia, type 2b.

Multiple endocrine neoplasia, type 2b (MEN 2b) is a disorder characterized by C-cell disease of the thyroid gland (medullary carcinoma or C-cell hyperplasia, or both), pheochromocytoma, ganglioneuromatosis, and skeletal and connective tissue abnormalities. The medullary thyroid carcinoma (MTC) is bilateral and multicentric; it metastasizes locally and distally, often before the disease is recognized. Histologically proven C-cell disease was present in 89 of the 107 patients (83%) reported with the condition, including 17 Mayo Clinic patients (average age at diagnosis, 19.2 years). Nineteen of the 107 patients (18%) died of MTC (average age at death, 25.3 years); 9 (8%) succumbed to pheochromocytoma, 7 of these also having metastatic MTC; 13 12%) died of other or unknown causes, but 2 of these had disseminated MTC as well; 29 (27%) survive with metastatic MTC; an additional 21 (20%) are alive, but concentrations of plasma immunoreactive calcitonin (iCT) have not been measured; 6 more (6%), 5 of whom had thyroidectomy before the age of 12 years, are alive with normal plasma concentrations of iCT; and the remaining 10 (9%) have been lost to follow-up. Survival of patients with MEN 2b after operation was reduced when compared with that of a control population -- 80% versus 99% at 5 years and 50% versus 98% at 10 years. The only effective treatment for MTC is total thyroidectomy before metastasis occurs. "Cure" of MTC in patients with MEN 2b has generally been obtained in those having total thyroidectomy before age 12. Therefore, in young patients suspected of having MEN 2b, we recommend prompt evaluation of C-cell function by measurement of stimulated concentrations of iCT and treatment by total thyroidectomy if results are abnormal.

Adolescent↗

PubMed1978

Multiple endocrine neoplasia, type 2b.

Multiple endocrine neoplasia, type 2b, is a disorder of unknown etiology with major involvement of the thyroid and adrenal glands, the autonomic nervous system, and connective tissue. It is transmissible with an autosomal dominant pattern of inheritance, but since most cases are not familial, they presumably represent mutations. The thyroid gland exhibits bilateral medullary carcinoma, which is a metastasizing lethal neoplasm in the syndrome requiring total thyroidectomy once abnormal basal or stimulated concentrations of plasma immunoreactive calcitonin have been demonstrated. The adrenal medullary tumors--pheochromocytomas--although rarely malignant, are potentially lethal because of their cardiovascular effects. Since the adrenal involvement is usually bilateral, total bilateral adrenalectomy with excision of any extraadrenal paraganglioma is the surgical treatment. Parathyroid hyperplasia occurs rarely in the syndrome. Treatment of it should be conservative, that is, limited to excision of enlarged parathyroid glands. Major portions of the autonomic nervous system, both sympathetic and parasympathetic, nerves and ganglia, exhibit hypertrophy, hyperplasia, and disorder of structure--a group of changes designated ganglioneuromatosis. This may be largely responsible for the striking eye and oral findings--the hallmarks of the syndrome--and also for some of the serious symptoms and complications of the syndrome, particularly those referable to the alimentary tract. Ganglioneuromatosis is also found in the salivary glands, pancreas, gallbladder, upper respiratory tract, and urinary bladder. The connective tissue abnormality is manifested by increased growth of long bones, ribs, and skull, resulting in a marfanoid habitus, and also by skeletal and joint abnormalities together with increased laxity of ligaments. Ninety cases of MEN 2b have been reported, and although follow-up information is incomplete, 27 patients (30 percent) are known to be dead because of the syndrome. The causes of death have been medullary thyroid carcinoma (15 deaths), pheochromocytoma (10 deaths), and alimentary tract complications (2 deaths). An additional 21 patients (22 percent) are known to have metastatic MTC. We are aware of only 2 patients who, 5 years after thyroidectomy, have apparently been cured of MTC, but both are still at risk for adrenal medullary disease. MEN 2b is, therefore, a very serious disorder that requires urgent treatment of the endocrine tumors. Fortunately, the majority of patients with the syndrome are easily recognized because of an abnormal phenotype typified by thick, bumpy lips and a marfanoid habitus. Since these findings signal high risk for the potentially lethal endocrine neoplasms, patients having the characteristic appearance need evaluation of thyroidal C-cell and adrenal medullary function.

Adrenal Gland Neoplasms↗

PubMed1981

Ocular histopathology in multiple endocrine neoplasia type 2b.

Multiple endocrine neoplasia type 2b is a syndrome, often familial, characterized by medullary carcinoma of the thyroid gland, pheochromocytoma, and many mucosal neuromas in patients who frequently have a marfanoid habitus. The ophthalmic findings are distinctive and include conjunctival and eyelid neuromas, keratoconjunctivitis sicca, and, most characteristically, greatly thickened corneal nerves. Ocular histopathologic study of a 30-year-old man demonstrated thickened nerves in the ciliary body, iris, and corneoscleral limbal regions. In these regions, the nerves were a mixture of myelinated and unmyelinated fibers. Sections through the thickened corneal nerves, 1.5 mm centrally from the corneoscleral limbus, showed only nonmyelinated nerves associated with Schwann cells. The many axons were normal in appearance but varied in diameter; some were between 0.1 and 0.2 ng and others between 1.0 and 1.4 ng. An unexpected finding was numerous ganglion cells in the ciliary body. The subconjunctival tissue showed neuromas with a minimum of fibrous structure. Sections of the lacrimal gland showed normal glandular tissue.

Adult↗

PubMed1976

Mucosal ganglioneuromatosis, medullary thyroid carcinoma, and pheochromocytoma: multiple endocrine neoplasia, type 2b.

Multiple endocrine neoplasia, type 2b, is a designation that has been proposed for the combination of medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and somatic abnormalities. The neural lesions produce a characteristic diffuse or nodular enlargement of lips, tongue, and buccal mucosa. Microscopically, the lesions are composed of unencapsulated masses of hypertrophied and elongated nerves in which are found rare ganglion cells. The histologic similarity between the oral mucosal lesions and the alimentary tract ganglioneuromatosis in the syndrome suggests that the term ganglioneuromatosis is the most appropriate designation for the oral lesions. The oral lesions signal high risk for two potentially lethal neoplasms--medullary thyroid carcinoma and pheochromocytoma. Thus, patients having the characteristic findings are in urgent need of repeated evaluation of thyroidal C-cell and adrenal medullary function.

Adolescent↗

PubMed1992

Genetics of the multiple endocrine neoplasia type 2B syndrome.

Multiple endocrine neoplasia type 2B (MEN 2B) is similar to MEN 2A in that both autosomal dominant syndromes include medullary thyroid cancers and pheochromocytomas. It is distinct in that MEN 2B patients have much earlier age of onset with more aggressive tumors and mucosal neuromas of the lips and tongue. The neuromas allow ascertainment generally before age 5. Studies of two and three generations of 14 MEN 2B families disclosed close linkage of the MEN 2B gene to DNA markers to which MEN2A had been linked. Multipoint analysis utilizing additional results in three generations of a 15th family have disclosed a peak total lod score of 8.89 at the midpoint between the centromere markers D10Z1 and RBP3 on the long arm (band q11). One recombinant was observed between D10Z1 and MEN2B, but this individual was not recombinant with D10S94. These studies suggest physical proximity of MEN2A and MEN2B but do not establish allelism for the gene(s).

Adult↗

PubMed1995

Germ line mutation in the RET proto-oncogene associated with familial multiple endocrine neoplasia type 2B: a case report.

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome. MEN 2B is characterized by the combined occurrence of medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuroma and Marfanoid habitus. Recently, a missense mutation in codon 918 of the proto-RET has been reported in the germ line of apparently distinct families with MEN 2B. In the present paper we first show a familial case of MEN 2B in Japan also to be associated with a germ line mutation in codon 918 of the proto-RET. The mutation was the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein. The germ-like mutations of the proto-RET in MEN 2A and MEN 2B are the first examples of a dominantly acting oncogenic point mutation initiating human hereditary neoplasia.

Adrenal Gland Neoplasms↗

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↗

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↗

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↗

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↗