RESUMO
Over the past two decades advances in genomic technologies have transformed knowledge of the genetic basis of phaeochromocytoma and paraganglioma (PPGL). Though traditional teaching suggested that inherited cases accounted for only 10% of all phaeochromocytoma diagnosis, current estimates are at least three times this proportion. Inherited PPGL is a highly genetically heterogeneous disorder but the most frequently results from inactivating variants in genes encoding subunits of succinate dehydrogenase. Expanding knowledge of the genetics of PPGL has been translated into clinical practice by the provision of widespread testing for inherited PPGL. In this review, we explore how the molecular stratification of PPGL is being utilized to enable more personalized strategies for investigation, surveillance and management of affected individuals and their families. Translating recent genetic research advances into clinical service can not only bring benefits through more accurate diagnosis and risk prediction but also challenges when there is a suboptimal evidence base for the clinical consequences or significance of rare genotypes. In such cases, clinical, biochemical, pathological and functional imaging assessments can all contribute to more accurate interpretation and clinical management.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Medicina de Precisão , Succinato Desidrogenase/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapia , Humanos , Paraganglioma/genética , Paraganglioma/terapia , Feocromocitoma/genética , Feocromocitoma/terapia , Transdução de SinaisRESUMO
BACKGROUND: Pathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype. METHODS: Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes. RESULTS: Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001). CONCLUSIONS: SDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.
Assuntos
Proteínas de Membrana/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Adulto , Feminino , Mutação em Linhagem Germinativa/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Paraganglioma/patologia , Feocromocitoma/patologiaRESUMO
INTRODUCTION: Hemangioblastomas are rare, histologically benign, highly vascularized tumors of the brain, the spinal cord, and the retina, occurring sporadically or associated with the autosomal dominant inherited von Hippel-Lindau (VHL) disease. Children or adults with VHL disease have one of > 300 known germline mutations of the VHL gene located on chromosome 3. They are prone to develop hemangioblastomas, extremely rarely starting at age 6, rarely at age 12-18, and, typically and almost all, as adults. There is a plethora of VHL-associated tumors and cysts, mainly in the kidney, pancreas, adrenals, reproductive organs, and central nervous system. Due to a lack of causal treatment, alleviation of symptoms and prevention of permanent neurological deficits as well as malignant transformation are the main task. Paucity of data and the nonlinear course of tumor progression make management of pediatric VHL patients with hemangioblastomas challenging. METHODS: The Freiburg surveillance protocol was developed by combining data from the literature and our experience of examinations of > 300 VHL patients per year at our university VHL center. RESULTS: Key recommendations are to start screening of patients at risk by funduscopy with dilated pupils for retinal tumors with admission to school and with MRI of the brain and spinal cord at age 14, then continue biannually until age 18, with emergency MRI in case of neurological symptoms. Indication for surgery remains personalized and should be approved by an experienced VHL board, but we regard neurological symptoms, rapid tumor growth, or critically large tumor/cyst sizes as the key indications to remove hemangioblastomas. Since repeated surgery on hemangioblastomas in VHL patients is not rare, modern neurosurgical techniques should encompass microsurgery, neuronavigation, intraoperative neuromonitoring, fluorescein dye-based intraoperative angiography, intraoperative ultrasound, and minimally invasive approaches, preceded in selected cases by endovascular embolization. Highly specialized neurosurgeons are able to achieve a very low risk of permanent morbidity for the removal of hemangioblastomas from the cerebellum and spinal cord. Small retinal tumors of the peripheral retina can be treated by laser coagulation, larger tumors by cryocoagulation or brachytherapy. CONCLUSION: We consider management at experienced VHL centers mandatory and careful surveillance and monitoring of asymptomatic lesions are required to prevent unnecessary operations and minimize morbidity.
Assuntos
Hemangioblastoma , Neoplasias da Medula Espinal , Doença de von Hippel-Lindau , Adolescente , Adulto , Criança , Patrimônio Genético , Hemangioblastoma/diagnóstico por imagem , Hemangioblastoma/genética , Hemangioblastoma/cirurgia , Humanos , Procedimentos Neurocirúrgicos , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/cirurgia , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/cirurgiaRESUMO
BACKGROUND: Pheochromocytomas (PH) and paragangliomas (PGL) are rare tumours in children accounting for about 1% of the paediatric hypertension. While minimally invasive surgical techniques are well established in adult patients with PH, the experience in children is extremely limited. To the best of our knowledge, we herewith present the largest series of young patients operated on chromaffin tumours by minimally invasive access. MATERIALS: In the setting of a prospective study (1/2001-12/2016), 42 consecutive children and adolescents (33 m, 9 f) were operated on. Thirty-seven patients (88%) suffered from inherited diseases. Twenty-six patients had PH, 11 presented retroperitoneal PGL, and five patients suffered from both. Altogether, 70 tumours (mean size 2.7 cm) were removed (45 PH, 25 PGL). All operations were performed by a minimally invasive access (retroperitoneoscopic, laparoscopic, extraperitoneal). Partial adrenalectomy was the preferred procedure for PH (31 out of 39 patients). Twenty patients received α-receptor blockade preoperatively. RESULTS: One patient died after induction of anaesthesia due to cardiac arrest. All other complications were minor. Conversion to open surgery was necessary in two cases with PGL. Median operating time for unilateral PH was 55 min, in bilateral cases 125, 143 min in PGs, and 180 min in combined cases. Median blood loss was 20 ml (range 0-1000). Blood transfusion was necessary in two cases. Intraoperative, systolic peak pressure was 170 ± 39 mmHg with α-receptor blockade and 191 ± 33 mmHg without α-receptor blockade (p = 0.41). The median post-operative hospital stay was 3 days. After a mean follow-up of 8.5 years, two patients presented ipsilateral recurrence (after partial adrenalectomy). All patients with bilateral PH (n = 13) are steroid independent post-operatively. CONCLUSIONS: PH and PGL in children and adolescents should preferably be removed by minimally invasive surgery. Partial adrenalectomy provides long-term steroid independence in bilateral PH and a low rate of (ipsilateral) recurrence. α-Receptor blockade may not be necessary in these patients.
Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Paraganglioma/cirurgia , Feocromocitoma/cirurgia , Neoplasias Retroperitoneais/cirurgia , Adolescente , Criança , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma Extrassuprarrenal , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/história , Neoplasias das Glândulas Suprarrenais/cirurgia , Diagnóstico Diferencial , Feminino , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Masculino , Paraganglioma Extrassuprarrenal/diagnóstico , Paraganglioma Extrassuprarrenal/genética , Paraganglioma Extrassuprarrenal/cirurgia , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/história , Feocromocitoma/cirurgiaRESUMO
OBJECTIVE: The purpose was to determine the growth rate of succinate dehydrogenase subunit (SDHx) gene-related paragangliomas based on computed tomography (CT) measurements. METHODS: Twenty-seven patients with SDHx mutations who underwent subsequent CT examinations were enrolled in the study. Tumors were classified as head and neck (HNP), thoracic, or abdominal/pelvic paragangliomas (PGLs). The percentage volume increase and volume doubling time were estimated. RESULTS: We analyzed 56 PGLs (21 with SDHD, 6 with SDHB mutations) in 27 patients (16 men, 11 women; mean age 37.7 years). The estimated median of the follow-up was 23 months. Twenty-two (39.3%) PGLs were located in the abdomen, 8 (14.3%) in the thorax, and 26 (46.4%) in the head and neck region. The median volume growth rate was estimated at 10.4% per year (interquartile range [IQR]: -1.3; 36.3). The volume doubling time was estimated as 7.01 (2.24;+∞) years. By tumor site, the estimated medians of the annual volume growth rates were 13.6% (IQR:0.8 -30.4) for HNP, -6.06% (IQR: -1.79;47.32) for thoracic PGLs, and 10.5% (IQR: -2.2;44.6) for abdominal PGLs. The volume doubling time was 5.44 years (2.61; 87.0) for HNP, 11.8 years (1.79;+∞) for thoracic PGLs, and 6.94 years (1,88;+∞) for abdominal PGLs. There was no significant difference in the volume growth rate according to tumor location or initial size (P>.7 and P = .07, respectively) or gene mutation type (SDHB vs. SDHD, P>.8). CONCLUSION: PGLs related to SDHx mutations are slowly growing tumors. There were no correlations between tumor location, growth rate or initial size over a 23-month follow-up period. ABBREVIATIONS: CT = computed tomography HNP = head and neck paraganglioma IQR = interquartile range PGL = paraganglioma PPGL = pheochromocytoma and paraganglioma SDH = succinate dehydrogenase.
Assuntos
Mutação em Linhagem Germinativa , Paraganglioma/genética , Paraganglioma/patologia , Succinato Desidrogenase/genética , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico por imagem , Feocromocitoma/genética , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
SDH genes, encoding succinate dehydrogenase, act as tumour suppressor genes, linking mitochondrial dysfunction with tumourigenesis. Heterozygous germline mutations in SDHA, SDHB, SDHC, SDHD and in the assembly factor encoding gene SDHAF2 have all been shown to predispose to heritable endocrine neoplasias such as pheochromocytomas (PHEO) and paragangliomas (PGLs) called 'PHEO-PGL syndrome'. SDH genes mutations, in addition to deletions or truncations which are most likely pathogenic, often include missense substitutions which can be of uncertain significance. Unclassified missense substitutions may be difficult to interpret unless the cause-effect link between mutation and the disease is established by functional and in silico studies or by the familial segregation with the phenotype. Using the yeast model, here, we report functional investigations on several missense SDH mutations found in patients affected by pheochromocytomas or paragangliomas. The aim of this study was to evaluate whether and to which extent the yeast model may be useful for establishing the pathological significance of missense SDH mutations in humans. The results of our study demonstrate that the yeast is a good functional model to validate the pathogenic significance of SDHB missense mutations while, for missense mutations in SDHC and SDHD genes, the model can be informative only when the variation involves a conserved residue in a conserved domain.
Assuntos
Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Teste de Complementação Genética , Humanos , Fosforilação Oxidativa , Estresse Oxidativo , Paraganglioma/enzimologia , Fenótipo , Feocromocitoma/enzimologia , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética , SíndromeRESUMO
AIMS: The aim of this study was to assess the usefulness of somatostatin receptor scintigraphy (SRS) using (99m)Tc-[HYNIC, Tyr3]-octreotide (TOC) and 123I-metaiodobenzylguanidine (mIBG) in patients with SDHx-related syndromes in which paragangliomas were detected by computed tomography and to establish an optimal imaging diagnostic algorithm in SDHx mutation carriers. METHODS: All carriers with clinical and radiological findings suggesting paragangliomas were screened by SRS and 123I-mIBG. Lesions were classified by body regions, i.e. head and neck, chest, abdomen with pelvis and adrenal gland as well as metastasis. RESULTS: We evaluated 46 SDHx gene mutation carriers (32 index cases and 14 relatives; 28 SDHD, 16 SDHB and 2 SDHC). In this group, 102 benign tumors were found in 39 studied patients, and malignant disease was diagnosed in 7 patients. In benign tumors, the sensitivity of SRS was estimated at 77% and of 123I-mIBG at 22.0%. The SRS and mIBG sensitivity was found to be clearly region dependent (p < 0.001). The highest SRS sensitivity was found in head and neck paragangliomas (HNP; 91.4%) and the lowest was found in abdominal paragangliomas and pheochromocytomas (40 and 42.9%, respectively). The highest 123I-mIBG sensitivity was found in pheochromocytomas (sensitivity of 100%) and the lowest in HNP (sensitivity of 3.7%). In metastatic disease, SRS was superior to mIBG (sensitivity of 95.2 vs. 23.8%, respectively). CONCLUSION: SRS and 123I-mIBG single photon emission computed tomography (SPECT) sensitivity in SDHx patients is highly body region dependent. In malignant tumors, SRS is superior to 123I-mIBG SPECT.
Assuntos
Paraganglioma/diagnóstico por imagem , Feocromocitoma/diagnóstico por imagem , Cintilografia/métodos , Receptores de Somatostatina/metabolismo , 3-Iodobenzilguanidina , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/diagnóstico por imagem , Neoplasias Abdominais/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/genética , Heterozigoto , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Mutação , Octreotida , Paraganglioma/diagnóstico , Paraganglioma/genética , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Estudos Prospectivos , Compostos Radiofarmacêuticos , Tecnécio , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
OBJECTIVE: To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine. DESIGN AND METHODS: Biochemical testing for PPGL was performed on 762 patients at six centres, two of which complied with requirements for supine sampling after an overnight fast and four of which did not. Phaeochromocytomas and paragangliomas were found in 129 patients (67 noncompliant, 62 compliant) and not in 633 patients (195 noncompliant, 438 compliant). RESULTS: Plasma concentrations of normetanephrine and methoxytyramine did not differ between compliant and noncompliant sampling conditions in patients with PPGL but were 49-51% higher in patients without PPGL sampled under noncompliant compared with compliant conditions. The 97·5 percentiles of distributions were also higher under noncompliant compared with compliant conditions for normetanephrine (1·29 vs 0·79 nmol/l), metanephrine (0·49 vs 0·41 nmol/l) and methoxytyramine (0·42 vs 0·18 nmol/l). Use of upper cut-offs established from seated nonfasting sampling conditions resulted in substantially decreased diagnostic sensitivity (98% vs 85%). In contrast, use of upper cut-offs established from supine fasting conditions resulted in decreased diagnostic specificity for testing under noncompliant compared with compliant conditions (71% vs 95%). CONCLUSIONS: High diagnostic sensitivity of plasma normetanephrine, metanephrine and methoxytyramine for the detection of PPGL can only be guaranteed using upper cut-offs of reference intervals established with blood sampling under supine fasting conditions. With such cut-offs, sampling under seated nonfasting conditions can lead to a 5·7-fold increase in false-positive results necessitating repeat sampling under supine fasting conditions.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Coleta de Amostras Sanguíneas/métodos , Dopamina/análogos & derivados , Metanefrina/sangue , Normetanefrina/sangue , Feocromocitoma/diagnóstico , Decúbito Dorsal/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Criança , Dopamina/sangue , Dopamina/urina , Jejum/sangue , Feminino , Alimentos , Humanos , Masculino , Metanefrina/urina , Pessoa de Meia-Idade , Normetanefrina/urina , Feocromocitoma/sangue , Postura , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs. MATERIALS AND METHODS: Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. RESULTS AND CONCLUSIONS: LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Biomarcadores Tumorais/genética , Perda de Heterozigosidade , Proteínas Mitocondriais/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Doença de von Hippel-Lindau/complicações , Neoplasias das Glândulas Suprarrenais/etiologia , Estudos de Coortes , Metilação de DNA , Marcadores Genéticos , Técnicas de Genotipagem , Humanos , Mutação de Sentido Incorreto , Feocromocitoma/etiologia , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Doença de von Hippel-Lindau/genéticaRESUMO
The definitive universally accepted treatment for carotid body tumors (CBT) is surgery. The impact of surgery on cranial nerves and the carotid artery has often been underestimated. Alternatively, a few CBTs have been followed without treatment or irradiation. The goal of this study is to summarize the existing evidence concerning the efficacy and safety of surgery and external beam radiotherapy (EBRT) for CBT. Relevant articles were identified using strict criteria for systematic searches. Sixty-seven articles met the criteria which included 2,175 surgically treated patients. On the other hand, 17 articles including 127 patients treated with EBRT were found. Long-term control of the disease was obtained in 93.8% of patients who received surgical treatment and in 94.5% of the radiotherapy group. Surgery resulted in 483 (483/2,175 = 22.2%) new cranial nerve permanent deficits, whereas in the EBRT group, no new deficits were recorded (p = 0.004). The common/internal carotid artery was resected in 271 (12.5%) patients because of injury or tumor encasement, with immediate reconstruction in 212 (9.7%) patients. Three percent (60) of patients developed a permanent stroke and 1.3% (26) died due to postoperative complications. The major complications rates and the mortality after completion of the treatment also were significantly higher in surgical series compared to EBRT series. This systematic analysis highlights evidence that EBRT offers a similar chance of tumor control with lower risk of morbidity as compared to surgery in patients with CBT. This questions the traditional notion that surgery should be the mainstay of treatment.
Assuntos
Tumor do Corpo Carotídeo/radioterapia , Tumor do Corpo Carotídeo/cirurgia , Humanos , Resultado do TratamentoRESUMO
A 26-year-old male presented to the emergency department complaining of obstipation, severe headache and abdominal pain. An autopsy revealed bilateral pheochromocytoma and acute myocardial infarction. The tumor cells showed positive immunoreactivity of both chromogranin A and synaptophysin and were negative for adrenocortical markers such as SF-1, c17, scc, 3ï¢-HSD as well as SDHB, suggesting a germline mutation of the gene SDHB or SDHD. Molecular genetic analyses did not show a mutation in these two genes, but a mutation in the VHL gene, in exon 3: VHL c.499C>T. This is a missense mutation and causes an amino acid change (Arg167Trp).
Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Infarto do Miocárdio/etiologia , Feocromocitoma/complicações , Doença de von Hippel-Lindau/complicações , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Evolução Fatal , Humanos , Masculino , Feocromocitoma/patologia , Doença de von Hippel-Lindau/patologiaRESUMO
OBJECTIVE: Subarachnoid hemorrhage from ruptured intracranial aneurysms is associated with a severe prognosis. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the identification of risk patients by genetic analyses is not possible because of lack of candidate genes. Collagen type I α2 (COL1A2) has been associated with the presence of aneurysms in patients from Japan, China, and Korea. In this study, we investigate whether COL1A2 is a possible aneurysm candidate gene in the German population. METHODS: Patients admitted with intracranial aneurysms to our department and collaborating departments were enrolled. Three single-nucleotide polymorphisms (SNPs) of the COL1A2 gene, namely rs42524 in exon 28, rs1800238 in exon 32, and rs2621215 in intron 46 were investigated using restriction enzymes and sequencing. HapMap data were used for comparison of allelic frequencies with the normal population by χ2 test to identify significant associations between genotypes and the presence of aneurysms. RESULTS: Two hundred sixty-nine patients were enrolled into the study. There was a significant correlation with the presence of aneurysms for the GC allele of the SNP rs42524 in exon 28 (P = .02). The other polymorphisms did not show significant correlations. CONCLUSIONS: The COL1A2 gene is associated with intracranial aneurysms in a subset of the German population. However, it is not responsible for the majority of aneurysms, and further candidate genes need to be identified to develop sensitive genetic screening for patients at risk.
Assuntos
Colágeno Tipo I/genética , Aneurisma Intracraniano/genética , Polimorfismo de Nucleotídeo Único , Distribuição de Qui-Quadrado , Éxons , Frequência do Gene , Predisposição Genética para Doença , Alemanha/epidemiologia , Humanos , Aneurisma Intracraniano/diagnóstico , Aneurisma Intracraniano/epidemiologia , Íntrons , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Análise de Sequência de DNA , Hemorragia Subaracnóidea/epidemiologia , Hemorragia Subaracnóidea/genéticaRESUMO
BACKGROUND: Phaeochromocytoma (PCC) and paraganglioma (PGL) can occur sporadically or as a part of familial cancer syndromes. Red flags of hereditary syndromes are young age and multifocal tumours. We hypothesized that such patients are candidates for further molecular diagnosis in case of normal results in 'classical' genes. MATERIAL AND METHODS: We selected patients with PCC/PGL under the age of 40 and/or with multiple tumours. First, we tested the genes RET, VHL, NF1, SDHB, SDHC and SDHD. Patients without mutations in these genes were tested for mutations in MAX, TMEM127 and SDHAF2. RESULTS: In 153 patients included, mutations were detected in the classical genes in 72 patients (47%) [RET-22 (14%), VHL-13 (9%), NF1-3 (2%), SDHB-13 (9%), SDHC-3 (2%), SDHD-16 (11%), SDHB large deletions- 2 (1%)]. One patient with MAXc.223C>T (p.R75X) mutation was detected. It was a male with bilateral, metachronous phaeochromocytomas diagnosed in 36 and 40 years of age. Remarkably, he showed in the period before the MAX gene was detected, a RET p. Y791F variant. During 10-year follow-up, we did not find any thyroid abnormalities. LOH examination of tumour tissue showed somatic loss of the wild-type allele of MAX. CONCLUSION: Analysis of the MAX gene should be performed in selected patients, especially those with bilateral adrenal phaeochromocytoma in whom mutations of the classical genes are absent. Our study provides with further support that Y791F RET is a polymorphism.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Mutação , Síndromes Neoplásicas Hereditárias/genética , Paraganglioma/genética , Feocromocitoma/genética , Adulto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias Primárias Múltiplas/genética , Polônia , Proteínas Proto-Oncogênicas c-ret/genética , Sistema de RegistrosRESUMO
Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The "NOTCH signaling pathway" was the most significantly enriched term in the list (P = 0.002 after Bonferroni or Benjamini correction). Expression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunohistochemistry in 47 head and neck paraganglioma cases. There were no relationships between level and pattern of NOTCH1/JAG2 protein expression and germline mutation status in the SDH genes, implicated in paraganglioma predisposition, or the presence/absence of immunostaining for SDHB, a surrogate marker of SDH mutations. Interestingly, NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of this pathway. To address this issue we performed microarray-based microRNA expression analyses. Notably 5 microRNAs (miR-200a,b,c and miR-34b,c), including those most downregulated in the tumors, correlated to NOTCH signaling and directly targeted NOTCH1 in in vitro experiments using SH-SY5Y neuroblastoma cells. Furthermore, lentiviral transduction of miR-200s and miR-34s in patient-derived primary tympano-jugular paraganglioma cell cultures was associated with NOTCH1 downregulation and increased levels of markers of cell toxicity and cell death. Taken together, our results provide an integrated view of common molecular alterations associated with head and neck paraganglioma and reveal an essential role of NOTCH pathway deregulation in this tumor type.
Assuntos
Epigênese Genética/fisiologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Paraganglioma/genética , Paraganglioma/patologia , Receptores Notch/genética , Receptores Notch/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Western Blotting , Caspases/metabolismo , Morte Celular/genética , Linhagem Celular Tumoral , Análise Mutacional de DNA , Imunofluorescência , Humanos , Imuno-Histoquímica , Lentivirus/genética , Análise em Microsséries , Microscopia Imunoeletrônica , Nervos Periféricos/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Succinato Desidrogenase/genética , TransfecçãoRESUMO
PURPOSE: Surgical management of autosomal dominant polycystic kidney disease (ADPKD) in patients awaiting renal transplantation is a challenging task. METHODS: From 1998 to 2009, a total of 100 consecutive renal transplantations with simultaneous unilateral nephrectomy were performed in 59 men and 41 women with ADPKD and end-stage renal failure. About 38% received kidney allografts from living donors. The ipsilateral polycystic kidney was removed at the time of renal transplantation. Immunosuppressive therapy was not modified. Cold ischaemia time was 155 (38-204 min) versus 910 min (95-2760 min) for living versus deceased donor transplantation. Mean weight of removed kidneys was 2002 g (414-8850 g). Mean follow-up was 3.0 years (0.8-10.0 years). RESULTS: Overall patient and graft survival were 97 and 96% at 1 year and 93 and 80% at 5 years, respectively. Serum creatinine at current follow-up was 1.49 (0.8-2.8) mg/dL. Surgical complications, which might be associated with simultaneous nephrectomy requiring re-operation, occurred in 12% (lymphocele 4%, hernia 4%, post-operative haematoma or bleeding 4%). None of the patients died peri-operatively. CONCLUSION: Renal transplantation with simultaneous unilateral nephrectomy in ADPKD is a reasonable procedure for patients suffering from massively enlarged native kidneys.
Assuntos
Falência Renal Crônica/cirurgia , Transplante de Rim , Nefrectomia/métodos , Rim Policístico Autossômico Dominante/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Rim/fisiologia , Falência Renal Crônica/mortalidade , Transplante de Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: As we emerge into the genomic medicine era, the epidemiology of diseases is taken for granted. Accurate prevalence figures, especially of rare diseases (RDs, ≤50/100,000), will become even more important for purposes of health care and societal planning. We noticed that the numbers of affected individuals in regionally established registries for mainly hereditary RDs do not align with published estimated and expected prevalence figures. We therefore hypothesized that such non-population-based means overestimate RDs and sought to address this by recalculating prevalence for an important 'common' hereditary disease, autosomal-dominant polycystic kidney disease (ADPKD) whereby presumed-prevalence is 100-250/100,000 METHODS: The Else-Kroener-Fresenius-ADPKD-Study in south-west Germany with a population of 2,727,351 inhabitants was established with the cooperation of all nephrology centres. Furthermore, general practitioners, internists, urologists, human geneticists and neurosurgery centres were contacted with questionnaires for demographic, family and kidney function data. Germline-mutation screening of susceptibility genes PKD1 and PKD2 was offered. Official population data for 2010 were used for overall and kidney function-adjusted prevalence estimations. RESULTS: A total of 891 subjects, 658 index-cases and 233 relatives, aged 10-89 (mean 52), were registered, with >90% response rate, 398 by nephrologists and 493 by non-nephrologists. Molecular-genetic analyses contributed to confirmation of the diagnosis in 57%. The overall prevalence of ADPKD was 32.7/100,000 reaching a maximum of 57.3/100,000 in the 6th decade of life. CONCLUSIONS: Prevalence of ADPKD is overestimated by 2- to 5-fold and close to the limit of RDs which may be of broad clinical, logistic and policy implications.
Assuntos
Mutação em Linhagem Germinativa/genética , Rim Policístico Autossômico Dominante/epidemiologia , Canais de Cátion TRPP/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Ligação Genética , Alemanha/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Sistema de Registros , Adulto JovemRESUMO
BACKGROUND: The role of autosomal dominant polycystic kidney disease (ADPKD) as a risk factor for renal cell carcinoma (RCC) is still under discussion. Data on prevalence of RCC in ADPKD are limited, especially on a large population scale. The aim of this study was to analyze the prevalence of RCC in ADPKD kidneys and characterize the clinical features of this coincidence. METHODS: Based on our histopathological registry for ADPKD and the Else Kröner-Fresenius Registry, we retrospectively reviewed malignant and benign renal lesions in patients with ADPKD who had undergone renal surgery from 1988 to 2011. RESULTS: 240 ADPKD patients underwent 301 renal surgeries. Mean age at surgery was 54 years. Overall, 16 malignant and 11 benign lesions were analyzed in 301 kidneys (5.3%; 3.7%), meaning that 12/240 (5%; 1:20) patients presented with malignant renal lesions. 66.7% (8/12) of these patients had undergone dialysis prior to surgery. We found 10/16 (63%) papillary RCC, 5/16 (31%) clear cell RCC, and 1/16 (6%) papillary noninvasive urothelial cancer. Regarding all renal lesions, 6/17 (35.3%) patients had more than one histological finding in their kidneys. In 2 cases, metachronous metastases were removed. Mean follow-up was 66.7 months. CONCLUSION: Kidney-related prevalence of RCC in ADPKD kidneys was surprisingly high. Whether or not this is due to chronic dialysis or due to the underlying disease is still speculative. Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant potential of ADPKD, especially with concomitant dialysis.
Assuntos
Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Rim Policístico Autossômico Dominante/epidemiologia , Rim Policístico Autossômico Dominante/patologia , Diálise Renal/estatística & dados numéricos , Carcinoma de Células Renais/cirurgia , Comorbidade , Feminino , Alemanha/epidemiologia , Humanos , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/cirurgia , Prevalência , Medição de RiscoRESUMO
BACKGROUND: The rupture of intracranial aneurysms leads to subarachnoid hemorrhage, which is often associated with poor outcome. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the lack of candidate genes precludes identifying patients at risk by genetic analyses. We observed intracranial aneurysms in 2 patients with von Hippel-Lindau (VHL) disease and the known disease-causing mutation c.292T > C (p.Tyr98His) in the VHL tumor suppressor gene. This study investigates whether the VHL gene is a possible candidate gene for aneurysm formation. METHODS: Patients with intracranial aneurysms admitted to our department between 2006 and 2009 were enrolled. The peripheral leukocyte DNA of 200 patients was investigated for sequence variations in the VHL gene using denaturing high performance liquid chromatography. Peripheral leukocyte DNA of 100 randomly sampled probands was investigated as a control group. The allelic frequencies of sequence variations between both groups were compared using the Fisher exact test. RESULTS: Fourteen of 200 patients with intracranial aneurysms had sequence variations at 6 different loci in the VHL gene. In contrast, no sequence variations were identified in 100 probands in the control group (P = 0.0062). However, none of the single-sequence variations had a statistically significant difference in the allelic frequencies compared to the control group. CONCLUSIONS: There is accumulating evidence for a genetic basis of aneurysm development. Our investigations lead to the conclusion that the VHL gene is potentially involved in the formation of intracranial aneurysms in a subset of patients. Additional candidate genes need to be identified in order to develop sensitive genetic screening for at-risk patients.