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Characterization of mutations in patients with multiple endocrine neoplasia type 1.

ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene, on chromosome 11q13, has recently been cloned, and mutations have been identified. We have characterized such MEN1 mutations, assessed the reliability of SSCP analysis for the detection of these mutations, and estimated the age-related penetrance for MEN1. Sixty-three unrelated MEN1 kindreds (195 affected and 396 unaffected members) were investigated for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. We identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice-site mutation, and 6 missense mutations), that were scattered throughout the coding region, together with six polymorphisms that had heterozygosity frequencies of 2%-44%. More than 10% of the mutations arose de novo, and four mutation hot spots accounted for >25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected >85% of the mutations. Two hundred and one MEN1 mutant-gene carriers (155 affected and 46 unaffected) were identified, and these helped to define the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. These results provide the basis for a molecular-genetic screening approach that will supplement the clinical evaluation and genetic counseling of members of MEN1 families.

SUBMITTER: Bassett JH

PROVIDER: S-EPMC1376903 | biostudies-other | 1998 Feb

REPOSITORIES: biostudies-other

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Characterization of mutations in patients with multiple endocrine neoplasia type 1.

Bassett J H JH Forbes S A SA Pannett A A AA Lloyd S E SE Christie P T PT Wooding C C Harding B B Besser G M GM Edwards C R CR Monson J P JP Sampson J J Wass J A JA Wheeler M H MH Thakker R V RV

American journal of human genetics 19980201 2

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene, on chromosome 11q13, has recently been cloned, and mutations have been identified. We have characterized such MEN1 mutations, assessed the reliability of SSCP analysis for the detection of these mutations, and estimated the age-related penetrance for MEN1. Sixty-three unrelated MEN1 kindreds (195 affected and 396 unaff ...[more]

PMID: 9463336

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Project description:Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare hereditary complex disorder characterized by the presence of medullary thyroid carcinoma (MTC), unilateral or bilateral pheochromocytoma (PHEO) and other hyperplasia and/or neoplasia of different endocrine tissues within a single patient. MEN2 has been reported in approximately 500 to 1000 families worldwide and the prevalence has been estimated at approximately 1:30,000. Two different forms, sporadic and familial, have been described for MEN2. Sporadic form is represented by a case with two of the principal MEN2-related endocrine tumors. The familial form, which is more frequent and with an autosomal pattern of inheritance, consists of a MEN2 case with at least one first degree relative showing one of the characteristic endocrine tumors. Familial medullary thyroid carcinoma (FMTC) is a subtype of MEN2 in which the affected individuals develop only medullary thyroid carcinoma, without other clinical manifestations of MEN2. Predisposition to MEN2 is caused by germline activating mutations of the c-RET proto-oncogene on chromosome 10q11.2. The RET gene encodes a single-pass transmembrane tyrosine kinase that is the receptor for glial-derived neurotrophic growth factors. The combination of clinical and genetic investigations, together with the improved understanding of the molecular and clinical genetics of the syndrome, helps the diagnosis and treatment of patients. Currently, DNA testing makes possible the early detection of asymptomatic gene carriers, allowing to identify and treat the neoplastic lesions at an earlier stage. In particular, the identification of a strong genotype-phenotype correlation in MEN2 syndrome may enable a more individualized treatment for the patients, improving their quality of life. At present, surgical treatment offers the only chance of cure and therefore, early clinical and genetic detection and prophylactic surgery in subjects at risk are the main therapeutic goal.

Project description:ImportanceIntrinsic near-infrared (NIR) autofluorescence of the parathyroid gland enables intraoperative gland identification without the need for contrast agent injection. However, whether real-time autofluorescence imaging is useful in patients with multiple endocrine neoplasia type 1 (MEN1) and primary hyperparathyroidism is unknown.ObjectiveTo compare quantified intraoperative parathyroid autofluorescence imaging results for patients with MEN1-associated vs those with non-MEN1 sporadic primary hyperparathyroidism.Design, setting, and participantsA retrospective analysis of prospectively collected data on a cohort of 71 consecutive patients undergoing surgery for primary hyperparathyroidism by 2 experienced endocrine surgeons between June 1, 2017, and July 31, 2018, was conducted. Intraoperative imaging was performed with a handheld NIR autofluorescence device and images were captured for analysis. Post hoc blinded imaging analysis was conducted with Image J software to quantify representative areas of greatest autofluorescence from the parathyroid, thyroid, and adjacent soft tissue.Main outcomes and measuresPrimary end points were parathyroid autofluorescence and background thyroid and soft tissue autofluorescence, reported as median values with interquartile ranges. Rates of false-negative (lack of significant parathyroid gland autofluorescence compared with background autofluorescence, defined as parathyroid autofluorescence-background autofluorescence ratio <1.10) and false-positive autofluorescence (aberrant autofluorescence of nonparathyroid tissue confirmed by pathologic testing) were analyzed.ResultsOf the 71 consecutive patients with primary hyperparathyroidism who underwent parathyroidectomy during the study period, 6 patients had genetically or clinically diagnosed MEN1 and 65 had sporadic non-MEN1 hyperparathyroidism. Most patients were women (MEN1: 4 [67%]; non-MEN1: 51 [78%]). Median (interquartile range) age was 49.0 (38.0-53.8) years in the MEN1 cohort and 61.0 (54.0-67.0) years in the non-MEN1 cohort. No clinically significant differences in serum preoperative parathyroid hormone level or parathyroid gland size or weight on pathologic examination were observed between the 2 cohorts. The median absolute value of in situ parathyroid autofluorescence was significantly lower in the MEN1 cohort than the non-MEN1 cohort (54.4 vs 74.3; Hedges g = -1.03; 95% CI, -1.89 to -0.17), as was the ratio of parathyroid to background autofluorescence (1.08 vs 1.59; g = -1.59; 95% CI, -2.23 to -0.96). Three patients (50%) with MEN1 had false-negative nonfluorescent parathyroid adenomas vs 6 patients (9%) without MEN1. Nonparathyroid fibroadipose tissue of patients with MEN1 exhibited greater background autofluorescence, leading to high false-positive rates (5 of 6 patients [83%]) vs only 3 of 65 (5%) false-positive autofluorescence nonparathyroid specimens among patients without MEN1.Conclusions and relevanceIntraoperative identification of parathyroid glands using their autofluorescence by real-time NIR imaging appears to have utility in patients with primary hyperparathyroidism. In this initial cohort of patients with MEN1, decreased parathyroid autofluorescence and increased background autofluorescence of nonparathyroid tissue may be associated with high rates of false-negative and false-positive fluorescence, potentially limiting the utility of this adjunct in this specific subset of patients.

Project description:Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation 3-9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which is activated by H3K4 methylation.

Dataset Information

Characterization of mutations in patients with multiple endocrine neoplasia type 1.

Publications

Characterization of mutations in patients with multiple endocrine neoplasia type 1.

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