RESUMEN
Thirty per cent of the paragangliomas and pheochromocytomas reported are hereditary. Mutations in SDHB, SDHC, SDHD, and more recently SDHAF2 and TMEM127 genes have been described in these hereditary tumors. We looked for mutations in these 5 genes in a series of 269 patients with paragangliomas and/or pheochromocytomas. The SDHB, SDHC, and SDHD genes were analyzed in a series of 269 unrelated index patients with paragangliomas and/or pheochromocytomas using dHPLC screening of point mutations followed by direct sequencing and Multiplex PCR Liquid Chromatography to detect large rearrangements confirmed by quantitative PCR. In a second phase, we adapted Multiplex PCR Liquid Chromatography to the SDHAF2 and TMEM127 genes. This method and direct sequencing were applied to 230 patients without the SDHB, C, D mutations. Of the 269 patients, 44 carried a mutation (16.3%). Thirty-seven different mutations were identified: 18 in SDHB (including 2 large deletions), 8 in SDHD, 6 in SDHC, 5 in TMEM127, and no mutations in SDHAF2. Thirteen mutations have not been published so far. An exhaustive study of the different genes is needed to make possible a familial genetic diagnosis in paraganglioma and pheochromocytoma hereditary syndromes. Although mutations in SDHC and TMEM127 are less frequent than mutations in SDHB and SDHD, they also have less evident clinical feature indicators. Analyzing SDHAF2 must be restricted to familial extra-adrenal paragangliomas. Multiplex PCR Liquid Chromatography is a sensitive, fast, and inexpensive method for screening large rearrangements, which are infrequent in these syndromes.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Predisposición Genética a la Enfermedad , Mutación , Paraganglioma/genética , Feocromocitoma/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/congénito , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Niño , Femenino , Pruebas Genéticas , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Paraganglioma/congénito , Paraganglioma/diagnóstico , Feocromocitoma/congénito , Feocromocitoma/diagnóstico , Succinato Deshidrogenasa/genética , Adulto JovenRESUMEN
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are catecholamine-secreting tumors of neural crest origin. Once collectively known as the '10% tumor', based on the frequency of inherited forms of the disease, they are now referred to as the '10-gene tumor', based on the number of susceptibility genes identified to date. Most familial cases of pheochromocytoma and/or paraganglioma and 10-20% sporadic cases carry germline mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, or MAX. The finding of somatic mutations in VHL and RET in an additional 10-15% of tumors has brought the proportion of all patients with PCC and/or PGL due to a genetic disruption in these genes to approximately one half. These findings impact on the clinical management of patients. The diversity in the genetic etiology has transcription correlates, which are reflected in the 2 main transcription signatures underlying these mutations: a pseudohypoxic cluster (VHL and SDH gene mutation carriers) and a cluster rich in kinase receptor signaling and protein translation pathways (RET, NF1, TMEM127 and MAX mutation carriers). Recognition of these clusters offers clues to better understand tumor pathogenesis as well as a rationale for the development of targeted therapies. In this report we provide an overview of the transcription-based classification of PCCs and PGLs, an update on the more recently identified susceptibility genes and an outline of current gaps in this research field as well as challenges for the coming years.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias de las Glándulas Suprarrenales/congénito , Animales , Predisposición Genética a la Enfermedad , Humanos , Mutación , Paraganglioma/congénito , Feocromocitoma/congénitoRESUMEN
Mitochondrial complex II, or succinate dehydrogenase, is a key enzymatic complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation as part of the mitochondrial respiratory chain. Germline succinate dehydrogenase subunit A (SDHA) mutations have been reported in a few patients with a classical mitochondrial neurodegenerative disease. Mutations in the genes encoding the three other succinate dehydrogenase subunits (SDHB, SDHC and SDHD) have been identified in patients affected by familial or 'apparently sporadic' paraganglioma and/or pheochromocytoma, an autosomal inherited cancer-susceptibility syndrome. These discoveries have dramatically changed the work-up and genetic counseling of patients and families with paragangliomas and/or pheochromocytomas. The subsequent identification of germline mutations in the gene encoding fumarase--another TCA cycle enzyme--in a new hereditary form of susceptibility to renal, uterine and cutaneous tumors has highlighted the potential role of the TCA cycle and, more generally, of the mitochondria in cancer.
Asunto(s)
Predisposición Genética a la Enfermedad , Mitocondrias/genética , Mutación , Paraganglioma/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/deficiencia , Animales , Ciclo del Ácido Cítrico/genética , Fumarato Hidratasa/genética , Humanos , Paraganglioma/congénito , Feocromocitoma/congénito , Succinato Deshidrogenasa/genéticaRESUMEN
Jugulotympanic glomus tumors have been called many things, but "paraganglioma of the temporal bone" is perhaps a more suitable term. This tumor is generally described as benign with a predilection for middle-aged women. Herein we report the case of an 11-month-old female infant with this condition. The extensiveness of the tumor with intracranial involvement at presentation suggests that the lesion might have been present for some time and raises the question of it being congenital in origin. We emphasize the overall importance of including paraganglioma of the temporal bone in the differential diagnosis of a "bleeding polyp" of the ear.