A newly recognized germline mutation of MEN1 gene identified in a patient with parathyroid adenoma and carcinoma
ABSTRACT We report on a patient with primary hyperparathyroidism, owing to the concurrence of parathyroid adenoma with carcinoma, who
had a newly recognized germline mutation of the multiple endocrine neoplasia type 1 gene (MEN1 gene). The patient underwent total parathyroidectomy, and histological examination revealed parathyroid carcinoma and multiple
adenoma of the other three glands. Genetic analysis revealed a newly recognized heterozygous germline mutation (842deIC, exon
4) of the MEN1 gene. Both imaging studies and laboratory data showed no evidence of MEN 1 in the patient. Four family members—three sisters
and one daughter—had neither clinical features of MEN 1 nor genetic evidence of the MEN1 gene. This is the first report of a germline mutation of the MEN 1 gene found in a patient who exhibited the concurrence of parathyroid adenoma with carcinoma, suggesting that long-term hyperactivity
of the parathyroids may result in the formation of carcinoma.
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ABSTRACT: MEN1 is an autosomal dominant disorder characterized by parathyroid, pituitary, and pancreatic tumors. The MEN1 gene is located on chromosome 11q13 and encodes a 610-amino acid protein. MEN1 mutations are of diverse types and are scattered throughout the coding region, such that almost every MEN1 family will have its individual mutation. To further characterize such mutations we ascertained 34 unrelated MEN1 probands and undertook DNA sequence analysis. This identified 17 different mutations in 24 probands (2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletional-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a g-->a transition that resulted in a novel acceptor splice site in intron 4). The intron 4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this intron 4 mutation is the most frequently occurring germline MEN1 mutation ( approximately 10% of all mutations), and together with 5 others at codons 83-84, 118-119, 209-211, 418, and 516, accounts for 36.6% of all mutations, a finding that indicates an approach for identifying the widely diverse MEN1 mutations.Journal of Clinical Endocrinology & Metabolism 06/2002; 87(6):2688-93. · 6.43 Impact Factor
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ABSTRACT: Heterozygous germline mutations of the tumor suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized by the combined occurrence of pituitary, parathyroid, and enteropancreatic tumors. Various types of mutations likely causing loss of the gene function have been identified throughout the entire gene region in patients with MEN1 and related disorders including a small fraction of familial isolated hyperparathyroidism (FIHP). Neither mutation hot spot nor phenotype-genotype correlation has been established in classical MEN1, although some missense mutations may be specifically associated with a phenotype of FIHP. Familial isolated pituitary tumor and atypical familial MEN1 consisting of only pituitary tumor and hyperparathyroidism usually lack germline MEN1 mutations, suggesting that these familial endocrine tumor syndromes are genetic entities distinct from MEN1. DNA test for MEN1 germline mutations is a robust tool for diagnosis of predisposition to MEN1, and will be useful for the counseling and management of patients and their families. In this review, we will summarize the most recent findings on the MEN1 gene, focusing primarily on germline mutations and associated diseases.Endocrine Pathology 02/2001; 12(3):259-73. · 1.60 Impact Factor
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ABSTRACT: In the last few years, causative genes have been identified for most of the familial hyperparathyroidism conditions. Germline mutations in the tumour suppressors multiple endocrine neoplasia type 1 (MEN1) and hyperparathyroidism 2 (HRPT2) provide a molecular diagnosis of multiple endocrine neoplasia type 1 and hyperparathyroidism jaw tumour syndrome, respectively. Germline mutations in the proto-oncogene RET (rearranged during transfection) provide a molecular diagnosis of multiple endocrine neoplasia type 2. Germline mutations of both MEN1 and, less frequently HRPT2, have been found in familial isolated hyperparathyroidism. A molecular diagnosis can now be incorporated into the management of patients with these conditions, however, the ease of diagnostics and value of genetic information in the context of clinical screening and early surgical intervention varies between these disorders. This review focuses on familial hyperparathyroidism and its known causative genes in the setting of neoplastic syndromes, with particular discussion of recent developments in the molecular diagnosis of parathyroid carcinoma.Expert Opinion on Medical Diagnostics 11/2007; 1(3):377-392.