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PubMed1997

A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A.

Activating germline mutations in the cysteine-rich domain of the RET proto-oncogene are found in >92% of the cases of multiple endocrine neoplasia type 2A (MEN2A) and 85% of familial medullary thyroid carcinoma (FMTC). In virtually 100% of patients with identified mutations one of five cysteines is altered by a missense mutation. In a MEN2A family with 14 affected and 11 unaffected living members, hypercalcemia was diagnosed in eight patients and histological evaluation revealed parathyroid hyperplasia in all cases examined (10/10). No member of this family showed any evidence for the existence of pheochromocytoma. This is the first documentation of a family without pheochromocytoma but with a high incidence of parathyroid disease. Genetic analysis revealed the presence of an unusual heterozygous mutation in exon 11 of the RET proto-oncogene representing a duplication of 12 bp resulting in the insertion of four amino acids between codon 634 (Cys) and 635 (Arg), thus creating an additional cysteine residue.

Alleles↗
PubMed1986

Linkage analyses of multiple endocrine neoplasia, type 2A (MEN-2A) with 20 DNA polymorphisms: 5% of the genome excluded.

Pairwise linkage analyses are reported between the locus for multiple endocrine neoplasia type 2A (MEN-2A) and 20 restriction fragment length polymorphisms (RFLPs) in a single large kindred which was previously screened for linkage with this form of cancer using 23 blood group and serum protein polymorphisms. No significant, positive lod scores have been obtained so far. These 20 RFLPs have excluded the MEN2 locus from about as much of the genome as did the 23 classical markers previously reported. This is a clear demonstration of the value of RFLPs for linkage studies since these 20 RFLPs were not selected for being the most polymorphic of those available. Over 10% of the human genome has been excluded from linkage with the MEN2 locus in this particular family.

Chromosome Mapping↗
PubMed2002

Simultaneous occurrence of papillary intrafollicular and microcarcinomas with bilateral medullary microcarcinoma of the thyroid in a patient with multiple endocrine neoplasia type 2A: report of a case.

We report the case of a simultaneous occurrence of papillary intrafollicular and microcarcinomas with bilateral medullary microcarcinoma of the thyroid in a patient with multiple endocrine neoplasia type 2A. The concurrent presence of two thyroid carcinomas is rare. The simultaneous occurrence of two different tumors in the same thyroid each being multifocal and smaller than 1 cm in diameter has not been previously reported in the literature. Furthermore, we define the first case of intrafollicular papillary thyroid carcinoma (carcinoma in situ).

Adult↗
PubMed1992

High-sensitivity serum calcitonin assays applied to screening for thyroid C-cell disease in multiple endocrine neoplasia type 2A.

UNLABELLED: Two serum calcitonin assays with sensitivities < or = 10 pg/mL were compared to our standard radioimmunoassay (sensitivity 100 pg/mL) in multiple endocrine neoplasia type 2A (MEN 2A) screening. Values from the Nichols displacement radioimmunoassay averaged 38% higher than values from the CIS immunoradiometric assay; values from both were highly correlated, r = 0.845. In three individuals, both of the newer assays revealed abnormalities in pentagastrin tests three to four years before abnormalities were detected by the standard assay. Pentagastrin tests after total thyroidectomy were assayed by the newer methods in patients with medullary thyroid carcinoma (MTC) diagnosed at initial testing (group I); in patients with early MTC diagnosed by prospective screening (group II); and in patients with pure C-cell hyperplasia detected by prospective screening (group III). At least 64% of group I, at least 25% of group II, but none of group III had detectable postoperative C-cell function. CONCLUSIONS: 1) The previous estimate of 12 years as median age of onset of C-cell disease in MEN 2A is probably three to four years too old. 2) Patients diagnosed with early MTC by screening had not necessarily skipped a preneoplastic phase of C-cell hyperplasias. At least some early disease was not detected by the standard assay. Higher sensitivity assay should improve screening for C-cell disease by earlier disease detection. 3) Biochemical cure by thyroidectomy after the development of MTC is not as frequent as previously thought, but the apparent cure rate of pure C-cell hyperplasia remains 100%.

Adolescent↗
PubMed1994

Identification of the Cys634-->Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis.

Following the recent identification of specific germline mutations of the RET proto-oncogene in Multiple Endocrine Neoplasia type 2A (MEN2A) patients, we looked for mutations of this gene in a pedigree showing recurrence of MEN2A and localized Cutaneous Lichen Amyloidosis (CLA). Basal calcitonin and/or pentagastrin test performed in all the 10 available members of this pedigree confirmed the clinical diagnosis and allowed the presymptomatic identification of an additional carrier. A cys634-->tyr missense mutation, already reported as causative in MEN2A patients, was identified after SSCP analysis and direct sequencing of exon 11 of the RET protooncogene in one individual affected with both MEN2A and CLA, thus suggesting a common etiology for the two disorders. Taking advantage of the observation of an RsaI restriction site in the sequence surrounding the mutated codon, we could demonstrate that the same mutation is present in three other affected members, in the presymptomatic carrier and in one additional 25 years old healthy member who shows a mildly positive pentagastrin test.

Amyloidosis↗
PubMed2005

Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations.

OBJECTIVE AND DESIGN: Genetic screening in multiple endocrine neoplasia type 2 (MEN 2) has led to specific management guidelines based on genotype-phenotype analysis. However, there is controversy regarding the appropriate age for prophylactic thyroidectomy in families with mutations in codon 804 in exon 14 of the RET proto-oncogene, where medullary thyroid cancer (MTC) may not develop until adulthood. We prospectively studied two MEN 2A families, one with the V804L and the other with the V804M RET mutation, to report our experience of genetic and biochemical screening and prophylactic thyroidectomy. Family 1 is one of the largest MEN 2A families in the literature, where 22 prophylactic thyroidectomies have been performed. PATIENTS AND RESULTS: C-cell hyperplasia (CCH) was found in 23 out of 25 thyroidectomy specimens from family members of ages 5 years and upwards. MTC was found in 10 out of 18 adults of age 25 years upwards, including the family 2 proband, who was found to have MTC with lymph node metastases at age 28. Phaeochromocytoma was only observed in one patient, but six cases of histologically confirmed hyperparathyroidism were seen in family 1. CONCLUSION: We suggest that prophylactic thyroidectomy should not be delayed until adulthood in MEN 2A families carrying codon 804 RET mutations, but should be performed when there is CCH, before the development of MTC, as close as possible to age 6 years, which is the age of the youngest reported case of MTC in '804' families.

Adolescent↗
PubMedDate not supplied

Multiple endocrine neoplasia type 2a (MEN2a): a call for psycho-social research.

This paper summarizes what is known about the diagnosis, treatment, and follow-care of people with the inherited disorder multiple endocrine neoplasia type 2a (MEN2a). Several databases were searched throughout the year 2000, including MEDLINE, CINAHL, CancerLit, PsychINFO, and Dissertation Abstracts International. MEN2a is a complex disease involving cancer care and control by surgery, health maintenance, and life-long observation of gene mutation carriers. Genetic testing is the standard of care, prophylactic surgery is recommended during directive counseling, and life-long surveillance is encouraged for people with MEN2a. A substantial body of scientific literature describes morbidity and mortality outcomes of disease treatment, and the monitoring of multiple organ systems. Research is scant concerning the psychological consequences and social impact of the MEN2a diagnosis, treatment, and follow-up. Nearly all that is known from a psycho-social perspective comes from data in The Netherlands. Little is known of the psychological responses to and social consequences of genetic predisposition testing, prophylactic and curative surgery, and life-long surveillance. Psycho-social research is essential to provide comprehensive care for patients and family members with this disorder and it is necessary to guide the development of risk management strategies for patients with this inherited cancer syndrome. Since MEN2a has been labeled a prototype for medical genetics, information on MEN2a patient experiences may be relevant to the care of individuals with other inherited cancer syndromes.

Adaptation, Psychological↗
PubMed2001

Pheochromocytoma in a pregnant woman with multiple endocrine neoplasia type 2a.

Pheochromocytoma is a rare cause of hypertension. Its coexistence with pregnancy is exceptional and laparoscopic removal has rarely been reported. We describe the case of a 34-year-old woman with multiple endocrine neoplasia type 2a (MEN 2a) with adrenal pheochromocytoma diagnosed in the 6th week of pregnancy. After pretreatment with phenoxybenzamine, a successful transperitoneal laparoscopic adrenalectomy was performed in the twentieth week of gestation. The management of pheochromocytoma in pregnancy and the indications for laparoscopic surgery in pregnant patients are discussed.

Adrenal Gland Neoplasms↗
PubMed1994

Predictive testing for multiple endocrine neoplasia type 2A (MEN 2A) based on the detection of mutations in the RET protooncogene.

BACKGROUND: The identification of inherited mutations in the RET protooncogene (RET) associated with multiple endocrine neoplasia type 2A (MEN 2A) has enabled the development of a genetic test to identify asymptomatic carriers of disease. METHODS: Genomic DNA was extracted from 96 members of an MEN 2A kindred. The polymerase chain reaction was used to amplify the RET exon known to contain the associated mutation. The mutation results in a new restriction endonuclease site and is detected by digestion with the appropriate enzyme. Inheritance of the mutation was verified with a previously developed genetic linkage test. RESULTS: We found that (1) mutations vary among kindreds but are consistently inherited within kindreds, (2) invariable correlation exists between mutation and disease (43 mutations in 43 affected individuals), (3) determination of the genetic status by linkage-based testing was precluded by recombination events and the informativeness of genetic markers, and (4) mutation analysis presymptomatically identified two genetically affected individuals. CONCLUSIONS: Direct genetic analysis for mutations in RET circumvents the limitations of linkage-based genetic testing and current biochemical screening assays. This method will be the diagnostic test of choice for the identification of asymptomatic individuals at risk for MEN 2A.

Amino Acid Sequence↗
PubMed1996

Genetic analysis of seven Mediterranean families with multiple endocrine neoplasia type 2A.

OBJECTIVE: Genetic analysis is now essential for the accurate screening of families with multiple endocrine neoplasia type 2 (MEN2). We present the genetic analyses by both haplotype and direct RET proto-oncogene mutation analysis in seven Mediterranean MEN 2A families and have compared these results with biochemical screening tests and pathological examinations. DESIGN: Total DNA was extracted from leucocytes. Linkage analysis was performed using five RFLP systems from three loci that flank the MEN2A locus (FNRB, RBP3, D10S15). RET proto-oncogene analysis was carried out by automatic DNA sequencing and adequate digestion of PCR amplified products for exons 10 and 11. Screening for medullary thyroid carcinoma or C-cell hyperplasia was performed by the pentagastrin provocation test. Adrenal medullary function was assessed by measurements of 24-hour urinary excretion of catecholamines and their metabolites. Serum calcium and phosphate measurements were the initial screen for hyperparathyroidism. Serum PTH was determined only if hyperparathyroidism was suggested by the former determinations. PATIENT: Genetic study was performed in 59 individuals (39 at risk) from seven kindreds of Mediterranean origin with MEN 2A. RESULTS: Diagnosis by linkage analysis was not possible in 30% of individuals at risk, but RET proto-oncogene analysis identified all these individuals. Mutations of the RET proto-oncogene were detected in exon 10 (codon 618) in one MEN 2A kindred and in exon 11 (codon 634) in the others. The results of direct analysis were concordant with linkage studies in each case. Three individuals from different MEN 2A kindreds, who were subsequently shown not to be gene carriers, had false positive pentagastrin stimulation tests. CONCLUSION: Biochemical tests can be replaced by direct DNA mutation analysis as the first line screening test in order to identify gene carriers of MEN 2A.

Base Sequence↗
PubMed1992

Improved predictive test for MEN2, using flanking dinucleotide repeats and RFLPs.

Gene(s) for the autosomal dominant endocrine cancer syndromes, multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B), and familial medullary thyroid carcinoma (MTC1) all map to the pericentromeric region of chromosome 10. Predictive testing for the inheritance of mutant alleles in individuals at risk for these disorders has been limited by the availability of highly informative and closely linked flanking markers. We describe the development of eight new markers, including two PCR-based dinucleotide repeat polymorphisms and six RFLPs that flank the disease loci. One of the dinucleotide repeat markers (sJRH-1) derives from the RBP3 locus on 10q11.2 and has a PIC of .88. The other dinucleotide repeat (sTCL-1) defines a new locus, D10S176, that maps by in situ hybridization to 10p11.2 and has a PIC of .68. We have constructed a new genetic linkage map of the pericentromeric region of chromosome 10, on the basis of 13 polymorphisms at six loci, which places the MEN2A locus between the dinucleotide repeat markers, with odds of 5,750:1 over the next most likely position. Using this set of markers, predictive genetic testing of 130 at-risk individuals from six families segregating MEN2A revealed that 95% were jointly informative with flanking markers, representing a significant improvement in genetic testing capabilities.

Base Sequence↗
PubMed2007

Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: mutation in C620 is associated with Hirschsprung's disease.

PURPOSE: Prophylactic total thyroidectomy is now recommended after having confirmed RET mutations in children of parents with multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. We reviewed our experience to determine the incidence of medullary thyroid carcinoma with respect to age at surgery, the location of the mutation, and its association with Hirschsprung's disease (HD). METHODS: A retrospective review from 1996 to 2005 revealed 20 children with genetic screening for multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma who underwent a prophylactic total thyroidectomy with parathyroid gland preservation. RESULTS: The median age of the 20 patients (9 boys and 11 girls) included in this study was 8.2 years (range, 3.7-16.9 years) at the time of their surgery. Final pathology revealed normal thyroid tissue (n = 3; median age, 5.9 years), C-cell hyperplasia (n = 13; median age, 10 years), or medullary thyroid carcinoma (n = 4; median age, 8 years). Four children, all with mutations in C620, had a previous diagnosis of HD. At a median follow-up of 3.7 years (range, 1 month to 8.4 years), all patients were well and cancer free. CONCLUSIONS: There is no correlation between histologic findings and median age at surgery. Hirschsprung's disease was found in 50% of the patients with the RET mutation in C620. In children of C620 parents, symptoms of HD should be actively sought, and if such are found, rectal biopsies should be performed even if mutation results are not yet available. Based on the age of the earliest cancer and the safety of total thyroidectomy, children should promptly undergo surgery after genetic screening and before their fifth year of life.

Adolescent↗
PubMed1999

Subtotal adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia type 2A.

OBJECTIVE: To describe our surgical technique for, and results of, subtotal adrenalectomy for phaeochromocytoma in multiple endocrine neoplasia (MEN) type 2. DESIGN: Retrospective study. SETTING: Teaching hospital, The Netherlands. SUBJECTS: 6 patients (four women and 2 men, mean age 35 years, range 31-46) with MEN type 2 who presented between 1993 and 1996. INTERVENTIONS: Cortical sparing adrenalectomy (n =4) together with contralateral total adrenalectomy in bilateral disease (n = 2). MAIN OUTCOME MEASURES: Morbidity, mortality, adrenal function postoperatively, and recurrence. RESULTS: Cortical sparing adrenalectomy leaving adequate adrenal reserve was possible in all cases. There was no operative morbidity or mortality. Mean follow-up was 40 months (range 1347). One patient developed a recurrent phaeochromocytoma 24 months after subtotal adrenalectomy. CONCLUSIONS: Subtotal adrenalectomy with preservation of adequate adrenal cortical reserve was feasible in all cases. Long term follow-up is necessary to establish its definitive place in the treatment of familial phaeochromocytoma.

Adrenal Cortex↗
PubMed1996

Detection of RET mutations in multiple endocrine neoplasia type 2a and familial medullary thyroid carcinoma by denaturing gradient gel electrophoresis.

Germline missense mutations within the coding region of the RET proto-oncogene have recently been described in patients with the dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). To date, the sequence variations occur in RET exons 10 and 11 and alter highly conserved cysteine residues in the proposed extracellular domain at codons 609, 611, 618, 620, and 634. To expedite rapid screening of populations at risk of MEN 2a or FMTC, we developed a PCR-based denaturing gradient gel electrophoresis (DGGE) strategy that detects polymorphisms occurring at all five Cys codons in both RET exons using identical gel conditions. In this report, the screening results from DGGE analysis of 15 distinct MEN 2a and FMTC mutations are shown. Each mutation generated a clearly distinguishable and unique homo- and heteroduplex band pattern. Given the highly efficient, reproducible, and sensitive nature of this approach, DGGE is particularly appropriate for rapid, large-scale screening of patients. Since prior knowledge of the RET mutation is unnecessary for analysis, DGGE is potentially valuable for distinguishing germline from seemingly sporadic medullary thyroid cancer as well as identifying novel sequence changes.

Base Sequence↗