Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 61530001; ICD10CM: E31.23; ICD9CM: 258.03; ORPHA: 247709, 653; DO: 10016;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q11.21 | Multiple endocrine neoplasia IIB | 162300 | Autosomal dominant | 3 | RET | 164761 |
A number sign (#) is used with this entry because of evidence that multiple endocrine neoplasia type IIB (MEN2B) is caused by heterozygous mutation in the RET gene (164761) on chromosome 10q11. Most patients (95%) carry a specific M918T mutation (164761.0013) in exon 16 of the RET gene.
Multiple endocrine neoplasia type IIB (MEN2B) is an autosomal dominant hamartoneoplastic syndrome characterized by aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and thickened corneal nerves. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus. Other more variable features include skeletal anomalies and gastrointestinal problems (review by Morrison and Nevin, 1996).
For a discussion of genetic heterogeneity of multiple endocrine neoplasia (MEN), see MEN1 (131100).
Williams and Pollock (1966) described 2 unrelated patients with multiple true neuromas, pheochromocytoma and thyroid carcinoma. The thyroid cancer was of the medullary type (MTC) as in MEN2A. Although the association of pheochromocytoma with neurofibromatosis is well known, the nervous tumor is a true neuroma, i.e., consists mainly of nerve cells, in this condition. The patients sometimes have cafe-au-lait spots. The neuromas occur as pedunculated nodules on the eyelid margins, lips and tongue. The lips are diffusely hypertrophied. The father of one of Williams and Pollock's cases had very thick lips and eyelid and tongue lesions as did his daughters. He had a medullary thyroid cancer and died at age 38 after an abdominal operation, having had symptoms suggestive of pheochromocytoma. Schimke et al. (1968) also reported cases. Cunliffe et al. (1968) demonstrated calcitonin-secretion in a medullary carcinoma of the thyroid. The patient was a 19-year-old girl with acne, features of Marfan syndrome, neuromas of tongue and eyelid, prominent lips, nodular goiter, pigmentation of hands, feet and circumoral area, proximal myopathy, loose motions, and flushing attacks. The features suggesting Marfan syndrome were high arched palate, pectus excavatum, bilateral pes cavus, high patella and scoliosis. Marfanoid habitus and pes cavus are striking features in most. Megacolon with plexus hyperplasia is a feature (Carney and Hayles, 1977). Colonic diverticula also occur. Mucosal neuromas involve the lips, anterior tongue, conjunctiva and nasal and laryngeal mucosa. Medullated nerve fibers traverse the cornea. Bartlett et al. (1968) described affected persons in 6 generations. Prophylactic thyroidectomy should be performed when the phenotype is recognized (Wolfe et al., 1973). In addition to histaminase, DOPA decarboxylase is high in medullary carcinoma of the thyroid (Atkins et al., 1973). The latter enzyme is found in pheochromocytomas also.
Carney et al. (1976) and Dyck et al. (1979) described a kindred with 7 affected persons in 3 generations. In contrast to MEN2A, no parathyroid disease was found in any of them. The authors proposed the designation 'multiple endocrine neoplasia, type 2b.' Carney et al. (1980) confirmed the lack of clinically important involvement of the parathyroids in this disorder. Kullberg and Nieuwenhuijzen Kruseman (1987) described a patient who was known to have had liver metastases of medullary carcinoma of the thyroid for at least 22 years. Other features illustrating an indolent course of the disorder were displayed by affected members of this family. Derangement of esophageal motility with an achalasia-type clinical picture may be a leading problem (Baylin, 1989).
Fryns and Chrzanowska (1988) gave a review. Mutation in a gene controlling a paracrine or an autocrine growth factor seemed a possibility in this disorder.
Morrison and Nevin (1996) presented a review of this syndrome. They used the term Wagenmann-Froboese syndrome, because Wagenmann (1922) and Froboese (1923) initially described this disorder. Thyroid carcinoma and multiple mucosal neuromata occur in virtually all affected persons. Neoplasias of enteric ganglia were found in more than 40% of patients; pheochromocytoma in 50%; and marfanoid habitus in 75%. The absence of mucosal neuromata in persons with MEN2A is the main criterion for differential diagnosis.
Enlarged nerves of the gastrointestinal tract (ganglioneuromatosis), often with megacolon, is a feature of MEN2B; corneal nerve thickening (medullated corneal nerve fibers) is a comparable feature, as are mucosal neuromas. Kane et al. (1995) described an unusual kindred in which medullary thyroid carcinoma was associated with corneal nerve thickening without other aspects of the multiple endocrine neoplasia syndromes. The grandfather and 1 daughter, both of whom had corneal nerve thickening, had medullary thyroid carcinoma, and a daughter of that daughter had both corneal nerve thickening and C-cell hyperplasia. Three adults in the middle generation had corneal nerve thickening only. DNA sequence analysis revealed no mutations in exon 10 or 11, or in exon 16 of the RET gene, regions where mutations had been described for MEN2A and MEN2B, respectively.
Clinical Variability
Dennehy et al. (1995) reported a 2-generation family in which a mother and her 2 children had prominent corneal nerves and lesions of the tongue resembling neuromas, but had no evidence of endocrine abnormalities. Targeted screening excluded the RET M918T mutation (164761.0013).
Gordon et al. (1998) reported 4 unrelated patients with a pure mucosal neuroma syndrome that presented as a partial MEN2B phenotype, but without medullary thyroid carcinoma, other endocrine tumors, or germline or somatic RET mutations. Three patients presented in the teenage years and one at age 5 years with multiple unilateral neuromas affecting the facial mucosa, including the mouth, tongue, eyes, nose, and lips. One patient had neuromas affecting multiple branches of the trigeminal nerve. Two patients had medullated corneal nerve fibers, but no Lisch nodules. Extensive endocrine workup in all 4 patients showed no abnormalities. Prophylactic thyroidectomy was performed in 1 patient, but histology showed no evidence of C-cell hyperplasia or tumor nodules. None of the patients or tumor tissues carried the RET M918T mutation (164761.0013), and 3 patients studied did not have mutations in other selected RET exons. Gordon et al. (1998) concluded that pure mucosal neuroma syndrome does not appear to be a forme fruste of MEN2B at the genetic level.
Gomez et al. (1998) reported a mother and daughter with multiple mucosal neuromas and visible corneal nerves. Neither had a marfanoid habitus, and endocrine workup was normal, and the RET M918T mutation was not found. The authors concluded that familial multiple mucosal neuromas is a distinct entity.
Spyer et al. (2006) reported a 13-year-old girl who presented with photophobia and was noted to have prominent corneal nerve fibers. She also had many features of MEN2B, including thick lips, multiple bilateral mucosal neuromas, a marfanoid habitus, and high-arched palate. Extensive endocrine workup revealed no abnormalities, but prophylactic thyroidectomy was performed. Histologic examination of the thyroid showed no evidence of medullary thyroid carcinoma or C-cell hyperplasia. Direct sequencing of exons 1-20 of the RET gene showed no mutations. She remained well over 18 years of follow-up. Spyer et al. (2006) concluded that patients with features of the mucosal neuroma syndrome do not need to have a thyroidectomy, but should be followed for possible endocrine abnormalities.
Babovic-Vuksanovic et al. (2012) reported 4 unrelated females with a similar constellation of physical features, including marfanoid habitus, coarse facial features, and multiple painful subcutaneous neurofibromas and nodules of the peripheral nerves occurring all over the body. All presented in the teenage or young adult years (range, 13-24 years) with clinical sequelae of the tumors. Two had orbital soft tissue swelling and proptosis/ptosis due to tumors of the corneal or trigeminal nerves, resulting in unilateral loss of vision in 1 patient. The other 2 patients presented with hemiparesis, and 1 also had lumbosacral pain due to multiple spinal nerve tumors. Histology showed neurofibromas with abundant mucin. All had a history of or later developed multiple painful subcutaneous nodules that were shown to be neurofibromas with abundant mucin. Tumors occurred in the head and neck region, spinal cord, trunk, and limbs. Other more variable features included pectus excavatum, scoliosis, and keloid scars. None had Lisch nodules, axillary or inguinal freckling, or cafe au lait spots. Two patients had evidence of a neuronal migration defect in the brain, with schizencephaly, but only 1 patient had seizures and learning disabilities. One patient had a severe axonal and demyelinating polyneuropathy. None had a family history of a similar disorder, and mutations in multiple candidate genes, including NF1 (613113), NF2 (607379), SMARCB1 (601607), RET, and PTEN (601728), were excluded in 2 patients. Babovic-Vuksanovic et al. (2012) noted the phenotypic similarities to MEN2B and to mucosal neuroma syndrome, but concluded that the unusual findings of a developmental brain anomaly and nonmucosal nerve neurofibromas in their patients may represent a new condition.
Jackson et al. (1988) found evidence suggesting that MEN3 (MEN2B) maps to chromosome 10, probably in the same region as MEN2A (171400). It is possible that MEN2A and MEN2B are allelic disorders; if indeed such is the case, there would be every justification for calling them MEN2A and MEN2B rather than MEN2 and MEN3. Norum (1989) presented compelling evidence that MEN3 is allelic to MEN2: both mapped to chromosome 10 near the centromere and are on the same side of the RBP3 gene (180290). Lairmore et al. (1991) presented evidence that the MEN2B locus maps in the pericentric region of chromosome 10. They found no evidence for linkage genetic heterogeneity among families with medullary thyroid carcinoma, MEN2B, or MEN2A. By genetic linkage analysis, Gardner et al. (1993) demonstrated that the MEN2B locus is flanked by D10S141 and RBP3, proximally and distally, respectively; both markers are located in 10q11.2.
In 9 unrelated MEN2B patients, Hofstra et al. (1994) identified a substitution of a threonine for a methionine in the tyrosine kinase domain of the RET protein (M918T; 164761.0013). The M918T mutation in the tyrosine kinase domain is the only RET mutation identified in cases of MEN2B (Bongarzone et al., 1998).
Carlson et al. (1994) estimated that 50% of cases of MEN2B arise de novo. A single identical point mutation in the catalytic core of the tyrosine kinase domain of RET has been found to be associated with both inherited and de novo MEN2B. Carlson et al. (1994) analyzed 25 cases of de novo MEN2B in order to determine the parental origin of the mutated RET allele. In all cases, the new mutation was of paternal origin. They observed a distortion of sex ratio in both de novo MEN2B patients and the affected offspring of MEN2B-transmitting males. Specifically, as pointed out by Sapienza (1994), the report by Carlson et al. (1994) and that of another group includes 45 females and 24 males with de novo MEN2B. These results suggested a differential susceptibility of RET mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development.
Prophylactic total thyroidectomy before the age of 4 years was proposed for children with this disorder (Morrison et al., 1991; Utiger, 1994).
Because the optimal age of thyroidectomy is poorly established and the course of medullary thyroid carcinoma in MEN2B is ill-defined, Leboulleux et al. (2002) reviewed 18 patients in a single-center retrospective study: 9 men and 9 women with a mean age of 13 years at diagnosis. The diagnosis of MTC was based on the presence of a thyroid nodule or involved neck lymph nodes and on dysmorphic features of MEN2B in 60% and 40% of the cases, respectively. The classic M918T mutation in exon 16 of the RET gene was found in all 16 patients in whom it was investigated. At diagnosis, 2 patients had stage I MTC, 15 had stage III, and 1 had stage IV disease. Five- and 10-year overall survival rates were 85% and 75%, respectively. Leboulleux et al. (2002) concluded that the study confirmed the need for early treatment of MTC in patients with the MEN2B syndrome, preferably within the first 6 months of life. The phenotype of MTC occurring in the MEN2B syndrome was, however, not more aggressive than sporadic MTC or MTC occurring in other familial syndromes.
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