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Novel Folliculin Gene Mutations in Polish Patients with Birt–Hogg–Dubé Syndrome Elżbieta Radzikowska1*, Urszula Lechowicz2, Jolanta Winek3 and Lucyna Opoka4
Radzikowska et al. Orphanet J Rare Dis (2021) 16:302 https://doi.org/10.1186/s13023-021-01931-0 RESEARCH Open Access Novel folliculin gene mutations in Polish patients with Birt–Hogg–Dubé syndrome Elżbieta Radzikowska1*, Urszula Lechowicz2, Jolanta Winek3 and Lucyna Opoka4 Abstract Background: Birt–Hogg–Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by muta- tions in the folliculin gene (FLCN). The disease is characterised by skin lesions (fbrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts with pneumothoraces and renal tumours. We present the features of Polish patients with BHDS. Materials and methods: The frst case of BHDS in Poland was diagnosed in 2016. Since then, 15 cases from 10 fami- lies have been identifed. Thirteen patients were confrmed via direct FLCN sequencing, and two according to their characteristic clinical and radiological presentations. Results: BHDS was diagnosed in 15 cases (13 women and 2 men) from 10 families. The mean ages at the time of frst pneumothorax and diagnosis were 38.4 13.9 and 47.7 13 years, respectively. Five patients (33%) were ex- smokers (2.1 1.37 packyears), and 10 (67%)± had never smoked± cigarettes. Twelve patients (83%) had a history of recurrent symptomatic± pneumothorax. Three patients had small, asymptomatic pneumothoraces, which were only detected upon computed tomography examination. All patients had multiple bilateral pulmonary cysts, distributed predominantly in the lower and middle, peripheral, and subpleural regions of the lungs. Generally, patients exhibited preserved lung function. Skin lesions were seen in four patients (27%), one patient had renal angiomyolipoma, and one had bilateral renal cancer. -
Adrenal Neuroblastoma Mimicking Pheochromocytoma in an Adult With
Khalayleh et al. Int Arch Endocrinol Clin Res 2017, 3:008 Volume 3 | Issue 1 International Archives of Endocrinology Clinical Research Case Report : Open Access Adrenal Neuroblastoma Mimicking Pheochromocytoma in an Adult with Neurofibromatosis Type 1 Harbi Khalayleh1, Hilla Knobler2, Vitaly Medvedovsky2, Edit Feldberg3, Judith Diment3, Lena Pinkas4, Guennadi Kouniavsky1 and Taiba Zornitzki2* 1Department of Surgery, Hebrew University Medical School of Jerusalem, Israel 2Endocrinology, Diabetes and Metabolism Institute, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Israel 3Pathology Institute, Kaplan Medical Center, Israel 4Nuclear Medicine Institute, Kaplan Medical Center, Israel *Corresponding author: Taiba Zornitzki, MD, Endocrinology, Diabetes and Metabolism Institute, Kaplan Medical Center, Hebrew University Medical School of Jerusalem, Bilu 1, 76100 Rehovot, Israel, Tel: +972-894- 41315, Fax: +972-8 944-1912, E-mail: [email protected] Context 2. This is the first reported case of an adrenal neuroblastoma occurring in an adult patient with NF1 presenting as a large Neurofibromatosis type 1 (NF1) is a genetic disorder asso- adrenal mass with increased catecholamine levels mimicking ciated with an increased risk of malignant disorders. Adrenal a pheochromocytoma. neuroblastoma is considered an extremely rare tumor in adults and was not previously described in association with NF1. 3. This case demonstrates the clinical overlap between pheo- Case description: A 42-year-old normotensive woman with chromocytoma and neuroblastoma. typical signs of NF1 underwent evaluation for abdominal pain, Keywords and a large 14 × 10 × 16 cm left adrenal mass displacing the Adrenal neuroblastoma, Neurofibromatosis type 1, Pheo- spleen, pancreas and colon was found. An initial diagnosis of chromocytoma, Neural crest-derived tumors pheochromocytoma was done based on the known strong association between pheochromocytoma, NF1 and increased catecholamine levels. -
To View the ESE Recommended Curriculum of Specialisation in Clinical Endocrinology, Diabetes and Metabolism
European Society of Endocrinology Recommended Curriculum of Specialisation in Clinical Endocrinology, Diabetes and Metabolism Version 2, November 2019 Contents Endorsement ........................................................................................................................................ 2 Introduction .......................................................................................................................................... 3 1. Diabetes mellitus .............................................................................................................................. 4 2. Lipid disorders ................................................................................................................................... 5 3. Obesity and bariatric endocrinology ................................................................................................. 5 4. Pituitary ............................................................................................................................................ 5 5. Thyroid .............................................................................................................................................. 6 6. Parathyroid, calcium and bone ......................................................................................................... 7 7. Adrenal ............................................................................................................................................. 8 8. Reproductive endocrinology and sexual function -
Cerebellar Neuroblastoma in 2.5 Years Old Child
Case Report Cerebellar Neuroblastoma in 2.5 Years Old Child Mohammad Pedram1, Majid Vafaie1, Kiavash Fekri1, Sabahat Haghi1, Iran Rashidi2, Chia Pirooti3 Abstract 1. Thalassemia and Neuroblastoma is the third most common malignancy of childhood, after leukemia Hemoglobinopathy Research Center, Ahvaz Jondishapur University of and brain tumors. Only 2% of all neuroblastoma occur in the brain. Primary Medical Sciences, Ahvaz, Iran cerebellar neuroblastoma is an specific subset of Primitive Neuroectodermal 2. Dept. of Pathology, Shafa Tumors (PNET). Meduloblastoma is a relatively common and well-established Hospital , Ahvaz Jondishapur entity, consisting of primitive and multipotential cells that may exhibit some University of Medical Sciences, evidence of neuroblastic or gliad differentiation. But cerebellar neuroblastoma Ahvaz, Iran with ultrastractural evidence of significant neuroblastic differentiation is 3. Dept. of Neurosurgery, Golestan extremely rare. We report a rare case of neuroblastoma in the cerebellum. A Hospital, Ahvaz Jondishapur 2.5-year-old Iranian boy presented with vomiting and nausea in the morning and University of Medical Sciences, ataxia. CT scan showed a tumor mass in the cerebellum and the report of Ahvaz, Iran radiologist was medulloblastoma. Light microscopic assay showed a small cell Corresponding Author: neoplasm with lobules of densely packed cells (lobulated pattern) and better Mohammad Pedram, MD; differentiated cells. Neuron-Specific Enolase was positive. Pathologic diagnosis Professor of Pediatrics Hematology- confirmed the existence of cerebellar neuroblastoma. Chemotherapy followed Oncology surgical removal. No relapse occurred 12 months after surgery. Tel: (+98) 611 374 32 85 Email: Keywords: Neuroblastoma; Cerebellum; Chemotherapy [email protected] Please cite this article as: Pedram M, Vafaie M, Fekri K, Haghi S, Rashidi I, Pirooti Ch. -
Piggybac Mutagenesis and Exome Sequencing Identify Genetic Driver
Noorani et al. Genome Biology (2020) 21:181 https://doi.org/10.1186/s13059-020-02092-2 RESEARCH Open Access PiggyBac mutagenesis and exome sequencing identify genetic driver landscapes and potential therapeutic targets of EGFR-mutant gliomas Imran Noorani1,2* , Jorge de la Rosa1†, Yoon Ha Choi1,3†, Alexander Strong1, Hannes Ponstingl1, M. S. Vijayabaskar1, Jusung Lee3, Eunmin Lee3, Angela Richard-Londt4, Mathias Friedrich1,5, Federica Furlanetto5, Rocio Fuente1, Ruby Banerjee1, Fengtang Yang1, Frances Law1, Colin Watts2,6, Roland Rad5, George Vassiliou1, Jong Kyoung Kim3, Thomas Santarius2, Sebastian Brandner4 and Allan Bradley1* * Correspondence: [email protected]; [email protected] Abstract †Jorge de la Rosa and Yoonha Choi contributed equally to this work. Background: Glioma is the most common intrinsic brain tumor and also occurs in 1The Wellcome Trust Sanger the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. Institute, Wellcome Trust Genome However, the cooperative partners of EGFR driving gliomagenesis remain poorly Campus, Hinxton, Cambridgeshire CB10 1SA, UK understood. Full list of author information is Results: We explore EGFR-mutant glioma evolution in conditional mutant mice by available at the end of the article whole-exome sequencing, transposon mutagenesis forward genetic screening, and transcriptomics. We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord. We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations. Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3. -
The Risk of Cancer in Patients with Psoriasis a Population-Based Cohort Study in the Health Improvement Network
Research Original Investigation The Risk of Cancer in Patients With Psoriasis A Population-Based Cohort Study in the Health Improvement Network Zelma C. Chiesa Fuxench, MD; Daniel B. Shin, MS; Alexis Ogdie Beatty, MD, MSCE; Joel M. Gelfand, MD, MSCE IMPORTANCE The risk of cancer in patients with psoriasis remains a cause of special concern due to the chronic inflammatory nature of the disease, the use of immune-suppressive treatments and UV therapies, and the increased prevalence of comorbid, well-established risk factors for cancer, such as smoking and obesity, all of which may increase the risk of carcinogenesis. OBJECTIVE To compare the overall risk of cancer, and specific cancers of interest, in patients with psoriasis compared with patients without psoriasis. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of patients ages 18 to 89 years with no medical history of human immunodeficiency virus, cancer, organ transplants, or hereditary disease (albinism and xeroderma pigmentosum), prior to the start date, conducted using The Health Improvement Network, a primary care medical records database in the United Kingdom. The data analyzed had been collected prospectively from 2002 through January 2014. The analysis was completed in August 2015. EXPOSURES OF INTEREST Patients with at least 1 diagnostic code for psoriasis were classified as having moderate-to-severe disease if they had been prescribed psoralen, methotrexate, cyclosporine, acitretin, adalimumab, etanercept, infliximab, or ustekinumab or phototherapy for psoriasis. Patients were classified as having mild disease if they never received treatment with any of these agents. MAIN OUTCOMES AND MEASURES Incident cancer diagnosis. RESULTS A total of 937 716 control group patients without psoriasis, matched on date and practice visit, and 198 366 patients with psoriasis (186 076 with mild psoriasis and 12 290 with moderate-to-severe disease) were included in the analysis. -
Clinical and Genetic Characteristics of Chinese Patients with Birt-Hogg
Liu et al. Orphanet Journal of Rare Diseases (2017) 12:104 DOI 10.1186/s13023-017-0656-7 RESEARCH Open Access Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome Yaping Liu1†, Zhiyan Xu2†, Ruie Feng3, Yongzhong Zhan4,5, Jun Wang4, Guozhen Li4, Xue Li4, Weihong Zhang6, Xiaowen Hu7, Xinlun Tian4*†, Kai-Feng Xu4† and Xue Zhang1† Abstract Background: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax. The known causative gene for BHD syndrome is the folliculin (FLCN) gene on chromosome 17p11.2. Studies of the FLCN mutation for BHD syndrome are less prevalent in Chinese populations than in Caucasian populations. Our study aims to investigate the genotype spectrum in a group of Chinese patients with BHD. Methods: We enrolled 51 patients with symptoms highly suggestive of BHD from January 2014 to February 2017. The FLCN gene was examined using PCR and Sanger sequencing in every patient, for those whose Sanger sequencing showed negative mutation results, multiplex ligation-dependent probe amplification (MLPA) testing was conducted to detect any losses of large segments. Main results: Among the 51 patients, 27 had FLCN germline mutations. In total, 20 mutations were identified: 14 were novel mutations, including 3 splice acceptor site mutations, 2 different deletions, 6 nonsense mutations, 1 missense mutation, 1 small insertion, and 1 deletion of the whole exon 8. Conclusions: We found a similar genotype spectrum but different mutant loci in Chinese patients with BHD compared with European and American patients, thus providing stronger evidence for the clinical molecular diagnosis of BHD in China. -
Megalencephaly and Macrocephaly
277 Megalencephaly and Macrocephaly KellenD.Winden,MD,PhD1 Christopher J. Yuskaitis, MD, PhD1 Annapurna Poduri, MD, MPH2 1 Department of Neurology, Boston Children’s Hospital, Boston, Address for correspondence Annapurna Poduri, Epilepsy Genetics Massachusetts Program, Division of Epilepsy and Clinical Electrophysiology, 2 Epilepsy Genetics Program, Division of Epilepsy and Clinical Department of Neurology, Fegan 9, Boston Children’s Hospital, 300 Electrophysiology, Department of Neurology, Boston Children’s Longwood Avenue, Boston, MA 02115 Hospital, Boston, Massachusetts (e-mail: [email protected]). Semin Neurol 2015;35:277–287. Abstract Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and Keywords behavioral problems; specific disorders have associations with overgrowth or abnor- ► megalencephaly malities in other tissues. The molecular underpinnings of many of these disorders are ► hemimegalencephaly now understood, providing insight into how dysregulation of critical pathways leads to ► -
RD-Action Matchmaker – Summary of Disease Expertise Recorded Under
Summary of disease expertise recorded via RD-ACTION Matchmaker under each Thematic Grouping and EURORDIS Members’ Thematic Grouping Thematic Reported expertise of those completing the EURORDIS Member perspectives on Grouping matchmaker under each heading Grouping RD Thematically Rare Bone Achondroplasia/Hypochondroplasia Achondroplasia Amelia skeletal dysplasia’s including Achondroplasia/Growth hormone cleidocranial dysostosis, arthrogryposis deficiency/MPS/Turner Brachydactyly chondrodysplasia punctate Fibrous dysplasia of bone Collagenopathy and oncologic disease such as Fibrodysplasia ossificans progressive Li-Fraumeni syndrome Osteogenesis imperfecta Congenital hand and fore-foot conditions Sterno Costo Clavicular Hyperostosis Disorders of Sex Development Duchenne Muscular Dystrophy Ehlers –Danlos syndrome Fibrodysplasia Ossificans Progressiva Growth disorders Hypoparathyroidism Hypophosphatemic rickets & Nutritional Rickets Hypophosphatasia Jeune’s syndrome Limb reduction defects Madelung disease Metabolic Osteoporosis Multiple Hereditary Exostoses Osteogenesis imperfecta Osteoporosis Paediatric Osteoporosis Paget’s disease Phocomelia Pseudohypoparathyroidism Radial dysplasia Skeletal dysplasia Thanatophoric dwarfism Ulna dysplasia Rare Cancer and Adrenocortical tumours Acute monoblastic leukaemia Tumours Carcinoid tumours Brain tumour Craniopharyngioma Colon cancer, familial nonpolyposis Embryonal tumours of CNS Craniopharyngioma Ependymoma Desmoid disease Epithelial thymic tumours in -
Multiple Orbital Neurofibromas, Painful Peripheral Nerve Tumors, Distinctive
European Journal of Human Genetics (2012) 20, 618–625 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg ARTICLE Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome D Babovic-Vuksanovic*,1, Ludwine Messiaen2, Christoph Nagel3, Hilde Brems4, Bernd Scheithauer5, Ellen Denayer4, Rong Mao6, Raf Sciot7, Karen M Janowski2, Martin U Schuhmann3, Kathleen Claes8, Eline Beert4, James A Garrity9, Robert J Spinner10, Anat Stemmer-Rachamimov11, Ralitza Gavrilova1, Frank Van Calenbergh12, Victor Mautner13 and Eric Legius4 Four unrelated patients having an unusual clinical phenotype, including multiple peripheral nerve sheath tumors, are reported. Their clinical features were not typical of any known familial tumor syndrome. The patients had multiple painful neurofibromas, including bilateral orbital plexiform neurofibromas, and spinal as well as mucosal neurofibromas. In addition, they exhibited a marfanoid habitus, shared similar facial features, and had enlarged corneal nerves as well as neuronal migration defects. Comprehensive NF1, NF2 and SMARCB1 mutation analyses revealed no mutation in blood lymphocytes and in schwann cells cultured from plexiform neurofibromas. Furthermore, no mutations in RET, PRKAR1A, PTEN and other RAS-pathway genes were found in blood leukocytes. Collectively, the clinical and pathological findings in these four cases fit no known syndrome and likely represent a new disorder. European Journal of Human Genetics (2012) 20, 618–625; doi:10.1038/ejhg.2011.275; published online 18 January 2012 Keywords: orbital neurofibroma; plexiform neurofibroma; enlarged corneal nerves; marfanoid habitus INTRODUCTION Ruvalcaba syndrome, a part of the PHTS spectrum, develop cafe´- Peripheral nerve sheath tumors, specifically neurofibromas and au-lait spots and macules of the glans penis. -
Association Between Birt Hogg Dubé Syndrome and Cancer Predisposition
ANTICANCER RESEARCH 30: 751-758 (2010) Review Association Between Birt Hogg Dubé Syndrome and Cancer Predisposition RAFFAELE PALMIROTTA1, ANNALISA SAVONAROLA1, GIORGIA LUDOVICI1, PIETRO DONATI2, FRANCESCO CAVALIERE3, MARIA LAURA DE MARCHIS1, PATRIZIA FERRONI1 and FIORELLA GUADAGNI1 1Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, 00165 Rome, Italy; 2Unit of Skin Histopathology, IRCCS San Gallicano Dermatologic Institute, 00144 Rome, Italy; 3Breast Unit, San Giovanni Hospital, 00184 Rome, Italy Abstract. The Birt Hogg Dubé syndrome (BHD) is a rare Clinically, the BHD syndrome exhibits numerous autosomal dominant genodermatosis predisposing patients to asymptomatic, skin colored, dome-shaped papules over the developing fibrofolliculoma, trichodiscoma and acrochordon. face, neck, and upper trunk. These lesions represent benign The syndrome is caused by germline mutations in the folliculin proliferations of the ectodermal and mesodermal components (FLCN) gene, encoding the folliculin tumor-suppressor of the pilar apparatus (2). Fibrofolliculomas are benign protein. Numerous mutations have been described in the tumors of the perifollicular connective tissue, occurring as FLCN gene, the most frequent occurring within a C8 tract of one or more yellowish dome-shaped papules, usually on the exon 11. This hypermutability is probably due to a slippage in face. Trichodiscomas are parafollicular mesenchymal DNA polymerase during replication, resulting in gains/losses hamartomas of the mesodermal portion of the hair disk, of repeat units, causing cancer predisposition. The main usually occurring as multiple small papules. Acrochordons phenotypic manifestations related to this disease are lung are small outgrowths of epidermal and dermal tissue, which cysts, leading to pneumothorax, and a 7-fold increased risk may be pedunculated, smooth or irregular, flesh-colored and for renal neoplasia, although other neoplastic manifestations benign; they usually appear as pedunculated skin tags, have been described in BHD-affected individuals. -
Cardiomyopathy Precision Panel Overview Indications
Cardiomyopathy Precision Panel Overview Cardiomyopathies are a group of conditions with a strong genetic background that structurally hinder the heart to pump out blood to the rest of the body due to weakness in the heart muscles. These diseases affect individuals of all ages and can lead to heart failure and sudden cardiac death. If there is a family history of cardiomyopathy it is strongly recommended to undergo genetic testing to be aware of the family risk, personal risk, and treatment options. Most types of cardiomyopathies are inherited in a dominant manner, which means that one altered copy of the gene is enough for the disease to present in an individual. The symptoms of cardiomyopathy are variable, and these diseases can present in different ways. There are 5 types of cardiomyopathies, the most common being hypertrophic cardiomyopathy: 1. Hypertrophic cardiomyopathy (HCM) 2. Dilated cardiomyopathy (DCM) 3. Restrictive cardiomyopathy (RCM) 4. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) 5. Isolated Left Ventricular Non-Compaction Cardiomyopathy (LVNC). The Igenomix Cardiomyopathy Precision Panel serves as a diagnostic and tool ultimately leading to a better management and prognosis of the disease. It provides a comprehensive analysis of the genes involved in this disease using next-generation sequencing (NGS) to fully understand the spectrum of relevant genes. Indications The Igenomix Cardiomyopathy Precision Panel is indicated in those cases where there is a clinical suspicion of cardiomyopathy with or without the following manifestations: - Shortness of breath - Fatigue - Arrythmia (abnormal heart rhythm) - Family history of arrhythmia - Abnormal scans - Ventricular tachycardia - Ventricular fibrillation - Chest Pain - Dizziness - Sudden cardiac death in the family 1 Clinical Utility The clinical utility of this panel is: - The genetic and molecular diagnosis for an accurate clinical diagnosis of a patient with personal or family history of cardiomyopathy, channelopathy or sudden cardiac death.