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PubMed1997

Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype.

We investigated the transforming activity of the ret proto-oncogene with a mutation in cysteine 609, 611, 618, 620, 630, or 634 detected in patients with multiple endocrine neoplasia type 2A (MEN 2A), familial medullary thyroid carcinoma (FMTC), or Hirschsprung's disease. Of these cysteine mutations, codon 634 mutations are known to be correlated with the development of MEN 2A, whereas codon 609, 618, or 620 mutations were detected in two-thirds of FMTCs and in several cases of Hirschsprung's disease. Analysis of a total of 18 mutant genes revealed that codon 634 mutations have the highest transforming activity. The activity of ret with a codon 609, 611, 618, or 620 mutation and with a codon 630 mutation was approximately 3- to 5-fold and 2-fold lower than that of ret with a codon 634 mutation, respectively. In addition, different amino acid substitutions for the same cysteine displayed comparable transforming activity. The expression of the cell surface form of Ret with codon 609, 611, 618, or 620 mutation was very low compared with that of Ret with codon 634 mutation, indicating that the former four mutations might impair transport of Ret to the plasma membrane, as observed for several Hirschsprung mutations affecting the Ret extracellular domain. These results thus suggest that mutations in cysteine 609, 611, 618, or 620 may have the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC.

3T3 Cells↗
PubMed1993

Multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis: description of a new family.

Multiple endocrine neoplasia (MEN) 2A associated to cutaneous lichen amyloidosis is a variant of MEN 2A recently reported in few families. We describe an additional family with this syndrome. The skin lesion is a pruritic one, located over the upper back showing, at biopsy, cutaneous amyloid. The propositus of our family was a 35-year-old woman already treated with total thyroidectomy for medullary thyroid cancer and with bilateral adrenalectomy for pheochromocytoma. The patient referred that the skin lesion was present since childhood and increased with time. Skin biopsy showed negative staining for amyloid, for calcitonin and neuron-specific enolase. The paraspinal muscles corresponding to the area of affected skin showed slight neurogenic abnormalities. Ten other members of her family were affected by MEN 2A, three of whom (all females) had the same cutaneous alteration.

Adrenal Gland Neoplasms↗
PubMed1992

A cluster of CpG islands at D10S94, near the locus responsible for multiple endocrine neoplasia type 2A (MEN2A).

We report the characterization of a dense cluster of CpG islands at D10S94 in proximal 10q11.2. D10S94 is tightly linked to the gene responsible for multiple endocrine neoplasia type 2A (MEN 2A), a dominantly inherited tumor syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and/or parathyroid adenoma. To date, no recombinants between D10S94 and MEN2A have been identified. The gene(s) responsible for two additional dominantly inherited disorders involving cancer of the medullary thyroid, MEN 2B (MEN2B), and dominantly inherited MTC without additional clinical features (MTC1), also map to this region. The gene or genes responsible for these disorders may be located at or near the D10S94 locus. A 570-kb long-range restriction map has been generated by pulsed-field gel electrophoresis using probes developed during a 160-kb bidirectional cosmid walk at D10S94. Six CpG islands are clustered within a 180-kb region; five fall within a 145-kb NotI restriction fragment that is contained in its entirety in our cosmid contig. The SacII, SfiI, and NotI restriction maps for lymphoblast and cloned DNA are concordant. These CpG islands may represent the 5' ends of candidate genes for MEN2A, MEN2B, and/or MTC1. One gene designated mcs94-1, which is associated with one of the CpG islands in this cluster, has been isolated and characterized in detail.

Base Sequence↗
PubMed1997

The molecular genetics of multiple endocrine neoplasia type 2A and related syndromes.

Identification of RET gene mutations in patients at-risk for the development of the hereditary forms of medullary thyroid carcinoma has simplified management and expanded the scope of indications for surgical intervention. Patients who carry this mutation can be offered thyroidectomy at a very young age, hopefully at a point when the cancer has not yet developed or spread. Those who are found not to have inherited the mutation are spared further genetic and biochemical screening. This achievement marks a new paradigm in surgery--the recommendation that an operation be performed based on the result of a genetic test. Experience with management of patients with multiple endocrine neoplasia types 2A and 2B and with familial, non-multiple endocrine neoplasia medullary thyroid carcinoma will provide information that will aid in the future management of patients with other hereditary cancers.

Carcinoma, Medullary↗
PubMed1991

Tight linkage of the ret proto-oncogene with the multiple endocrine neoplasia type 2A locus.

The ret proto-oncogene has been mapped to 10q11.2 near the MEN2A locus by in situ hybridization. We carried out a linkage study of Japanese multiple endocrine neoplasia type 2A (MEN2A) families using a cosmid clone containing the ret proto-oncogene as probe. Two polymorphic alleles (A1 and A2) could be detected by digesting DNA with EcoRI: allele A1 was detected as a 10 kb fragment and A2 as 5.4 and 4.6 kb fragments. Of 11 Japanese MEN2A families analysed, four were informative, and the maximum lod score was 4.23 at a recombination fraction of 0.00. This result suggests the ret proto-oncogene to be close to the MEN2A gene and therefore possibly to be a useful DNA marker for cloning the latter.

Chromosome Mapping↗
PubMed1999

Multiple endocrine neoplasia type 2A with the identical somatic mutation in medullary thyroid carcinoma and pheochromocytoma without germline mutation at the corresponding site in the RET proto-oncogene.

A germline mutation either in exon 10 or 11 of the RET proto-oncogene is found in the majority of patients with multiple endocrine neoplasia type 2A (MEN 2A). A 41-year-old female patient was referred for further evaluation of incidentally discovered right adrenal tumor. She had bilateral adrenal pheochromocytomas and medullary thyroid carcinomas detected by endocrinological and radiological examination, and diagnosed as MEN 2A. Molecular genetic testing of the RET exons 10 and 11 exhibited the identical somatic missense mutation at codon 634 in both tumors but did not confirm germline mutations in the corresponding sites. Possible mechanisms for tumorigenesis in this patient are discussed.

Adrenal Gland Neoplasms↗
PubMed1986

Progress toward resolving the possible linkage of multiple endocrine neoplasia type 2A to haptoglobin and group-specific loci: use of restriction fragment length polymorphisms extends exclusion region.

In an earlier paper, positive but nonsignificant lod scores were found in pair-wise linkage tests between multiple endocrine neoplasia type 2A (MEN-2A) and both the haptoglobin (HP) locus on chromosome 16 and group-specific component (GC) locus on chromosome 4. Recently discovered restriction fragment length polymorphisms for HP and for metallothionein 2 processed pseudogene 1 (MT2P1) near GC have made it possible to carry out a more powerful set of linkage tests with MEN-2A. This paper reports the results of such linkage analyses employing both pair-wise and multipoint tests. Close linkage of HP on chromosome 16 and MEN-2A is excluded. Linkage of MEN-2A on chromosome 4 with GC is excluded on the MT2P1 side of GC in a 7-centimorgan interval around MT2P1.

Blood Protein Electrophoresis↗
PubMed2003

Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis.

OBJECTIVES: The aim of this study was first to investigate whether early total thyroidectomy (ETT; 1-5 years of age) can prevent medullary thyroid carcinoma with persistent or recurrent disease (PRD) in pediatric patients with multiple endocrine neoplasia type 2A (MEN-2A) and second, to evaluate the strength of codon analysis in children with MEN-2A as prognostic parameter. METHODS: Case reports and review of the literature for pediatric patients with MEN-2A were conducted. Inclusion criteria were age (0-20 years) and histologic degree of C-cell disease (normal = N, C-cell hyperplasia = CCH, medullary thyroid carcinoma = MTC, metastatic MTC = MMTC). To evaluate therapeutic results of ETT (1-5 years) versus late total thyroidectomy (LTT; 6-20 years), age-dependent histologic stages of C-cell disease and postoperative occurrence of PRD were compared. Prognostic value of specific codons, age-dependent histologic distribution, and long-term outcome were analyzed. RESULTS: In a total of 260 cases, 42 (16%) underwent ETT, and 218 (84%) underwent LTT. Histologic analysis showed significant difference between ETT versus LTT (57% vs 76%) regarding malignant stage of C-cell disease (of combined rate of MTC and MMTC). Long-term outcome was documented in 74 patients (28%). During a median follow-up period of 2 years (range: 0-15 years), 21 of 65 of the LTT group versus 0 of 9 of the ETT group suffered PRD. Information about codon analysis was available in 150 patients (58%). Mutated codons were c634 (63%), c618 (19%), c620 (9%), and c804 (6%). Codon-related histologic analysis resulted in prognostic differences: 81% of patients with c634-mutation had MCT or MMTC in contrast to c804 (44%), c618 (34%), and c620 (7%). Fifteen of 17 MMTC and 7 of 9 PRD occurred in patients with c634-mutation. CONCLUSIONS: 1) ETT until 5 years of age in MEN-2A gene carriers results in significant reduction of MTC and MMTC in favor of CCH and improved disease-free long-term outcome. 2) Codon analysis is an important prognostic factor. Timing of TT could be individualized based on codon-specific prognosis. Until more detailed knowledge is available, consequent genetic and biochemical screening is mandatory for appropriate individual timing of ETT before age of 5 years.

Adolescent↗
PubMed1992

A preliminary analysis of consortium data for markers tightly linked to multiple endocrine neoplasia type 2A.

We have analyzed DNA marker typing data contributed by six independent groups to estimate the pairwise genetic distances between these markers and the locus for multiple endocrine neoplasia type 2A (MEN 2A). We used LIPED to calculate these distances for female, male, and sex-average linkage maps and to determine the corresponding LOD scores. The preliminary analyses of this large data set (89 MEN 2A families and five non-MEN 2A references families, with 1,934 total individuals) are reported here. These refined estimates of the genetic map in this region will aid in the assignment of presymptomatic diagnoses. This study clearly points out the limitation of pairwise linkage analysis in further refining the position of MEN2A in this small region of chromosome 10. Further refinement of the genetic map position of MEN2A will be best accomplished by finding, verifying, and accurately mapping crossovers in specific families.

Chromosome Mapping↗
PubMed1992

Screening for multiple endocrine neoplasia type 2A with DNA-polymorphism analysis.

Nine chromosome 10 DNA markers (FNRB, D10S34, D10Z1, MEN203, D10S94, RBP3, D10S15, MBP [48.11], D10S22) were typed in two large Canadian pedigrees with multiple endocrine neoplasia type 2A (MEN 2A). These markers and the gene for MEN 2A (MEN2A) are believed to be in one linkage group spanning approximately 15 cM (male). MEN203 and D10S94 were informative and tightly linked to MEN2A with no recombinants observed in 26 meiotic events. D10S15 (MCK2), widely used in DNA genotyping predictions, demonstrated two recombinants in these two families. The use of multiple flanking markers increases both the likelihood of informativeness and the accuracy of risk assessments for predictive testing. We were able to assign a risk estimate for all 10 at-risk individuals.

Female↗
PubMed2003

Localization of medullary thyroid carcinoma metastasis in a multiple endocrine neoplasia type 2A patient by 6-[18F]-fluorodopamine positron emission tomography.

6-[(18)F]fluorodopamine, a substrate for the norepinephrine transporter, has been used as a tumor-seeking tracer in positron emission tomography (PET) to localize pheochromocytomas and other chromaffin tumors. Here, we report the case of a 42-yr-old woman with multiple endocrine neoplasia type 2A, in whom biopsy-proven recurrent medullary thyroid cancer (MTC) was detected by 6-[(18)F]fluorodopamine PET scanning. The patient had previously undergone bilateral adrenalectomy for pheochromocytoma, total thyroidectomy, and extirpation of a parapharyngeal MTC metastatic deposit. An increase in plasma calcitonin 5 yr after her initial presentation was further investigated, leading to the discovery of a mass in the left parapharyngeal space. Levels of serum and urine catecholamines and metanephrines were normal. To exclude a hormonally silent pheochromocytoma metastasis, 6-[(18)F]fluorodopamine PET was performed. The study showed a focus of radionuclide accumulation corresponding to the parapharyngeal mass. After resection of the latter, pathology confirmed metastatic MTC. To our knowledge, this is the first case of metastatic, histologically proven MTC, which was unequivocally detected by 6-[(18)F]fluorodopamine PET scanning. Because norepinephrine transporter systems have been previously found in MTC, it is conceivable that 6-[(18)F]fluorodopamine PET scanning can be used for the diagnostic localization of this tumor and its metastatic deposits because total and early resection is beneficial to the outcome of the patient.

Adult↗
PubMed1992

Isolation of YAC clones from the pericentromeric region of chromosome 10 and development of new genetic markers linked to the multiple endocrine neoplasia type 2A gene.

Genetic linkage mapping and contig assembly using yeast artificial chromosome (YAC) technology form the basis of our strategy to clone and define the genomic structure of the pericentromeric region of chromosome 10 containing the multiple endocrine neoplasia type 2A gene. Thus far YAC walks have been initiated from five chromosome 10 pericentromeric loci including RBP3, D10S94, RET, D10Z1, and FNRB. Long range pulsed-field gel electrophoresis maps are constructed from the YACs isolated to define clone overlaps and to identify putative CpG islands. Bidirectional YAC walks are continued by rescreening the YAC library with sequence-tagged site assays developed from end-clones. Several new restriction fragment length polymorphisms and simple sequence repeat polymorphism markers have been identified from the YAC clones. In particular, two highly informative (CA)n dinucleotide repeat markers, sTCL-1 from proximal chromosome 10p (16 alleles, PIC = 0.68) and sJRH-1 from the RBP3 locus (18 alleles, PIC = 0.88), provide useful reagents for a polymerase chain reaction-based predictive genetic test that can be performed rapidly from small amounts of DNA.

Chromosomes, Fungal↗
PubMed1999

Multiple endocrine neoplasia type 2A: a 25-year review.

BACKGROUND/PURPOSE: Before 1970, treatment decisions for the thyroid lesions in patients with multiple endocrine neoplasia (MEN) were based on physical findings. For the next 20 years, biological markers assumed a preeminent role, and at present, DNA testing is being used to define the need for therapeutic intervention. This report presents a 25-year review of 22 children with MEN-2A, with a mean follow-up of 12.5 years. METHODS: All 22 children underwent a total thyroidectomy, and four (18%) were rendered permanently hypoparathyroid. Since 1976, however, only one patient (6.7%) has lost parathyroid function. Despite the fact that biological screening studies routinely were performed once a year in the majority of our patients and surgery was recommended for any elevation in the serum calcitonin (CT) levels, medullary carcinoma of the thyroid (MTC) developed in 17 children (77%) and only five had C cell hyperplasia (CCH). Thirteen of the 17 had macroscopic tumor described by the pathologist, evidence of recurrent disease (MTC-REC) has developed in four children (24%). RESULTS: There was considerable overlap in both the basal and stimulated CT levels among the five children with CCH, the 13 with localized MTC (MTC-NED), and the four who later had recurrent MTC. The basal calcitonin levels were between 25 and 110 (mean, 58) in the CCH patients, 30 to 1,130 (mean, 184) in the MTC-NED group, and 108 to 201 (mean, 140) in those with recurrent MTC. The corresponding stimulated calcitonin levels were 45 to 417 (mean, 179) in CCH, 111 to 9,510 (mean, 1,407) in MTC-NED, and 449 to 5,093 (mean, 3,383) in MTC-REC. CONCLUSIONS: (1) Basal and pentagastrin-stimulated CT levels did not reliably discriminate between CCH and MTC and should not be used to define the timing of thyroid surgery in children with MEN-2A. (2) Surgical therapy should be undertaken early in childhood on the basis of molecular genetic testing. (3) Postoperative complications are infrequent in the modern era.

Adolescent↗
PubMed1995

Immunostains for collagen type IV discriminate between C-cell hyperplasia and microscopic medullary carcinoma in multiple endocrine neoplasia, type 2a.

At a light microscopic level, the separation of C-cell hyperplasia and microscopic medullary carcinoma of the thyroid (MCT) is difficult, and it ultimately rests on the finding of C cells outside of the thyroid follicular basement membranes (FBMs). To date, this has required ultrastructural examination for proper documentation. The assessment of thyroidectomy specimens from patients with multiple endocrine neoplasia, type 2a (MEN2a), a hereditary condition in which there is widespread C-cell hyperplasia (CCH) and multifocal MCT, presented an opportunity to the authors to assess the entire range of C-cell abnormalities. Total thyroidectomy specimens from 17 patients with MEN2a were examined. In addition to hematoxylineosin (H&E) stains, representative tissue sections were labeled for chromogranin A and collagen type IV (CIV), using the avidin-biotin-peroxidase complex (ABC) method. All patients in the study had multifocal C-cell proliferation that was both diffuse and nodular. Fifteen had microscopic MCTs, which were multifocal in eight instances. Three patterns of C-cell proliferation were recognized in CIV immunostains. The first was characterized by complete investment of C-cells by a continuous rim of CIV, corresponding to FBM and confirming an intrafollicular localization; hence, the diagnosis of CCH was made in such cases. The second pattern was distinctive and was typified by defects in the CIV layer; constituent C-cells assumed an extrafollicular location. These images yielded a diagnosis of micro-MCT. The latter findings were also accompanied by focal reduplication of basement membrane that was apparently tumor derived, producing a micronodular or microlobular configuration. The third pattern represented a combination of the first two, with C-cell nodules that were bounded by CIV and clearly situated in an intrafollicular location; however, focal reduplication of basement membranes was also evident in these cases. The biological significance of the third pattern of CIV staining is uncertain, but it may reflect the presence of a preinvasive proliferation of C-cells that is distinct from "usual" CCH in MEN2a.

Adolescent↗
PubMed2002

RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease.

BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.

Adult↗
PubMed2001

A large family with hereditary MTC: role of RET genetic analysis in differential diagnosis between MEN 2A and FMTC.

Germline mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In the absence of biochemical and/or clinical evidence of pheochromocytoma and hyperparathyroidism, patients with MEN 2A disease display the same phenotype of FMTC disease, although prognosis and clinical management in both affected and unaffected familial members are quite different. We studied a family with hereditary MTC, whose proband was referred to us because of enlarged cervical nodes and increased calcitonin serum levels 28 years after the total thyroidectomy for MTC. Cervical node dissection was carried out and subsequently the presence of MTC metastasis was histologically confirmed. A RET genomic mutation at codon 634 (TGC-->TTC) was identified in the proband and in seven out of 19 familial members studied. Accordingly, a hereditary disease was suggested. However, the strong association of RET mutation at codon 634 with the presence of pheochromocytoma in MEN 2 disease suggested a more rigorous management in all gene carriers. Indeed, during the follow-up pheochromocytoma was subsequently identified in the proband. This finding suggests that all families with a pedigree suggestive of FMTC should be regarded at risk from MEN 2A disease, at least when a critical mutation in the RET cysteine domain is detected.

Adolescent↗
PubMed1996

[Multiple endocrine neoplasia type 2A. Report of a case with an unusually aggressive outcome].

We report a 28 years old woman who consulted for diarrhea of two years and a thyroid nodule. A medullary thyroid carcinoma was diagnosed and a thyroidectomy performed. There was a local relapse two months later and distant metastases were found five months later. A MIBG-1131 scintigraphic image of the adrenals lead to the suspicion of a bilateral pheochromocytoma. The surgical resection of the adrenals confirmed the diagnosis. There was no response to chemotherapy and the patient continued with severe hypercalcemia, repeated infections, persistent diarrhea and cachexia, dying one year after the diagnosis. There was no family history of the disease. We conclude that this is a particularly aggressive presentation of a multiple endocrine neoplasia type 2A.

Adrenal Gland Neoplasms↗