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Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70-80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.
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In paediatric oncology, genomics raises new ethical, legal and psychological issues, as somatic and constitutional situations intersect throughout the care pathway. The discovery of potential predisposition in this context is sometimes carried out outside the usual framework. This article focuses on the views of children, adolescents, and young adults (AYA) with cancer and their parents about their experience with genomic testing. Forty-eight semi-structured interviews were performed with children or AYAs with cancer and one of their parents, before and/or after receiving the genetic test results. The interviews were fully transcribed, coded and thematically analysed using an inductive method. This analysis revealed several themes that are key issues: perceived understanding and consenting, apprehension about the test outcomes (expectations and fears), perception and attitude towards incidental findings. The main expectation was an aetiological explanation. Children and AYAs also emphasised the altruistic meaning of genetic testing, while parents seemed to expect a therapeutic and preventive approach for their child and the rest of the family. Parents were more concerned about a family risk, while patients were more afraid of cancer relapse or transmission to their descendants. Both groups suggested possible feelings of guilt concerning family transmission and imaginary representations of what genomics may allow. Incidental findings were not understood by patients, while some parents perceived the related issues and hesitated between wanting or not to know. A multidisciplinary approach would be an interesting way to help parents and children and AYAs to better grasp the complexity of genetic and/or genomic testing.
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Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.
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Neoplasias das Glândulas Suprarrenais , Cortisona , Síndrome de Cushing , Diabetes Mellitus , Hipertensão , Paraganglioma , Feocromocitoma , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Hidrocortisona/metabolismo , Estudos Retrospectivos , Síndrome de Cushing/complicações , Esteroides , Neoplasias das Glândulas Suprarrenais/complicações , Hipertensão/complicações , Feocromocitoma/complicações , Paraganglioma/complicações , Catecolaminas , DesidroepiandrosteronaRESUMO
We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance.
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Neoplasias das Glândulas Suprarrenais , Hemoglobinopatias , Paraganglioma , Humanos , Hemoglobinas/genética , Hipóxia/genética , Mutação , Paraganglioma/genética , Paraganglioma/patologiaRESUMO
BACKGROUND: The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling. METHODS: The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/). RESULTS: Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11. CONCLUSION: Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review.
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Neoplasias Renais , Doença de von Hippel-Lindau , Humanos , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Testes Genéticos , Predisposição Genética para Doença , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia , Estudos de Associação Genética , Neoplasias Renais/genética , Mutação em Linhagem GerminativaRESUMO
Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Adulto , Humanos , Criança , Feocromocitoma/genética , Feocromocitoma/terapia , Feocromocitoma/diagnóstico , Paraganglioma/genética , Paraganglioma/terapia , Mutação em Linhagem Germinativa/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Succinato Desidrogenase/genéticaRESUMO
Pheochromocytomas and paragangliomas are rare neuroendocrine tumors, developed respectively in the adrenal medulla and in extra-adrenal locations. Their malignancy is defined by the presence of distant metastases. Forty percent of them are inherited and can be part of different hereditary syndromes. Their management is ensured in France by the multidisciplinary expert centers of the ENDOCAN-COMETE national network "Cancers of the Adrenal gland", certified by the National Cancer Institute and discussed within multidisciplinary team meetings. The diagnostic and therapeutic work-up must be standardized, based on an expert analysis of clinical symptoms, hormonal biological secretions, genetics, morphological and specific metabolic imaging. In the context of a heterogeneous survival sometimes beyond seven to ten years, therapeutic intervention must be justified. This is multidisciplinary and relies on surgery, interventional radiology, external or internal radiotherapy and medical treatments such as sunitinib or dacarbazine and temodal chemotherapy. The personalized approach based on functional imaging fixation status and genetics is progressing despite the extreme rarity of this disease.
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The adrenocortical carcinoma (ACC) is a primary malignant tumor developed from the adrenal cortex, defined by a Weiss score≥3. Its prognosis is poor and depends mainly on the stage of the disease at diagnosis. Care is organized in France by the multidisciplinary expert centers of the national ENDOCAN-COMETE "Adrenal Cancers" network, certified by the National Cancer Institute. This document updates the guidelines for the management of ACC in adults based on the most robust data in the literature. It's divided into 11 chapters: (1) circumstances of discovery; (2) pre-therapeutic assessment; (3) diagnosis of ACC; (4) oncogenetics; (5) prognostic classifications; (6) treatment of hormonal hypersecretion; (7) treatment of localized forms; (8) treatment of relapses; (9) treatment of advanced forms; (10) follow-up; (11) the particular case of ACC and pregnancy. R0 resection of all localized ACC remains an unmet need and it must be performed in expert centers. Flow-charts for the therapeutic management of localized ACC, relapse or advanced ACC are provided. It was written by the experts from the national ENDOCAN-COMETE network and validated by all French Societies involved in the management of these patients (endocrinology, medical oncology, endocrine surgery, urology, pathology, genetics, nuclear medicine, radiology, interventional radiology).
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Neoplasias do Córtex Suprarrenal , Neoplasias das Glândulas Suprarrenais , Carcinoma Adrenocortical , Urologia , Humanos , Carcinoma Adrenocortical/cirurgia , Carcinoma Adrenocortical/diagnóstico , Neoplasias do Córtex Suprarrenal/cirurgia , Neoplasias do Córtex Suprarrenal/diagnóstico , Recidiva Local de Neoplasia , PrognósticoRESUMO
Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapia , Mutação em Linhagem Germinativa/genética , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/terapia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/terapia , Succinato Desidrogenase/genética , Guias de Prática Clínica como AssuntoRESUMO
Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single pathogenic variants that occur mutually exclusively in genes involved in multiple cellular processes, including the response to hypoxia, MAPK/ERK signaling, and WNT signaling. The discovery of driver mutations has led to active clinical surveillance with outcome implications in familial PGL. The spectrum of mutations continues to grow and reveal unique mechanisms of tumorigenesis that inform tumor biology and provide the rationale for targeted therapy. Here we review recent progress in the genetics and molecular pathogenesis of PGLs and discuss new prospects for advancing research with new disease models and ongoing clinical trials presented at the recent International Symposium of Pheochromocytomas and Paragangliomas (ISP2022) held in October 2022 in Prague.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/genética , Paraganglioma/genética , Mutação , Neoplasias das Glândulas Suprarrenais/genéticaRESUMO
Gain-of-function mutations in the EPAS1/HIF2A gene have been identified in patients with hereditary erythrocytosis that can be associated with the development of paraganglioma, pheochromocytoma and somatostatinoma. In the present study, we describe a unique European collection of 41 patients and 28 relatives diagnosed with an erythrocytosis associated with a germline genetic variant in EPAS1. In addition we identified two infants with severe erythrocytosis associated with a mosaic mutation present in less than 2% of the blood, one of whom later developed a paraganglioma. The aim of this study was to determine the causal role of these genetic variants, to establish pathogenicity, and to identify potential candidates eligible for the new hypoxia-inducible factor-2 α (HIF-2α) inhibitor treatment. Pathogenicity was predicted with in silico tools and the impact of 13 HIF-2b variants has been studied by using canonical and real-time reporter luciferase assays. These functional assays consisted of a novel edited vector containing an expanded region of the erythropoietin promoter combined with distal regulatory elements which substantially enhanced the HIF-2α-dependent induction. Altogether, our studies allowed the classification of 11 mutations as pathogenic in 17 patients and 23 relatives. We described four new mutations (D525G, L526F, G527K, A530S) close to the key proline P531, which broadens the spectrum of mutations involved in erythrocytosis. Notably, we identified patients with only erythrocytosis associated with germline mutations A530S and Y532C previously identified at somatic state in tumors, thereby raising the complexity of the genotype/phenotype correlations. Altogether, this study allows accurate clinical follow-up of patients and opens the possibility of benefiting from HIF-2α inhibitor treatment, so far the only targeted treatment in hypoxia-related erythrocytosis disease.
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Paraganglioma , Policitemia , Humanos , Policitemia/diagnóstico , Policitemia/genética , Mutação , Paraganglioma/complicações , Paraganglioma/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , HipóxiaRESUMO
Renal cell carcinoma (RCC) with rearrangement of transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3; TFE3-rearranged RCC) at Xp11.2 is a rare tumor entity but the most frequent among the microphthalmia transcription factor family translocation RCCs. Here, we report the identification of a new VCP::TFE3 fusion gene as the result of a t(X;9)(p11.23;p13.3) translocation identified by whole transcriptome sequencing. No other relevant molecular alteration was identified by whole exome sequencing. This case showed typical morphological features of TFE3-rearranged RCC with positive TFE3 immunostaining and positive TFE3 break-apart fluorescence in situ hybridization. MET was also overexpressed on immunohistochemistry. The patient had metastatic disease and was treated by surgery and five lines of therapy, including 24 months of stable disease on the mesenchymal epithelial transition (MET) inhibitor cabozantinib, with an overall survival of 7 years. In addition to expanding the spectrum of TFE3 rearrangement partners, this report highlights the complexity of these tumors and supports the development of translational programs in renal cancer.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Translocação Genética , Hibridização in Situ Fluorescente/métodos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Fusão Gênica , Fatores de Transcrição/genética , Cromossomos Humanos X/genética , Proteína com Valosina/genéticaRESUMO
Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the '3PAs' syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.
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Adenoma , Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias Hipofisárias , Prolactinoma , Humanos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Mutação , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Feocromocitoma/genética , Paraganglioma/patologia , Adenoma/genética , Adenoma/patologia , Mutação em Linhagem Germinativa , Espectroscopia de Ressonância Magnética , Neoplasias das Glândulas Suprarrenais/genética , Ácido SuccínicoRESUMO
BACKGROUND: Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches. RESULTS: Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods-Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine-predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL. CONCLUSIONS: The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.
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Neoplasias das Glândulas Suprarrenais , Hipertensão , Feocromocitoma , Humanos , Epigenoma , Metilação de DNA , Feocromocitoma/complicações , Feocromocitoma/genética , Hipertensão/diagnóstico , Hipertensão/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/complicações , BiomarcadoresRESUMO
BACKGROUND: Arterial hypertension is a major cardiovascular risk factor. Identification of secondary hypertension in its various forms is key to preventing and targeting treatment of cardiovascular complications. Simplified diagnostic tests are urgently required to distinguish primary and secondary hypertension to address the current underdiagnosis of the latter. METHODS: This study uses Machine Learning (ML) to classify subtypes of endocrine hypertension (EHT) in a large cohort of hypertensive patients using multidimensional omics analysis of plasma and urine samples. We measured 409 multi-omics (MOmics) features including plasma miRNAs (PmiRNA: 173), plasma catechol O-methylated metabolites (PMetas: 4), plasma steroids (PSteroids: 16), urinary steroid metabolites (USteroids: 27), and plasma small metabolites (PSmallMB: 189) in primary hypertension (PHT) patients, EHT patients with either primary aldosteronism (PA), pheochromocytoma/functional paraganglioma (PPGL) or Cushing syndrome (CS) and normotensive volunteers (NV). Biomarker discovery involved selection of disease combination, outlier handling, feature reduction, 8 ML classifiers, class balancing and consideration of different age- and sex-based scenarios. Classifications were evaluated using balanced accuracy, sensitivity, specificity, AUC, F1, and Kappa score. FINDINGS: Complete clinical and biological datasets were generated from 307 subjects (PA=113, PPGL=88, CS=41 and PHT=112). The random forest classifier provided â¼92% balanced accuracy (â¼11% improvement on the best mono-omics classifier), with 96% specificity and 0.95 AUC to distinguish one of the four conditions in multi-class ALL-ALL comparisons (PPGL vs PA vs CS vs PHT) on an unseen test set, using 57 MOmics features. For discrimination of EHT (PA + PPGL + CS) vs PHT, the simple logistic classifier achieved 0.96 AUC with 90% sensitivity, and â¼86% specificity, using 37 MOmics features. One PmiRNA (hsa-miR-15a-5p) and two PSmallMB (C9 and PC ae C38:1) features were found to be most discriminating for all disease combinations. Overall, the MOmics-based classifiers were able to provide better classification performance in comparison to mono-omics classifiers. INTERPRETATION: We have developed a ML pipeline to distinguish different EHT subtypes from PHT using multi-omics data. This innovative approach to stratification is an advancement towards the development of a diagnostic tool for EHT patients, significantly increasing testing throughput and accelerating administration of appropriate treatment. FUNDING: European Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 633983, Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE (to Z.E. and F.B.), and Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1).
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Hipertensão , MicroRNAs , Biomarcadores , Catecóis , Humanos , Hipertensão/diagnóstico , Aprendizado de Máquina , Estudos RetrospectivosRESUMO
Hypertension is a major global health problem with high prevalence and complex associated health risks. Primary hypertension (PHT) is most common and the reasons behind primary hypertension are largely unknown. Endocrine hypertension (EHT) is another complex form of hypertension with an estimated prevalence varying from 3 to 20% depending on the population studied. It occurs due to underlying conditions associated with hormonal excess mainly related to adrenal tumours and sub-categorised: primary aldosteronism (PA), Cushing's syndrome (CS), pheochromocytoma or functional paraganglioma (PPGL). Endocrine hypertension is often misdiagnosed as primary hypertension, causing delays in treatment for the underlying condition, reduced quality of life, and costly antihypertensive treatment that is often ineffective. This study systematically used targeted metabolomics and high-throughput machine learning methods to predict the key biomarkers in classifying and distinguishing the various subtypes of endocrine and primary hypertension. The trained models successfully classified CS from PHT and EHT from PHT with 92% specificity on the test set. The most prominent targeted metabolites and metabolite ratios for hypertension identification for different disease comparisons were C18:1, C18:2, and Orn/Arg. Sex was identified as an important feature in CS vs. PHT classification.
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Von Hippel-Lindau (VHL) disease is one of the most common cancer predisposition syndromes. Penetrance is high with around 20% of children presenting detectable and curable manifestations of the disease at 15 years old. VHL predictive genetic testing (PGT) is recommended during childhood from age 5 years in France. Insufficient compliance to surveillance of VHL pathogenic variant (PV) carriers is associated with severe outcome. PGT experienced by children and their parents is probably critical in influencing future acceptance of the result and adherence to surveillance. We conducted a retrospective study on minors tested (aged 5 to 16 years old) from 2010 to 2020, in a multidisciplinary oncogenetics consultation which follows a 3-step protocol based on psychological familial support. The objectives were to assess the adherence to follow-up within the National Expert Center for inherited predispositions to renal tumors (PREDIR) network of VHL PV carriers and its benefit through tumor detection and medical interventions. A VHL PGT was carried out in 34 children. Among the 16 children diagnosed as VHL PV carriers addressed to the PREDIR network, none had discontinued surveillance after a median of 41 months. Follow-up examinations detected 11 tumors in 6 children, 4 have been surgically treated. All had a favorable outcome. Our data suggest that a specific and adapted procedure for PGT in at-risk VHL children as well as a follow-up, organized within a specialized expert network, fosters a complete adherence to the surveillance protocol and thus lead to a favorable clinical outcome.
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Neoplasias Renais , Doença de von Hippel-Lindau , Adolescente , Criança , Pré-Escolar , Seguimentos , Testes Genéticos , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Estudos Retrospectivos , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/diagnóstico , Doença de von Hippel-Lindau/genéticaRESUMO
Research focused on succinate dehydrogenase (SDH) and its substrate, succinate, culminated in the 1950s accompanying the rapid development of research dedicated to bioenergetics and intermediary metabolism. This allowed researchers to uncover the implication of SDH in both the mitochondrial respiratory chain and the Krebs cycle. Nowadays, this theme is experiencing a real revival following the discovery of the role of SDH and succinate in a subset of tumors and cancers in humans. The aim of this review is to enlighten the many questions yet unanswered, ranging from fundamental to clinically oriented aspects, up to the danger of the current use of SDH as a target for a subclass of pesticides.
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Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing's syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.