Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype–phenotype correlation

Vierimaa, Outi; Ebeling, Tapani; Kytölä, Soili; Bloigu, Risto; Eloranta, Eija; Salmi, Jorma; Korpi-Hyövälti, Eeva; Niskanen, Leo; Orvola, A; Elovaara, E; Gynther, A; Sane, Timo; Välimäki, Matti; Ignatius, Jaakko; Leisti, J; Salmela, Pasi

doi:10.1530/eje-07-0195

Cited by 40 publications

(78 citation statements)

References 46 publications

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“…Although this interpretation was obviously not proved, the authors considered that this gender difference was due to a clinical bias. Recently, an overall female predominance was also observed in four MEN1 studies from the United States (nZ233), from the United Kingdom (nZ220), from Germany (nZ301), and from Finland (nZ82), showing proportions of women of 54, 57, 59, and 57%, thus very close to our figures of 58% (12,26,27,30). The 2007 study from Finland was particularly interesting because the cohort was constituted during a comparable period of time (1982)(1983)(1984)(1985)(1986)(1987)(1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001) and was exclusively made of patients with ascertained MEN1 mutations.…”

Section: Discussionsupporting

confidence: 89%

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'étude des Tumeurs Endocrines

Goudet¹,

Bonithon‐Kopp²,

Murat³

et al. 2011

European Journal of Endocrinology

103

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Context: Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed. Objective: The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1. Design: Data regarding a study of 734 cases of MEN1 from the multicenter 'Groupe d'étude des Tumeurs Endocrines' were analyzed. Results: There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (PZ0.06, PZ0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P!0.001, P!0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (PZ0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%). Conclusion: The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.European Journal of Endocrinology 165 97-105

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Section: Discussionsupporting

confidence: 89%

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'étude des Tumeurs Endocrines

Goudet¹,

Bonithon‐Kopp²,

Murat³

et al. 2011

European Journal of Endocrinology

103

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“…(2,3) Since then, approximately 500 different germline mutations that cause loss of MEN1 gene function have been identified in patients with MEN1 and related disorders. (4)(5)(6)(7)(8)(9)(10) The germline mutations are heterozygous, and somatic loss of the normal MEN1 allele has been observed in the tumors arising in MEN1, in agreement with the Knudson's two-hit model. (11) Somatic inactivation of both MEN1 alleles has also been detected in some sporadic endocrine tumors, indicating involvement of this gene in the development of sporadic tumors.…”

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confidence: 73%

MEN1 gene and its mutations: Basic and clinical implications

Tsukada¹,

Nagamura²,

Ohkura³

2009

Cancer Science

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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 pituitary, parathyroid, and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and related disorders. Neither mutation hot spot nor phenotype-genotype correlation has been established in MEN1 although some missense mutations may be specifically associated with a phenotype of familial isolated hyperparathyroidism. The gene product menin has been implicated in multiple roles, including gene transcription, maintenance of genomic integrity, and control of cell division and differentiation. These multiple functions are likely to be conferred by association with multiple protein factors. Occurrence of MEN1-causing missense mutations throughout menin also suggests the requirement of multiple binding factors for its full tumor-suppressive activity. The effect of menin depletion is highly tissue specific, but its underlying mechanism remains to be elucidated. A DNA test for MEN1 germline mutations is a useful tool for diagnosis of MEN1 although it needs further improvements. The germline mutations are heterozygous, and somatic loss of the normal MEN1 allele has been observed in the tumors arising in MEN1, in agreement with the Knudson's two-hit model. (11) Somatic inactivation of both MEN1 alleles has also been detected in some sporadic endocrine tumors, indicating involvement of this gene in the development of sporadic tumors. So far, MEN1 gene mutations have not been implicated in any other human diseases.The product of the MEN1 gene, menin, is a 610-amino acid protein that exhibits no apparent sequence similarity to any other known protein.(1) Thus, its biochemical function can not be deduced from its structure. In the last decade, a number of studies have demonstrated physical and functional associations between menin and diverse proteins of known function, shedding light on its molecular function. These menin-interacting proteins include nuclear proteins such as transcription factors, histone deacetylases, and histone methyltransferases, suggesting that menin is involved in gene transcription. Several lines of evidence also suggest that menin is involved in the maintenance of genomic integrity. Although menin is localized mainly to cell nuclei, possible extranuclear functions have not been excluded because various cytoplasmic proteins bind to menin.Although the molecular function of menin is still poorly understood, identification of the MEN1 gene has enabled a direct DNA test for predisposition to MEN1. In the present review, recent findings on the MEN1 gene are summarized and its mutations are discussed from basic and clinical points of view. Structure and expression of the MEN1 geneThe human MEN1 gene comprises 10 exons distributed over 7 kb in the chromosome region 11q13 and encodes mRNA of approximately 2.8 kb (Fig. 2).(1) Exons 2 through 10 encode th...

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“…These individuals may have mutations in promoter or UTRs, which remains to be investigated. In a recently published study, a genotype-phenotype correlation between different mutations and the incidence of nonfunctioning pancreatic tumours and gastrinomas could be established (15). However, this correlation was lacking for adrenal lesions.…”

Section: Discussionmentioning

confidence: 99%

Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study

Schaefer

Shipotko

Meyer

et al. 2008

European Journal of Endocrinology

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Objective: Adrenal lesion is one of the features of multiple endocrine neoplasia type 1 (MEN1). This study aimed to assess prevalence, natural course and clinical relevance of small adrenal lesions without clinical symptoms, endocrine activity, or mechanical problems and thus without clear indication for surgical therapy by endoscopic ultrasound (EUS). Design and methods: Forty-nine patients with familial MEN1 were studied. Twenty-seven of these with adrenal lesions were detected by EUS and at least two performed EUS examinations were included into a subgroup where changes in adrenal morphology were studied by measuring changes in the largest diameter of the dominant adrenal tumour. Results: EUS detected adrenal lesions in 36 (73%) patients: 6 (12%) plump adrenals, 17 (35%) nodular hyperplasia, 12 (24%) adenomas and 1 (2%) cyst. Bilateral adrenal lesions were detected in 17 patients and unilateral in 19 patients. A change in the largest tumour diameter was found to be for nodular hyperplasia K0.02G1.41% per month (range K2.56 to 4.58%) and for adenomas K0.61G1.95% per month (range K6.25 to 1.15%). One patient had an adrenal cyst with significant growth. There was no evidence of carcinoma or metastatic disease during the study. Conclusions: The prevalence of adrenal lesions in MEN1 is higher than that reported earlier. Except one cystic lesion, no significant change in the tumour size was observed over a mean observation period of more than 2 years. In a typical situation, small adrenal lesions in MEN1 seem to be constant in their morphology.European Journal of Endocrinology 158 699-704

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Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype–phenotype correlation

Cited by 40 publications

References 46 publications

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'étude des Tumeurs Endocrines

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'étude des Tumeurs Endocrines

MEN1 gene and its mutations: Basic and clinical implications

Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study

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