New Insights in the Genetics of Adrenocortical Tumors, Pheochromocytomas and Paragangliomas

Abstract

Correspondence Pr. J. Bertherat´Service des Maladies Endocriniennes et MØtaboliques, Hôpital Cochin, Pavillon Cornil2 7, rue du Faubourg Saint−Jacques´75014, Paris´France´Phone: +33 (1) 58 41 18 95´Fax: +33 (1) 46 33 80 60É −Abstract Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counsel− ling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific her− editary cancer susceptibility syndromes.In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors.The genetic predisposition to adrenocortical cancer in children has been well established in the Li−Fraumeni and Beckewith−Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF−2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syn− drome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inacti− vating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and so− matic PRKAR1A mutations in secreting adrenocortical adeno− mas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocyto− ma and paraganglioma, the demonstration that three genes en− coding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary para− ganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at−risk of dis− ease by the presymptomatic genetic testing Key wordsAdrenocortical tumor´Li−Fraumeni syndrome´Beckwith−Wie− demann syndrome´Multiple endocrine neoplasia type 1´Carney complex´Paraganglioma´Pheochromocytoma

Transcatheter Arterial Embolization for the Treatment of Liver Metastases in a Patient with Malignant Pheochromocytoma

“…A recent retrospective study of 84 apparently sporadic pheochromocytoma showed that 12% of the patients had germ-line mutations of the VHL and succinate de- hydrogenase subunit B (SDHB) genes. Moreover, the identification of a mutation in SDHB gene was indicated as a high risk factor for extra-adrenal location of paraganglioma and for malignant disease [24]. The present patient was not definitely diagnosed as malignant pheochromocytoma at time of first surgery.…”

Clinicopathological analysis of paraganglioma with literature review

“…The occurrence of these tumors in familial settings, their association with hereditary syndromes, and their genetic alterations revealed that some cases are familial [7,8] . Multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) and von Hippel Lindau (VHL) syndrome subtypes 2A, 2B, and 2C account for about 10% of cases; the genes involved being the RET proto-oncogene and the NF1 and VHL tumor suppressor genes, respectively.…”

“…Multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) and von Hippel Lindau (VHL) syndrome subtypes 2A, 2B, and 2C account for about 10% of cases; the genes involved being the RET proto-oncogene and the NF1 and VHL tumor suppressor genes, respectively. However, with the identification of the familial paraganglioma syndromes, characterized by mutations in the subunits of the succinic dehydrogenase (SDH) enzyme (Table 2, Note: The syndromes were named in the order in which they were identified) [8] , it now appears that over 30% of cases are associated with an inherited genetic disposition [8][9][10] . In our investigation, a very high malignancy rate of 19.74% was obtained, which may suggest that a significant proportion of these patients may have underlying familial SDH gene mutations.…”

Mesenteric paraganglioma: Report of a case

“…Hereditary paragangliomas are multicentric in 20%-50% of cases [8,9] , whereas sporadic paragangliomas are multicentric in 10% of cases. In hereditary cases, they may be associated with multiple endocrine neoplasia type 2, von Hippel-Lindau disease, familial paraganglioma, Carney triad and neurofibromatosis type 1 [10] . For this reason, especially in patients diagnosed before 50 years of age and in those who present with bilateral, multifocal, and malignant paragangliomas, genetic testing may be beneficial [11] .…”