Von Hippel-Lindau disease: an evaluation of natural history and functional disability

Background. Although many studies have been published about specific lesions characterizing von Hippel-Lindau(VHL) disease, none have dealt with the natural history of the whole disease and the consequent disabilities.We aim to define the comprehensive natural history of VHL disease and to describe the functional disabilities and their impact upon patients\u2019 quality of life, thereby tailoring the follow-up schedule accordingly. Methods. We performed a prospective analysis on 128 VHL-affected patients beginning in 1996. For each affected organ, we defined intervals between the first and subsequent VHL-related manifestations and compared them with current VHL surveillance protocols. We looked for any association of the number of involved organs with age, sex, type of VHL gene mutation, and functional domain mutation. Ultimately, we assessed the organ-specific disabilities caused by VHL disease. Results. Hemangioblastomas show different patterns of progression depending on their location, whereas both renal cysts and carcinomas have similar progression rates. Surgery for pheochromocytoma and CNS hemangioblastoma is performed earlier than for pancreatic or renal cancer. The number of involved organs is associated with age but not with sex, type of VHL gene mutation, or functional domain mutation. A thorough analysis of functional disabilities showed that age is related to the first-appearing functional impairment, but it is not predictive of the final number of disabilities. Conclusions. Our study defines the disease progression and provides a comprehensive view of the syndrome over time. We analyzed for the first time the functional disability of VHL patients, assessing the progression for each function

Von Hippel-Lindau disease and multispecialist team

[no abstract available

Multi-Design Differential Expression Profiling of COVID-19 Lung Autopsy Specimens Reveals Significantly Deregulated Inflammatory Pathways and SFTPC Impaired Transcription

The transcriptomic profiling of lung damage associated with SARS-CoV-2 infection may lead to the development of effective therapies to prevent COVID-19-related deaths. We selected a series of 21 autoptic lung samples, 14 of which had positive nasopharyngeal swabs for SARS-CoV-2 and a clinical diagnosis of COVID-19-related death; their pulmonary viral load was quantified with a specific probe for SARS-CoV-2. The remaining seven cases had no documented respiratory disease and were used as controls. RNA from formalin-fixed paraffin-embedded (FFPE) tissue samples was extracted to perform gene expression profiling by means of targeted (Nanostring) and comprehensive RNA-Seq. Two differential expression designs were carried out leading to relevant results in terms of deregulation. SARS-CoV-2 positive specimens presented a significant overexpression in genes of the type I interferon signaling pathway (IFIT1, OAS1, ISG15 and RSAD2), complement activation (C2 and CFB), macrophage polarization (PKM, SIGLEC1, CD163 and MS4A4A) and Cathepsin C (CTSC). CD163, Siglec-1 and Cathepsin C overexpression was validated by immunohistochemistry. SFTPC, the encoding gene for pulmonary-associated surfactant protein C, emerged as a key identifier of COVID-19 patients with high viral load. This study successfully recognized SARS-CoV-2 specific immune signatures in lung samples and highlighted new potential therapeutic targets. A better understanding of the immunopathogenic mechanisms of SARS-CoV-2 induced lung damage is required to develop effective individualized pharmacological strategies

Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas

Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein

Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib

Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts. We comparatively investigated these unique complementary materials using morphofunctional, ultrastructural and flow cytometric assays accompanied by microRNA studies. We found that paragangliomas contain stem-like cells with hybrid mesenchymal/vasculoneural phenotype, stabilized and expanded in the derived cultures. The viability and growth of such cultures depended on the downregulation of the miR-200 and miR-34 families, which allowed high PDGFRA and ZEB1 protein expression levels. Both tumour tissue- and cell culture-derived xenografts recapitulated the vasculoneural paraganglioma structure and arose from mesenchymal-like cells through a fixed developmental sequence. First, vasculoangiogenesis organized the microenvironment, building a perivascular niche which in turn supported neurogenesis. Neuroepithelial differentiation was associated with severe mitochondrial dysfunction, not present in cultured paraganglioma cells, but acquired in vivo during xenograft formation. Vasculogenesis was the Achilles’ heel of xenograft development. In fact, imatinib, that targets endothelial-mural signalling, blocked paraganglioma xenograft formation (11 xenografts from 12 cell transplants in the control group versus 2 out of 10 in the treated group, P = 0.0015). Overall our key results were unaffected by the SDHx gene carrier status of the patient, characterized for 70 out of 77 cases. In conclusion, we explain the biphasic vasculoneural structure of paragangliomas and identify an early and pharmacologically actionable phase of paraganglioma organization

Spectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomas

Context Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. Objectives To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. Design, Setting, and Participants We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. Main Outcome Measures The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. Results We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P=2.7 x 10(-4)) and/or with familial disease (5 of 20 samples; P=.005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P=.54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. Conclusions Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occured in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein. JAMA. 2010;304(23):2611-2619 www.jama.comUniversity of Texas Health Science Center at San Antonio (UTHSCSA)National Cancer Institute (NCI/NIH)[P30 CA54174]National Institute on Aging (NIA/NIH)[P30 AG013319]National Institute on Aging (NIA/NIH)[P01AG19316]Department of Microbiology, UTHSCSAFundacao Faculdade de MedicinaDivision of EndocrinologySao Paulo State Research Foundation (FAPESP)[2009/15386-6]Cancer Research UKBelgian Federal Science Policy, network[6/05]Belgian French Community Ministry[07/12-005]la Communaute Francaise de Wallonie-Bruxelles et la Lotterie NationaleFRS-FNRS (Fonds de la Recherche Scientifique), BelgiumNCI[5 P30 CA465920]Italian University and Research Ministry[2006060473]Fondazione della Comunita BrescianaCNPq Conselho Nacional de Desenvolvimento Cientifico e TecnologicoFondo de Investigaciones Sanitarias[PI 08/080883]Fundacion Mutua Madrilena[AP2775/2008]Voelcker FundAlex`s Lemonade Stand FoundationConcern FoundationNational Institutes of Health (NIH

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention

WOS: 000410676400011PubMed ID: 28384794IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.Deutsche Krebshilfe Grant from the German Cancer Foundation [107995]; Arthur Blank Foundation; Sondra J and Stephen R Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic; Fondazione Cassa di Risparmio di Trento e Rovereto; Janos Bolyai Research FellowshipHungarian Academy of Sciences; National Medical Research CouncilMedical Research Council UK (MRC)This study was supported in part by Deutsche Krebshilfe Grant 107995 from the German Cancer Foundation (Dr Neumann), the Arthur Blank Foundation (Dr Eng), the Sondra J and Stephen R Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic, a grant of the Fondazione Cassa di Risparmio di Trento e Rovereto (Dr Opocher), the Janos Bolyai Research Fellowship (Dr Patocs), and a Transition Award from the National Medical Research Council (Dr Ngeow)