Cushing's disease as the first clinical manifestation of multiple endocrine neoplasia type 1 (MEN1) associated with an R460X mutation of the MEN1 gene

Matsuzaki, Lisa N.; Canto-Costa, Marcelo H. S.; Hauache, Omar M.

doi:10.1111/j.1365-2265.2004.01943.x

Cited by 21 publications

(11 citation statements)

References 12 publications

(10 reference statements)

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“…Mutations in the p53 gene (TP53) are extremely rare and were found only in atypical corticotroph (i.e., aggressive) tumors and carcinomas (11,12). CD is rarely seen in the context of genetic syndromes like multiple endocrine neoplasia MEN1 (MEN1 encoding menin), MEN4 (CDKN1B encoding p27/KIP1), McCuneAlbright syndrome (GNAS oncogene encoding the stimulatory G protein Gsa) and never in Carney complex (PRKAR1A) (13,14,15). Patients with McCune-Albright and Carney complex suffer from Cushing's syndrome due to adrenal hyperplasia rather than CD.…”

Section: Genetic Events In CDmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

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Section: Genetic Events In CDmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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“…O tumor secretor de hormônio de crescimento (GH) é o segundo mais comum, e causa manifestações clínicas de acromegalia. Os tumores menos freqüentes são os não-funcionantes e o secretor de hormônio adrenocorticotrófico (ACTH) que causa a doença de Cushing (43). Apesar de raro, há casos reportados de tumores produtores de tirotropina e de gonadotrofinas (44,45).…”

Section: Adenomas Hipofisáriosunclassified

“…A análise mutacional destas famílias revelou que, apesar de mostrarem um fenótipo específico, todas tinham mutações diferentes, sem correlação. Mais além, recentemente descrevemos um paciente que apresentava doença de Cushing como manifestação clínica inicial de MEN 1 e diagnóstico posterior de hiperparatiroidismo primário (43). Neste caso, a mutação identificada foi a R460X, mutação esta presente justamente em algumas destas famílias com incidência elevada de prolactinomas.…”

Section: Genética Molecular Da Menunclassified

Neoplasia endócrina múltipla tipo 1: diagnóstico clínico, laboratorial e molecular e tratamento das doenças associadas

Hoff

Hauache

2005

Arq Bras Endocrinol Metab

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RESUMOAs síndromes de neoplasias endócrinas múltiplas (NEM) incluem as do tipo 1 (MEN 1) e 2 (MEN 2), a síndrome de von Hippel-Lindau, neurofibromatose tipo 1 e o complexo de Carney. Estas são síndromes genéticas complexas decorrentes de ativação ou inativação de diferentes tipos de genes envolvidos na regulação da proliferação celular. Nesta revisão, discutiremos as manifestações clínicas e o acompanhamento da MEN 1, assim como o rastreamento genético de potenciais portadores de alterações no gene MEN 1. A MEN 1 inclui o desenvolvimento de hiperparatiroidismo primário multifocal, tumores de ilhotas pancreáticas e adenomas de hipófise. Além disso, alguns pacientes podem apresentar manifestações cutâneas como angiofibromas e colagenomas e ainda podem desenvolver outras neoplasias como tumores carcinóides, tumores de tiróide, adenomas de adrenal, lipomas, feocromocitomas e meningiomas. A MEN 1 é uma síndrome hereditária, transmitida de forma autossômica dominante e causada por mutação inativadora do gene MEN 1. O gene MEN 1 codifica uma proteína denominada "menin", que é um gene supressor tumoral. Vários estudos demonstraram sua importância na regulação da proliferação celular e confirmaram seu papel na patogênese da MEN 1. A identificação do gene MEN 1 e sua análise genética resultaram na possibilidade de monitoração de pacientes que ainda não apresentam manifestações clínicas associadas a esta síndrome e diagnóstico precoce e tratamento dos pacientes afetados. Tais medidas poderão implicar em sobrevida maior para estes pacientes. Estudos adicionais visando uma melhor compreensão da função e dos mecanismos de sinalização da proteína "menin" poderão propiciar alternativas terapêuticas para os pacientes que evoluem com malignização de tumores relacionados à MEN 1, podendo resultar em maior sobrevida. Multiple endocrine neoplasia (MEN) syndromes include types 1 (MEN 1) and 2 (MEN 2), von Hippel-Lindau syndrome, neurofibromatosis type 1 and Carney complex. These are complex genetic syndromes caused by activation or inactivation of different types of genes known to be involved in the regulation of cell proliferation. In this review we will discuss the clinical manifestations and management of the MEN 1 syndrome as well as the genetic screening of potential MEN 1 gene carriers. MEN 1 is a hereditary syndrome, transmitted in an autosomic dominant fashion and caused by an inactivating mutation of the MEN 1 gene, characterized by the development of primary hyperparathyroidism, islet cell tumors and pituitary adenomas. In addition, these patients can pre-

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“…Stratakis et al (5) reported that two mutations of MEN1 (a deletion mutation and p.Arg415X) were identified in CD patients. Matsuzaki et al (15) reported an R460X mutation in MEN1 in a Brazilian subject with early-onset CD and his sister. A heterozygote C→T transition was detected at codon 460 in exon 10 in MEN1, which converts codon 460 CGA (Arg) to a stop codon TGA (15).…”

Section: Menin 1 (Men1) Mutationmentioning

confidence: 99%

“…Matsuzaki et al (15) reported an R460X mutation in MEN1 in a Brazilian subject with early-onset CD and his sister. A heterozygote C→T transition was detected at codon 460 in exon 10 in MEN1, which converts codon 460 CGA (Arg) to a stop codon TGA (15). Thus, mutations in MEN1 lead to the early clinical manifestations of MEN1, and are involved in CD.…”

Section: Menin 1 (Men1) Mutationmentioning

confidence: 99%

Gene mutations in Cushing's disease

Xiong

2016

Biomedical Reports

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Abstract. Cushing's disease (CD) is a severe (and potentially fatal) disease caused by adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary gland (often termed pituitary adenomas). The majority of ACTH-secreting corticotroph tumors are sporadic and CD rarely appears as a familial disorder, thus, the genetic mechanisms underlying CD are poorly understood. Studies have reported that various mutated genes are associated with CD, such as those in menin 1, aryl hydrocarbon receptor-interacting protein and the nuclear receptor subfamily 3 group C member 1. Recently it was identified that ubiquitin-specific protease 8 mutations contribute to CD, which was significant towards elucidating the genetic mechanisms of CD. The present study reviews the associated gene mutations in CD patients.

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Cushing's disease as the first clinical manifestation of multiple endocrine neoplasia type 1 (MEN1) associated with an R460X mutation of the MEN1 gene

Cited by 21 publications

References 12 publications

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Neoplasia endócrina múltipla tipo 1: diagnóstico clínico, laboratorial e molecular e tratamento das doenças associadas

Gene mutations in Cushing's disease

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