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PubMed1995

[Multiple endocrine neoplasia type 2A, type 2B and familial medullary thyroid carcinoma syndrome].

Recently, germline mutations in the RET proto-oncogene were found to be associated with multiple endocrine neoplasia (MEN) syndromes, MEN 2A, MEN 2B and Familial medullary thyroid carcinoma (FMTC). In patients with MEN 2A and FMTC different point mutations have been identified in exons 10 and 11 of the cysteine rich regions of RET. Patients with MEN 2B have a single point mutation (ATG to ACG) at codon 918 of RET. Therefore, a direct DNA testing has been developed to provide a highly accurate technique of detecting kindred members who have inherited a specific mutation associated with MEN 2A, MEN 2B or FMTC. In USA and Europe, prophylactic thyroidectomy has been performed on the basis of positive DNA testing, and the presence of a C-cell hyperplasia or a small medullary thyroid carcinoma was confirmed in each patient operated. Through nationwide survey in Japan, 233 patients with MEN 2 syndrome have been identified. They consisted of 180 MEN 2A, 18 MEN 2B, 13 FMTC and 22 unclassified patients. At follow-up, 47% of patients had recurrent medullary thyroid carcinoma and 5.7% of patients died of the disease. Genetic analysis was performed on 15 patients of 6 unrelated families in our series, and the results revealed that germinal mutations of RET as previously reported were also responsible for MEN 2 syndrome in Japanese. DNA analysis and prophylactic thyroidectomy for kindred members at risk for MEN 2 are likely to be beneficial in Japan as well.

Carcinoma↗
PubMed1994

Germ line mutations of the ret proto-oncogene in Japanese patients with multiple endocrine neoplasia type 2A and type 2B.

We investigated mutations of the ret proto-oncogene in Japanese patients with multiple endocrine neoplasia (MEN) type 2A and type 2B. DNAs from pheochromocytomas and/or medullary thyroid carcinomas (MTCs) of five MEN 2A and three MEN 2B patients were amplified by a polymerase chain reaction (PCR) and analyzed. Tumors of four MEN 2A patients had missense mutations in Cys 634 in the extracellular domain of the ret proto-oncogene. The same mutations were detected in normal tissues of the patients, indicating that the mutations had arisen in the germ line. Using a reverse transcriptase(RT)-PCR, both normal and mutant transcripts of the ret proto-oncogene were detected in a tumor of one patient with MEN 2A mutation. In addition, three MEN 2B patients examined had the same point mutation (ATG-->ACG) at codon 918 in the tyrosine kinase domain of the ret proto-oncogene. Since all mutations identified in this study generated new restriction enzyme sites or eliminated a restriction site, the mutant alleles of affected family members could be readily detected without sequencing.

Base Sequence↗
PubMed1984

Chromosome 20 deletion in human multiple endocrine neoplasia types 2A and 2B: a double-blind study.

Multiple endocrine neoplasia type 2A and 2B (MEN-2A and MEN-2B) are autosomal dominantly inherited syndromes in which medullary thyroid cancers are associated with adrenal pheochromocytomas. A double-blind analysis of high-resolution G-banded chromosomes was performed on blood specimens from patients in four MEN-2A families and five MEN-2B (mucosal neuroma phenotype) families and from control subjects. Excluding studies on duplicate blood specimens, 9 of 11 control subjects were scored as having normal chromosomes 20, and 11 of 14 MEN-2 patients were scored as having chromosomal deletion: del(20)(p12.2p12.2) (phi 2 = 9.00; P less than 0.001). Two new mutant MEN-2B patients had apparently normal chromosomes 20. These findings demonstrate that the dominant mutation in most MEN-2A and MEN-2B families is a visible chromosome deletion within band 20p12.2.

Adrenal Gland Neoplasms↗
PubMed2003

Laryngeal solitary multiple mucosal neuromas without multiple endocrine neoplasia (MEN) type 2B.

The first case of laryngeal solitary multiple mucosal neuromas (MMN) was reported. A 73-year-old man who had complained of hoarseness and abnormal prickly sensation in the throat for 3 months visited our hospital. Many small whitish-yellow nodules were observed in the laryngeal mucosa from the right arytenoid to the interarytenoid region. Using laryngomicroscopy biopsy was performed twice. The pathological study showed neurogenic nodular lesions consisting of regularly arranged nerve bundles with many axons and Schwann cell proliferation, and so MMN was finally diagnosed. As MMN is regarded as a constant component of multiple endocrine neoplasia (MEN) type 2B, screening of MEN type 2B was performed, however, they were all within normal limits. This case was, therefore, diagnosed as a laryngeal solitary MMN without MEN type 2B.

Aged↗
PubMed1981

Multiple endocrine neoplasia with skeletal manifestations.

There are three types of familial multiple endocrine neoplasia, but type 2b, which is characterized by medullary thyroid carcinoma, pheochromocytoma, and ganglioneuromatosis, is the only one in which patients also have skeletal anomalies. These musculoskeletal abnormalities include marfanoid habitus, pes cavus, talipes equinovarus, slipped capital femoral epiphysis, kyphosis, scoliosis, lordosis, increased joint laxity, and weakness of the proximal muscles of the extremities. Affected patients have several facial abnormalities as well, the most striking being enlargement of the lips. Therefore, when a patient is seen with one or more of these musculoskeletal defects, the diagnosis of type-2b multiple endocrine neoplasia should be considered. If the characteristic facial features of the disorder are present, the patient should have a prompt examination for medullary thyroid carcinoma and pheochromocytoma.

Abnormalities, Multiple↗
PubMed1996

Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B.

Recently it has become possible to identify persons who have multiple endocrine neoplasia (MEN) syndrome types 2A and 2B based on the presence of missense mutations in the RET protooncogene. Kindred members who have inherited these syndromes can be identified before clinical or biochemical evidence of medullary thyroid carcinoma (MTC) develops, the malignancy that occurs in all affected patients. It is not known whether prophylactic removal of the thyroid gland early in childhood, based on a positive genetic test result, has a better clinical outcome than that associated with thyroidectomy after MTC is diagnosed clinically or biochemically. The authors' goal was to determine the long-term outcome for patients with MEN 2A and 2B who had thyroidectomy for MTC during childhood. These results were compared with those of patients who had prophylactic removal of the thyroid gland after the genetic diagnosis of MEN 2A was established. The hospital records of 49 children with MEN 2A or 2B were reviewed. Each patient had thyroidectomy for MTC before 16 years of age. The mean age at the time of operation was 10 years, and the mean follow-up period for those who had surgery before the availability of direct DNA genetic testing was 9.8 years. The indications for surgery included an elevated basal or stimulated plasma calcitonin level, a positive genetic test result, a thyroid mass, family history of MTC, or a phenotype diagnostic of MEN 2B. All children for whom the diagnosis of MEN 2A was established by direct genetic testing had thyroidectomy within the last 2 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, 10 had MTC, and only 3 (27%) remain free of disease after the mean follow-up period of 11 years. One patient died, and seven are alive with persistent MTC. Among the 24 patients with MEN 2A who had their thyroid glands removed because of a family history of MTC or because of biochemical evidence of the disease, 5 (21%) have persistent or recurrent MTC after the mean follow-up period of 9.3 years. In four of these, the MTC was confined to the thyroid gland at the time of thyroidectomy. Of the 14 children who had thyroidectomy based on direct DNA testing, MTC was present in 11. Only four had elevated levels of stimulated plasma calcitonin before surgery. None had lymph node metastasis or surgical complications. The authors conclude that a significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.

Adolescent↗
PubMed2006

Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre.

BACKGROUND: Evidence that germline mutations in the RET proto-oncogene are the underlying cause of the familial form of medullary thyroid carcinoma (MTC) made it possible to identify gene carriers with a very high degree of accuracy. Aiming to define the mutational profile observed in our patients and to assess gene carriers' compliance with an early surgery, we reviewed results of molecular analysis of RET performed at our institution since 1994. METHODS: One hundred fifty-eight individuals were screened for germline mutations of the RET proto-oncogene. Seventy-seven patients had apparently sporadic MTC; 8 patients had both MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B despite a negative family history; 8 patients were known to belong to affected kindreds; and 65 individuals were at-risk individuals to develop MTC. RESULTS: A germline mutation in RET was identified in 4% of apparently sporadic MTC patients, in 100% of patients with MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B, and in 100% of probands of clinically established kindreds. The most affected codon was 634 (58%) followed by codon 804 (16%). Among at-risk individuals, 49% were identified as gene carriers. Seven individuals were submitted to prophylactic thyroidectomy (mean age, 17.7 +/- 12.5 years; range: 3-42 years), and all but 1 had MTC. CONCLUSIONS: RET mutational spectrum observed in the present population disclosed a higher frequency of codon 804 mutations than expected. Compliance with an early prophylactic surgery seemed to be influenced not only by medical advice and cultural factors but also by the aggressiveness of disease in gene carriers' families.

Adolescent↗
PubMed1993

Cholecystitis, cholelithiasis, and ganglioneuromatosis of the gall bladder: an unusual presentation of MEN type 2b.

A 40 year old man with multiple endocrine neoplasia type 2b (MEN 2b) presented with cholecystitis caused by gall stones. Twenty four years earlier, he had had a partial thyroidectomy for a cold nodule. At his initial presentation MEN 2b with medullary carcinoma of the thyroid had not been made. This was diagnosed while investigating his gall bladder symptoms and he was found to have asymptomatic residual medullary thyroid carcinoma and bilateral adrenal phaeochromocytomas. The cholecystectomy specimen contained several mixed calculi and extensive ganglioneuromatosis with large, prominent nerves containing ganglion cells in the gall bladder wall.

Adult↗
PubMed1991

Incidence of prominent corneal nerves in multiple endocrine neoplasia type 2A.

We studied the increased visibility of corneal nerves inside an 8-mm diameter central corneal area in 14 patients with multiple endocrine neoplasia type 2A, one patient with multiple endocrine neoplasia type 2B, five patients with nonhereditary medullary thyroid carcinoma, ten patients with anterior keratoconus, and ten normal subjects. We used a grading system (grade 0 through grade 4) for nerve visibility based on slit-lamp biomicroscopic examination and photographic documentation. All 20 normal eyes showed either grade 0 or grade 1, which indicated no pathologic thickening of corneal nerves. Sixteen of the 28 eyes (57%) with multiple endocrine neoplasia type 2A, however, were evaluated as grade 2 or higher, which indicated thickened corneal nerves. The incidence of high nerve visibility in eyes with multiple endocrine neoplasia type 2A was significantly greater compared to normal eyes (P less than .0001), anterior keratoconus (P less than .0001), and nonhereditary medullary thyroid carcinoma (P = .0012). Furthermore, eight of the 28 eyes (29%) with multiple endocrine neoplasia type 2A showed markedly prominent corneal nerves (grade 3 and 4), a prominence similar to those seen in eyes with multiple endocrine neoplasia type 2B. There was no definite relationship among prominent nerve, age of the patient, and occurrence of pheochromocytoma. These findings suggest that over half of all patients with multiple endocrine neoplasia type 2A show corneal nerves pathologically thickened to different degrees.

Adult↗
PubMed1998

Somatic mutations in the RET protooncogene in Japanese and Chinese sporadic medullary thyroid carcinomas.

Despite advances in the understanding of the genotype-phenotype correlation in multiple endocrine neoplasia type 2A and 2B (multiple endocrine neoplasia (MEN) 2A, MEN 2B), and familial medullary thyroid carcinoma (FMTC), the frequency and prognostic relevance of RET protooncogene mutations in sporadic medullary thyroid carcinomas (MTCs) remain controversial. To study somatic mutations in the RET protooncogene in Japanese and Chinese sporadic MTCs and to analyze comparatively the correlation between RET mutation and tumor differentiation, we investigated somatic mutations in the RET protooncogene in 20 Japanese and 20 Chinese sporadic MTCs by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Of the 40 sporadic MTCs, 13 had a point mutation in codon 918 of exon 16, a frequency of 32.5%. There was no significant difference in the frequency between Japanese and Chinese sporadic MTCs, as 30% of the Japanese and 35% of the Chinese sporadic MTCs contained this mutation. We did not observe any correlation between the presence or absence of codon 918 mutation and tumor differentiation in either Japanese or Chinese sporadic MTCs. Our findings indicate that the frequency of RET somatic mutations is similar in Japanese and Chinese sporadic MTCs, and the presence or absence of RET mutation does not correlate with the differentiation of sporadic MTCs.

Carcinoma, Medullary↗
PubMed1995

Detection of a germline mutation at codon 918 of the RET proto-oncogene in French MEN 2B families.

Multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC) are three dominantly inherited disorders linked to the same disease locus on chromosome 10. Two types of germline mutation of the RET proto-onco-gene, which codes for a transmembrane tyrosine kinase, are associated with MEN 2. Missense mutations at cysteine residues in the extra-cytoplasmic domain are exclusively associated with MEN 2A and FMTC. In MEN 2B patients, a single point mutation at codon 918 has recently been characterized, leading to the replacement of a methionine by a threonine within the RET tyrosine kinase domain. We now report the identification of a mutation at codon 918 in the germline of 16 patients out of 18 unrelated MEN 2B families analyzed. In these families we have been able to demonstrate that, in five cases, the mutation arose de novo, and that, in one kindred, it was coinherited with the disease. These results indicate that a unique mutation at codon 918 of the RET gene is the most prevalent genetic defect causing MEN 2B, but also that rare MEN 2B cases are associated with different mutations yet to be defined.

Adolescent↗
PubMed2006

Multiple endocrine neoplasia 2B presenting with pseudo-Hirschsprung's disease.

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and typical phenotypic features, such as marfanoid habitus, multiple mucosal ganglioneuromas and thickened corneal nerves. Individuals with MEN 2B may develop megacolon and pseudo-obstruction due to intestinal ganglioneuromatosis simulating Hirschsprung's (HSCR) disease. We hereby describe the clinical and genetic features of a 21-year-old male patient with MEN 2B associated with pseudo-HSCR disease. The patient had MTC, pheochromocytoma, marfanoid habitus, multiple mucosal ganglioneuromas, thickened corneal nerves and severe gastrointestinal involvement. Emergent laparotomy was performed when he was presented with acute bowel obstruction. The myenteric and submucosal nerve plexuses in the small and large intestines were composed of diffusely hyperplasic, disorganized, mature ganglion cells. Genetic testing revealed a de novo ret proto-oncogene germline mutation in codon 918 in exon 16. Megacolon and pseudo-obstruction similar to the HSCR disease may develop in patients with MEN 2B. However, the observed dysmotility is the result of an abnormal proliferation of intramural ganglion cells in contrast to the absence of enteric ganglia which were present in the HSCR disease. Attentiveness about the phenotypic characteristics and unusual findings might lead to early and correct diagnosis of the MEN 2B syndrome. This approach improves the survival rate and quality of life considerably.

Adrenal Gland Neoplasms↗
PubMed1996

A mutation in the RET proto-oncogene in Hirschsprung's disease affects the tyrosine kinase activity associated with multiple endocrine neoplasia type 2A and 2B.

We demonstrate that a Hirschsprung (HSCR) mutation in the tyrosine kinase domain of the RET proto-oncogene abolishes in cis the tyrosine-phosphorylation associated with the activating mutation in multiple endocrine neoplasia type 2A (MEN2A) in transiently transfected Cos cells. Yet the double mutant RET2AHS retains the ability to form stable dimers, thus dissociating the dimerization from the phosphorylation potential. Co-transfection experiments with single and double mutants carrying plasmids RET2A and RET2AHS in different ratios drastically reduced the phosphorylation levels of the RET2A protein, suggesting a dominant-negative effect of the HSCR mutation. Also, the phosphorylation associated with the multiple endocrine neoplasia type 2B (MEN2B) allele was affected in experiments with single and double mutants carrying plasmids co-transfected under the same conditions. Finally, analysis of the enzymic activity of MEN2A and MEN2B tumours confirmed the relative levels of tyrosine phosphorylation observed in Cos cells, indicating that this condition, in vivo, may account for the RET transforming potential.

Animals↗
PubMed2004

A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma.

Hereditary medullary thyroid carcinoma, a tumor that arises from the parafollicular cells of the thyroid gland, occurs in isolation (as in familial medullary thyroid carcinoma), in association with hyperparathyroidism and pheochromocytoma (as in multiple endocrine neoplasia type 2A), or in association with pheochromocytoma, marfanoid habitus, and mucosal neuromas (as in multiple endocrine neoplasia type 2B). These genetic syndromes are associated with germline-activating mutations of the RET protooncogene, a cell surface tyrosine kinase receptor, which is believed to modulate specific intracellular signaling pathways involved in the regulation of C cell proliferation and apoptosis. RET-activating mutations involve two important functional areas of the receptor: the cysteine-rich extracellular domain and the intracellular tyrosine kinase domain. Multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma are more commonly associated with mutations in the cysteine-rich extracellular domain, whereas multiple endocrine neoplasia type 2B is exclusively associated with mutations involving the second intracellular tyrosine kinase domain. Here, we describe a novel missense mutation of the RET protooncogene that substitutes arginine for proline at codon 912 of the intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma.

Adolescent↗
PubMed1994

Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B.

BACKGROUND: Considerable emphasis has been placed on early diagnosis and surgery for multiple endocrine neoplasia (MEN)-related medullary thyroid carcinoma (MTC) during the past two decades. Genetic screening now promises earlier and more accurate diagnosis. We examine our experience with MTC in MEN 2A and MEN 2B and assess the benefits of biochemical screening during the past 20 years. PATIENTS AND METHODS: Seventy-seven patients undergoing 63 primary total thyroidectomies and 14 reoperative procedures for MEN-related invasive MTC and/or preinvasive C-cell hyperplasia are reported. Fifty-eight patients had MEN 2A and 19 had MEN 2B; 79% of patients had a family history of MTC; 27% had pheochromocytoma, and 25% had hyperparathyroidism. RESULTS: Patients with MEN 2B had more advanced disease than those with MEN 2A, in spite of presentation at a younger age (15 years versus 24 years). Every patient with MEN 2B had invasive carcinoma, whereas 14% of patients with MEN 2A had C-cell hyperplasia without invasive disease. Nodal metastases were found less frequently in MEN 2A (14%) than MEN 2B (38%), and biochemical cure was achieved in 56% of patients with MEN 2A compared with none in patients with MEN 2B. Among patients with MEN 2A the occurrence of invasive carcinoma increased with age (p = 0.0003); 40% of patients for less than 5 years had invasive MTC compared with 100% at more than 20 years. Cause-specific mortality among patients with MEN and invasive tumors at 6, 12, and 18 years was 2%, 4%, and 7%, respectively, lower than that of patients with sporadic MTC (12%, 17%, and 23%, respectively) treated during the same time period (p = 0.028). CONCLUSIONS: Intensive biochemical screening of MEN 2 kindreds for MTC can result in detection of early disease and a significant prospect of surgical cure. Genetic testing promises additional benefits through more reliable detection of preinvasive disease, allowing prophylactic thyroidectomy in infancy. In MEN 2B, MTC is considerably more aggressive than in MEN 2A. A policy of routine thyroidectomy in infants with MEN 2B, regardless of serum calcitonin levels, is justified.

Adolescent↗