Pheochromocytomas, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease

Neumann, Hartmut P. H.; Berger, Dietmar; Sigmund, G.; Blum, Ulrich; Schmidt, Dieter; Parmer, Robert J.; Volk, B; Kirste, Günter

doi:10.1056/nejm199311183292103

Cited by 431 publications

(252 citation statements)

References 27 publications

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“…Somatic VHL mutations are commonly involved in the tumorigenesis of hemangioblastomas, accounting for up to 50% of sporadic retinal and CNS hemangioblastomas [Maher et al, 1990a;Neumann et al, 1989;Oberstrass et al, 1996;Richard et al, 1998]. Interestingly, sporadic pheochromocytoma are rarely (3%) due to somatic VHL mutations [Bar et al, 1997;Eng et al, 1995;Glasker et al, 2001;Neumann et al, 1993;Sprenger et al, 2001]. However, up to 25% of seemingly sporadic pheochromocytomas actually have a germline VHL, NF-1, c-RET, or SDH mutations.…”

Section: Sporadic Diseasesmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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Section: Sporadic Diseasesmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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“…About 24% of them are associated with complex hereditary diseases, namely Von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF1), and the syndrome consisting of familial pheochromocytoma/paraganglioma associated with glomus tumors caused by mutations in succinate dehydrogenase subunit D or B (SDHD, SDAB) (1)(2)(3).…”

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confidence: 99%

Molecular analysis of the Von Hippel-Lindau (VHL) gene in a family with non-syndromic pheochromocytoma: the importance of genetic testing

Cruz

Fernandes

Clara

et al. 2007

Arq Bras Endocrinol Metab

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The two index patients of the family analyzed in this study had undergone bilateral adrenalectomy for pheochromocytomas. This prompted genetic analyses of the probands and seven first-degree relatives. The two pheochromocytoma patients and two additional asymptomatic family members were found to harbor a mutation c496G>T in exon 3 of the VHL gene. The family was then lost to systematic follow-up. Three years after performing the initial genetic evaluation, the sister of the probands, who was known to carry the same VHL germline mutation, was referred to our service after a pregnancy that was complicated by preeclampsia. She reported paroxysms suggestive for pheochromocytoma, but her urinary metanephrines were negative. However, computerized tomography of the abdomen showed an adrenal mass that was also positive on metaiodobenzylguanidine (MIBG) scintigraphy. This study illustrates that molecular analysis of the index patient(s) can lead to the identification of presymptomatic relatives carrying the mutation. Moreover, despite negative urinary metanephrines, the identification of a specific mutation has led to an increased suspicion and detection of a pheochromocytoma in the sister of the probands. Dois pacientes índices da família analisada neste estudo foram submetidos a adrenalectomia bilateral devido a feocromocitoma. Foi, então, realizado o estudo genético dos pacientes e de sete parentes de primeiro grau. Os dois pacientes com feocromocitoma e dois outros membros assintomáticos da família apresentaram a mutação c496G>T no exon 3 do gene VHL. A família perdeu seguimento médico. Três anos após a realização da avaliação genética, a irmã dos pacientes, portadora da mutação, foi encaminhada para o nosso serviço após uma gestação complicada por pré-eclampsia. Ela referia paroxismos sugestivos de feocromocitoma, mas as metanefrinas urinárias eram negativas. Entretanto, a tomografia computadorizada de abdômen evidenciou uma massa adrenal que também se contrastou na cintilografia com metaiodobenzilguanidina (MIBG). Esse estudo mostra que a análise molecular do paciente índice pode levar à identificação de parentes assintomáticos portadores da mutação. Além disso, mesmo com as metanefrinas urinárias negativas, a identificação de uma mutação específica levou a um aumento da suspeita e detecção de feocromocitoma na irmã dos afetados pela doença.

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“…Mutações do gene de VHL permitem a estabilização da transcrição de fatores induzíveis pela hipóxia, e o aumento desses fatores angiogênicos, sob condições de normoxemia, acarreta a aparição das lesões altamente vasculares, patognomônicas da enfermidade 27,29 . Os indivíduos afetados estão em risco de desenvolver seis diferentes tipos de lesões cardinais: hemangioblastomas do SNC e retinianos, cistos ou carcinomas renais e pancreáticos, feocromocitomas e tumores do saco endolinfático 7,8,12,14,[18][19][20][21][27][28][29] . Os critérios diagnósticos, segundo Melmon e Rosen, modificados por Neumann [27][28][29][30] , incluem hemangioblastomas múltiplos ou um hemangioblastoma mais uma lesão visceral maior.…”

Section: Discussionunclassified

“…Até 20% dos feocromocitomas associam-se a dVHL 1,28 . Não obstante, o feocromocitoma apresentase em 5% a 60% das famílias portadoras da enfermi-A manifestação pancreática mais freqüente do complexo de VHL são os cistos simples, presentes em 53% dos sujeitos positivos ao rastreamento durante este estudo.…”

Section: Discussionunclassified

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2008

Arquivos Brasileiros de Neurocirurgia: Brazilian Neurosurgery

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Pheochromocytomas, Multiple Endocrine Neoplasia Type 2, and von Hippel-Lindau Disease

Cited by 431 publications

References 27 publications

Genetic analysis of von Hippel-Lindau disease

Genetic analysis of von Hippel-Lindau disease

Molecular analysis of the Von Hippel-Lindau (VHL) gene in a family with non-syndromic pheochromocytoma: the importance of genetic testing

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