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Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols.Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers.Design and Setting: Retrospective multicentric study in 6 referral centers.Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled.Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up.Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data. [ABSTRACT FROM AUTHOR]

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

Patients with adrenal tumors are at risk of the consequences of tumor growth (including metastasis) and of hormone hypersecretion. These tumors arise from tissues with distinct embryonic origins. Pheochromocytomas and paragangliomas arise from the adrenal medulla and produce catecholamines; they may be benign or malignant, and sporadic or familial. Adrenal adenomas and carcinomas arise from the adrenal cortex. Patients with adrenocortical tumors may develop ACTH-independent hypercortisolism, mineralocorticoid excess, and androgen hypersecretion. The tumors are frequently large enough to provide material for biological studies in addition to diagnostic investigations. In France many patients with hypersecretory tumors are referred to the Hypertension Unit of Georges Pompidou European Hospital, and to the Department of Endocrinology at Cochin Hospital, Paris. In 1993, the heads of these departments created the COMETE network (COrtico et MEdullo-surrénale, les Tumeurs Endocrines). The overall objective of COMETE is to promote basic and clinical research into adrenal tumors. This implies - in cross-sectional studies: collecting adrenal tumors, maintaining a collection of tumor and leukocyte DNA samples, keeping a computerized record of relevant biological and clinical data, and distributing biological samples and bioclinical information anonymously to collaborating research laboratories; in prospective studies: ensuring indefinite follow-up of patients with tumors at risk of malignancy or recurrence, which means establishing and maintaining a cohort of patients with large adrenocortical tumors or carcinomas anda cohort of patients with pheochromocytomas or paragangliomas.

Clinical and fundamental research based on the pheochromocytoma cohort of the COMETE network has drastically improved our knowledge of pheochromocytoma (PH). Previously, it was widely thought that only 10 % of PH patients had familial forms and that the malignant phenotype of PH could not be diagnosed before the first metastasis had already occurred. Genetic studies of the COMETE DNA collection contributed to showing that 25% to 30% of patients in fact have hereditary PH, due to a germline mutation of the SDHB, SDHD, VHL, RET or NF1 genes. The high-quality post-surgical clinical data collected by the COMETE network also show that SDHB germline mutations are a major risk factor for malignancy and poor outcome. Fundamental research work on the COMETE tumour collection shows that SDH genes are new tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. Since 2001, work by the COMETE network has led to new recommendations for genetic counselling and genetic testing in pheochromocytoma, and also for patient management. Finally, it has identified new molecular mechanisms involved in PH-related tumorigenesis.

Background: Fibromuscular dysplasia (FD) is a non-atherosclerotic, non-inflammatory arterial disease of unknown cause, and most frequently affects the renal and internal carotid arteries. Our objectives were to determine whether quantitative and qualitative lesions could be detected by high-resolution echotracking techniques at two arterial sites generally considered as free of echographic lesions: the common carotid and the radial arteries, and to compare their frequency with a control population., Methods and Results: We studied 70 patients with renal FD and 70 control subjects matched for age, sex and systolic blood pressure. Arterial parameters were determined using non-invasive high-resolution echotracking systems. Carotid B-mode scans and radiofrequency signals were analysed and quoted by three observers blinded to diagnosis. FD patients had thicker carotid (+12%, P < 0.001) and radial arteries (+10%, P < 0.05) than controls. Abnormal echographic patterns of the carotid artery, including supernumerary interfaces and/or interruption of the blood-intima acoustic interfaces, were frequently observed in FD patients and rarely in control subjects. These abnormalities were quantified with a phenotypic score ranging from 2 to 7, and their sensitivity and specificity were 73 and 81%, respectively, as markers of FD. Having a phenotypic score > 3 conferred an odds ratio of 12.9 (95% CI 5.7-29.3) of having renal FD., Conclusion: We defined a new carotid phenotype in FD patients using a non-invasive echotracking system, and showed an increased wall thickness and distensibility of the radial artery. These data indicate the presence of subclinical lesions at arterial sites distant from the renal arteries, suggesting that renal FD is not a focal but a systemic arterial disease.