Detection of an <i>MEN1</i> gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing

Ellard, Sian; Hattersley, Andrew T.; Brewer, Carole; Vaidya, Bijay

doi:10.1111/j.1365-2265.2005.02190.x

Cited by 92 publications

(59 citation statements)

References 38 publications

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“…Most MEN1 cases carry a germline mutation in the MEN1 gene, which affects MENIN protein interaction with Jun-D and other factors involved in transcriptional regulation, DNA repair, genome stability, apoptosis regulation, and endocrine cell proliferation (3)(4)(5). Still, no important genotype-phenotype correlation in MEN1 has been established so far (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…We reviewed the literature and nine informative MEN1-S were found. These series were characterized mostly by small families, including 343 families with 873 affected cases and a highly variable prevalence of classic MEN1-related tumors (6,8,10,11,(15)(16)(17)(18)(19); Supplemental Table 1, which can be viewed online at http:// www.eje-online.org/supplemental/).…”

Section: Introductionmentioning

confidence: 99%

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Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

Lourenço¹,

Toledo²,

Mackowiak³

et al. 2008

European Journal of Endocrinology

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Objective: Only few large families with multiple endocrine neoplasia type 1 (MEN1) have been documented. Here, we aimed to investigate the clinical features of a seven-generation Brazilian pedigree, which included 715 at-risk family members. Design: Genealogical and geographic analysis was used to identify the MEN1 pedigree. Clinical and genetic approach was applied to characterize the phenotypic and genotypic features of the family members. Results: Our genetic data indicated that a founding mutation in the MEN1 gene has occurred in this extended Brazilian family. Fifty family members were diagnosed with MEN1. Very high frequencies of functioning and non-functioning MEN1-related tumors were documented and the prevalence of prolactinoma (29.6%) was similar to that previously described in prolactinoma-variant Burin (32%). In addition, bone mineral density analysis revealed severe osteoporosis (T, K2.87G0.32) of compact bone (distal radius) in hyperparathyroidism (HPT)/MEN1 patients, while marked bone mineral loss in the lumbar spine (T, K1.95G0.39), with most cancellous bone, and femoral neck (mixed composition; T, K1.48G0.27) were also present. Conclusions: In this study, we described clinically and genetically the fifth largest MEN1 family in the literature. Our data confirm previous findings suggesting that prevalence of MEN1-related tumors in large families may differ from reports combining cumulative data of small families. Furthermore, we were able to evaluate the bone status in HPT/MEN1 cases, a subject that has been incompletely approached in the literature. We discussed the bone loss pattern found in our MEN1 patients comparing with that of patients with sporadic primary HPT.European Journal of Endocrinology 159 259-274

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

Lourenço¹,

Toledo²,

Mackowiak³

et al. 2008

European Journal of Endocrinology

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“…Our fi nding of no MEN1 gene mutation in this patient may be related to the presence of disease phenocopy, to large deletions that are missed by DNA sequencing (27), to intronic mutations not detected by current primers or to mutations in regulatory elements or untranslated exons of the MEN1 gene, that were not tested in the present and earlier studies (28,29). Unfortunately, anomalies of PRKAR1A in the present patient cannot be examined but will be the next step.…”

Section: Supplemental Criteriamentioning

confidence: 61%

Possible association between Carney complex and multiple endocrine neoplasia type 1 phenotypes

Nunes

Chang

Mazeto³

et al. 2008

Arq Bras Endocrinol Metab

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Carney Complex (CNC) and Multiple Endocrine Neoplasia type 1 (MEN1) are forms of multiple endocrine neoplasia of dominant autosomal inheritance. Diagnosis of CNC occurs when two major criteria (lentiginoses, primary pigmented nodular adrenocortical disease, cardiac and cutaneous myxomas, acromegaly, testicular neoplasias, thyroid cancer) are observed and/or a major criterion associated with a supplementary criterion (affected relative, PRKAR1A gene mutation) occurs. On the other hand, diagnosis for MEN1 occurs through detection of two or more tumors located at the pituitary gland, parathyroid and/or pancreatic cells. The present case describes a 55 year-old male patient, diagnosed with acromegaly, primary hyperparathyroidism and papillary thyroid cancer, exhibiting components that meet the diagnostic criteria of both conditions described. Despite the occurrence of only one sporadic association or the acromegaly per se being responsible for the papillary cancer, new molecular mechanisms may not be ruled out. Complexo de Carney (CNC) e neoplasia endócrina múltipla tipo 1 (MEN1) são formas de neoplasias endócrinas múltiplas de herança autossômica dominante. O diagnóstico do CNC ocorre quando dois critérios maiores (lentiginose, doença nodular pigmentosa primária das adrenais, mixomas cardíacos e cutâneos, acromegalia, neoplasia testicular, carcinoma de tireóide) são observados e/ou um critério maior associado a um critério suplementar (familiar afetado, mutação do gene PRKAR1A) ocorre. Por outro lado, o diagnóstico de MEN1 dá-se pela detecção de dois ou mais tumores localizados na glândula hipofi sária, paratireóide e/ou células pancreáticas. O presente caso descreve um homem de 55 anos, com diagnóstico de acromegalia, hiperparatireoidismo primário e carcinoma papilífero de tireóide, exibindo critérios diagnósti-cos para as duas condições descritas. Embora possa ter ocorrido apenas uma associação esporádica, ou a acromegalia per se tenha predisposto ao carcinoma papilífero, novos mecanismos moleculares podem estar envolvidos.

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“…Genomic deoxyribonucleic acid (DNA) was isolated from peripheral blood. The AIP and MEN1 genes were sequenced with traditional methods, and large deletion was ruled out using multiplex ligation-dependent probe amplification (MLPA; MRC-Holland kit P244-B1, Amsterdam, Netherlands), as described elsewhere (16,17). The current list of pheochromocytoma/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and (19).…”

Section: Methods and Resultsmentioning

confidence: 99%

Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma

Boguszewski

Fighera

Bornschein

et al. 2012

Arq Bras Endocrinol Metab

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SUMMARYWe report on an adult woman with rare coexistence of acromegaly, pheochromocytoma (PHEO), gastrointestinal stromal tumor (GIST), intestinal polyposis, and thyroid follicular adenoma. At the age of 56, she was diagnosed with acromegaly caused by a pituitary macroadenoma, treated by transsphenoidal surgery, radiotherapy, and octreotide. During routine colonoscopy, multiple polyps were identified as tubular adenomas with high-grade dysplasia on histology. Years later, an abdominal mass of 8.0 x 6.2 cm was detected by routine ultrasound. Surgical exploration revealed an adrenal mass and another tumor adhered to the lesser gastric curvature, which were removed. Pathology confirmed the diagnosis of PHEO and GIST. PHEO immunohistochemistry was negative for GHRH. During follow-up, nodular goiter was found with normal levels of calcitonin and inconclusive cytology. Near-total thyroidectomy was performed, revealing a follicular adenoma. Her family history was negative for all of these tumor types. Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative. Though the finding of PHEO and acromegaly with multiple other tumors could be a fortuitous coexistence, we suggest that this case may represent a new variant of MEN syndrome with a de novo germline mutation in a not yet identified gene. Arq Bras Endocrinol Metab. 2012;56(8):507-12 SUMÁRIORelatamos o caso de uma mulher com rara coexistência de acromegalia, feocromocitoma (FEO), tumor do estroma gastrointestinal (GIST), polipose intestinal e adenoma folicular de tireoide. Aos 56 anos, ela foi diagnosticada com acromegalia por um macroadenoma hipofisário, tratado com cirurgia transesfenoidal, radioterapia e octreotide. Uma colonoscopia de rotina detectou múltiplos pólipos, que à histologia eram adenomas tubulares com alto grau de displasia. Anos mais tarde, uma ecografia detectou uma massa abdominal de 8.0 x 6.2 cm, que na exploração cirúrgica era uma lesão adrenal e outro tumor aderido à pequena curvatura gás-trica. A patologia confirmou os diagnósticos de FEO e GIST. A imuno-histoquímica do FEO foi negativa para GHRH. No seguimento, encontrou-se um bócio nodular com níveis normais de calcitonina e citologia inconclusiva. Após tireoidectomia total o diagnóstico histológico foi de adenoma folicular. A história familiar era negativa para todos esses tumores. As análises gené-ticas para genes de síndromes de FEO/paragangliomas (SDH A-D, SDHAF2, RET, VHL, TMEM127 e MAX) e para hipofisárias (AIP, MEN1 e p27) foram todas negativas. Embora a presença de FEO e acromegalia com múltiplos outros tumores possa ser uma coexistência fortuita, acreditamos na possibilidade de uma nova variante de NEM com uma mutação germinativa de novo em um gene ainda não identificado Arq Bras Endocrinol Metab. 2012;56(8):507-12

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Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing

Abstract: The likelihood of finding an MEN1 mutation depends on the clinical features of the patient and their family. This large series supports present referral criteria for diagnostic mutation screening, but suggests that patients with sporadic isolated tumours rarely have MEN1 mutations.

Cited by 92 publications

References 38 publications

Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

Possible association between Carney complex and multiple endocrine neoplasia type 1 phenotypes

Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma

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