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Atterton C, Trew I, Cale JM, Aung-Htut MT, Grens K, Kiernan J, Delagrammatikas CG, Piper M. Overgrowth-intellectual disability disorders: progress in biology, patient advocacy and innovative therapies. Dis Model Mech 2025; 18:dmm052300. [PMID: 40353642 DOI: 10.1242/dmm.052300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2025] Open
Abstract
Overgrowth-intellectual disability (OGID) syndromes encompass a group of rare neurodevelopmental disorders that frequently share common clinical presentations. Although the genetic causes of many OGID syndromes are now known, we lack a clear mechanistic understanding of how such variants disrupt developmental processes and ultimately culminate in overgrowth and neurological symptoms. Patient advocacy groups, such as the Overgrowth Syndromes Alliance (OSA), are mobilising patients, families, clinicians and researchers to work together towards a deeper understanding of the clinical needs of patients with OGID, as well as to understand the fundamental biology of the relevant genes, with the goal of developing treatments. In this Review, we summarise three OGID syndromes encompassed by the OSA, namely Sotos syndrome, Malan syndrome and Tatton-Brown-Rahman syndrome. We discuss similarities and differences in the biology behind each disorder and explore future approaches that could potentially provide a way to ameliorate some of the unmet clinical needs of patients with OGID.
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Affiliation(s)
- Cooper Atterton
- The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Isabella Trew
- Personalised Medicine Centre, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia
- Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Jessica M Cale
- Personalised Medicine Centre, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia
- Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - May T Aung-Htut
- Personalised Medicine Centre, Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia
- Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Kerry Grens
- TBRS Community, Stanfordville, NY 12581, USA
| | | | | | - Michael Piper
- The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
- The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
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Chu Y, Setayesh J, Dumontet T, Krumeich L, Werner J, Moretti IF, De Sousa K, Kennedy C, La Pensee C, Lerario AM, Hammer GD. Adrenocortical stem cells in health and disease. Nat Rev Endocrinol 2025:10.1038/s41574-025-01091-2. [PMID: 40065108 DOI: 10.1038/s41574-025-01091-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 04/13/2025]
Abstract
The adrenal cortex is the major site of production of steroid hormones, which are essential for life. The normal development and homeostatic renewal of the adrenal cortex depend on capsular stem cells and cortical progenitor cells. These cell populations are highly plastic and support adaptation to physiological demands, injury and disease, linking steroid production and adrenal (organ) homeostasis with systemic endocrine cues and organismal homeostasis. This Review integrates findings from the past decade, outlining the mechanisms that govern the establishment and maintenance of the adrenal stem cell niche under different physiological and pathological conditions. The sophisticated regulation of the stem cell niche by gene regulatory networks, coordinated through paracrine and endocrine signalling, is highlighted in a context-dependent and sex-specific manner. We discuss how dysregulation of this intricate regulatory network is implicated in a wide range of adrenal diseases, and how emerging knowledge from adrenal stem cell research is inspiring the future development of gene-based and cell-based therapeutic strategies.
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Affiliation(s)
- Yulan Chu
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Jordan Setayesh
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA
| | - Typhanie Dumontet
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Lauren Krumeich
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Johanna Werner
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
- Division of Endocrinology and Diabetology, Department of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, Germany
| | - Isabele F Moretti
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Kelly De Sousa
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Christopher Kennedy
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Christopher La Pensee
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Antonio M Lerario
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Gary D Hammer
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA.
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
- Endocrine Oncology Program, Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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Espinoza AF, Onwuka E, Siegel DA, Dai S, Vasudevan SA, Scheurer ME, Lupo PJ. Incidence and Survival of Children and Adolescents With Wilms Tumor, United States, 2001-2020. Cancer Med 2025; 14:e70598. [PMID: 39928531 PMCID: PMC11809554 DOI: 10.1002/cam4.70598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/16/2024] [Accepted: 01/03/2025] [Indexed: 02/12/2025] Open
Abstract
BACKGROUND Wilms tumor (WT) is the most common pediatric malignancy of the kidney. Past studies describing WT incidence and survival used surveillance data with < 30% of the US population. We evaluated differences in WT incidence and survival comparing demographic groups and tumor characteristics. METHODS We analyzed new cases of WT among patients aged < 20 years at diagnosis by using incidence data from US Cancer Statistics (USCS) for 2003-2020 and 5-year relative survival (RS) data from the National Program of Cancer Registries (NPCR) for 2001-2019. To assess incidence trends, average annual percent change (AAPC) was calculated by using joinpoint regression. Relative survival (RS) and all-cause survival were calculated overall and by demographic and clinical variables. RESULTS During 2003-2020, 8218 cases of WT were reported in USCS, which represented an age-adjusted incidence rate of 5.7 cases per million. Rates were the highest among females (6.3), children aged 0-4 years (17.2), and non-Hispanic Black patients (7.1). Overall, trends remained stable (AAPC = -0.4, 95% CI: -1.4 to 0.4). Among 7567 cases of WT in NPCR, 5-year RS was 92.6%. Patients with the lowest survival include the following: those aged 10-19 years (hazard ratio [HR] = 1.65, 95% CI: 1.02-2.65); non-Hispanic Black patients (HR = 1.39, 95% CI: 1.11-1.76); those with regional stage (HR = 1.93, 95% CI: 1.47-2.54) or distant stage (HR = 5.12, 95% CI: 3.99-6.57); and patients from nonmetropolitan counties (HR = 1.46, 95% CI: 1.09-1.96). Individuals diagnosed during 2011-2019 (HR = 0.64, 95% CI: 0.53-0.77) had higher survival than those diagnosed during 2001-2010. CONCLUSIONS The highest WT incidence rates were patients who were female, 0-4 years, and non-Hispanic Black. Survival improved during the study period; survival differed by race, ethnicity, metropolitan status, and age. Further studies to delineate the causes of these disparities may improve outcomes.
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Affiliation(s)
- Andres F. Espinoza
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program and Liver Tumor Program, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonTexasUSA
| | - Ekene Onwuka
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program and Liver Tumor Program, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonTexasUSA
- Department of Pediatrics, Hematology‐Oncology Section, Texas Children's Hospital, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonTexasUSA
| | - David A. Siegel
- Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health PromotionCenters for Disease Control and PreventionAtlantaGeorgiaUSA
| | - Shifan Dai
- Cyberdata Technologies Inc.HerndonVirginiaUSA
| | - Sanjeev A. Vasudevan
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program and Liver Tumor Program, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonTexasUSA
| | - Michael E. Scheurer
- Department of Pediatrics, Hematology‐Oncology Section, Texas Children's Hospital, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonTexasUSA
| | - Philip J. Lupo
- Department of Pediatrics, Hematology‐Oncology Section, Texas Children's Hospital, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonTexasUSA
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Luo C, Liu Y, Wang H, Chen L, Wu X, Geng Q, Wen H, Li S, Wu W, Zhong M. Aberrant Fetal Brain Sulcus Formation: A Clue to the Diagnosis of Sotos Syndrome. Prenat Diagn 2024; 44:1641-1646. [PMID: 39425694 PMCID: PMC11628212 DOI: 10.1002/pd.6686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/26/2024] [Accepted: 09/30/2024] [Indexed: 10/21/2024]
Abstract
OBJECTIVE This study aims to elucidate two distinct fetal ultrasound features associated with aberrant brain sulcus formation as potential prenatal markers for Sotos syndrome caused by mutations in the NSD1 gene. METHOD This retrospective study investigated three fetuses across two pregnancies, including a pair of monochorionic diamniotic twins, all diagnosed with Sotos syndrome via whole exome sequencing (WES). Comprehensive clinical and laboratory data were collected and analyzed. Each fetus underwent a series of specialized neurosonographic assessments to evaluate the development of the cerebral cortex. RESULTS All three fetuses exhibited aberrant brain sulcus formation characterized by Sylvian fissure (SF) abnormalities and shallow parietooccipital sulcus (POS). WES revealed the presence of two de novo NSD1 variants in these fetuses. CONCLUSIONS Fetal aberrant brain sulcus formation may represent a distinctive ultrasound feature indicative of Sotos syndrome, thereby offering additional diagnostic insights for the identification of this condition.
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Affiliation(s)
- Caiqun Luo
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangzhouChina
- Maternal Fetal Medicine CenterShenzhen Maternity and Child Healthcare HospitalSouthern Medical UniversityShenzhenChina
| | - Yang Liu
- Medical Genetic CenterShenzhen Maternity and Child Healthcare HospitalSouthern Medical UniversityShenzhenChina
| | - Hui Wang
- Maternal Fetal Medicine CenterShenzhen Maternity and Child Healthcare HospitalSouthern Medical UniversityShenzhenChina
| | - LiYuan Chen
- Maternal Fetal Medicine CenterShenzhen Maternity and Child Healthcare HospitalSouthern Medical UniversityShenzhenChina
| | - XiaoXia Wu
- Maternal Fetal Medicine CenterShenzhen Maternity and Child Healthcare HospitalSouthern Medical UniversityShenzhenChina
| | - Qian Geng
- Medical Genetic CenterShenzhen Maternity and Child Healthcare HospitalSouthern Medical UniversityShenzhenChina
| | - Huaxuan Wen
- Ultrasound DepartmentShenzhen Maternity and Child Healthcare HospitalShenzhenChina
| | - Shengli Li
- Ultrasound DepartmentShenzhen Maternity and Child Healthcare HospitalShenzhenChina
| | - Weiqing Wu
- Medical Genetic CenterShenzhen Maternity and Child Healthcare HospitalSouthern Medical UniversityShenzhenChina
| | - Mei Zhong
- Department of Obstetrics and GynecologyNanfang HospitalSouthern Medical UniversityGuangzhouChina
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Vaisfeld A, Neri G. Simpson-Golabi-Behmel syndrome. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2024; 196:e32088. [PMID: 38766979 DOI: 10.1002/ajmg.c.32088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/18/2024] [Accepted: 04/27/2024] [Indexed: 05/22/2024]
Abstract
The Simpson-Golabi-Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X-linked semi-dominant trait, with variable expressivity in males and reduced penetrance and expressivity in females. The clinical spectrum is broad, ranging from mild manifestations in both males and females to multiple malformations and neonatal death in the more severely affected cases. An increased risk of neoplasia is reported, requiring periodical surveillance. Intellectual development is normal in most cases. SGBS is caused by a loss-of-function mutation of the GPC3 gene, either deletions or point mutations, distributed all over the gene. Notably, GPC3 deletion/point mutations are not found in a significant proportion of clinically diagnosed SGBS cases. The protein product GPC3 is a glypican functioning as a receptor for Hh at the cell surface, involved in the Hh-Ptc-Smo signaling pathway, a regulator of cellular growth.
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Affiliation(s)
- Alessandro Vaisfeld
- Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Neri
- Institute of Genomic Medicine, Catholic University School of Medicine, Rome, Italy
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Neeman B, Sudhakar S, Biswas A, Rosenblum J, Sidpra J, D’Arco F, Löbel U, Gómez-Chiari M, Serrano M, Bolasell M, Reddy K, Ben-Sira L, Zakzouk R, Al-Hashem A, Mirsky DM, Patel R, Radhakrishnan R, Shekdar K, Whitehead MT, Mankad K. Sotos Syndrome: Deep Neuroimaging Phenotyping Reveals a High Prevalence of Malformations of Cortical Development. AJNR Am J Neuroradiol 2024; 45:1570-1577. [PMID: 39147584 PMCID: PMC11448971 DOI: 10.3174/ajnr.a8364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 05/16/2024] [Indexed: 08/17/2024]
Abstract
BACKGROUND AND PURPOSE Sotos syndrome is a rare autosomal dominant condition caused by pathogenic mutations in the NSD1 gene that presents with craniofacial dysmorphism, overgrowth, seizures, and neurodevelopmental delay. Macrocephaly, ventriculomegaly, and corpus callosal dysmorphism are typical neuroimaging features that have been described in the medical literature. The purpose of this study was to expand on the neuroimaging phenotype by detailed analysis of a large cohort of patients with genetically proved Sotos syndrome. MATERIALS AND METHODS This multicenter, multinational, retrospective observational cohort study systematically analyzed the clinical characteristics and neuroimaging features of 77 individuals with genetically diagnosed Sotos syndrome, via central consensus review with 3 pediatric neuroradiologists. RESULTS In addition to previously described features, malformations of cortical development were identified in most patients (95.0%), typically dysgyria (92.2%) and polymicrogyria (22.1%), varying in location and distribution. Incomplete rotation of the hippocampus was observed in 50.6% of patients and was associated with other imaging findings, in particular with dysgyria (100% versus 84.2%, P = .012). CONCLUSIONS Our findings show a link between the genetic-biochemical basis and the neuroimaging features and aid in better understanding the underlying clinical manifestations and possible treatment options. These findings have yet to be described to this extent and correspond with recent studies that show that NSD1 participates in brain development and has interactions with other known relevant genetic pathways.
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Affiliation(s)
- Bar Neeman
- From the Department of Radiology (B.N., L.B.-S.), Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Faculty of Medicine (B.N., L.B.-S.), Tel-Aviv University, Tel-Aviv, Israel
| | - Sniya Sudhakar
- Department of Radiology (S.S., A.B., F.D., U.L., K.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Asthik Biswas
- Department of Radiology (S.S., A.B., F.D., U.L., K.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Jessica Rosenblum
- Center of Medical Genetics (J.R.), Antwerp University Hospital/University of Antwerp, Antwerp, Belgium
| | - Jai Sidpra
- Developmental Biology and Cancer Section (J.S., K.M.), University College London Great Ormond Street Institute of Child Health, London, UK
| | - Felice D’Arco
- Department of Radiology (S.S., A.B., F.D., U.L., K.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Ulrike Löbel
- Department of Radiology (S.S., A.B., F.D., U.L., K.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Marta Gómez-Chiari
- Diagnostic Imaging Department (M.G.-C.), Hospital Sant Joan de Déu, Barcelona, Spain
- Institut de Recerca Sant Joan de Déu,(M.G.-C., M.S., M.B.), Barcelona, Spain
| | - Mercedes Serrano
- Institut de Recerca Sant Joan de Déu,(M.G.-C., M.S., M.B.), Barcelona, Spain
- Neuropediatric Department (M.S.), Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases, Barcelona, Spain
| | - Mercè Bolasell
- Institut de Recerca Sant Joan de Déu,(M.G.-C., M.S., M.B.), Barcelona, Spain
- Department of Genetic and Molecular Medicine/IPER (M.B.), Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
| | - Kartik Reddy
- Department of Radiology and Imaging Sciences (K.R.), Emory University School of Medicine, Atlanta, Georgia
| | - Liat Ben-Sira
- From the Department of Radiology (B.N., L.B.-S.), Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
- Faculty of Medicine (B.N., L.B.-S.), Tel-Aviv University, Tel-Aviv, Israel
| | - Reem Zakzouk
- Division of Neuroradiology (R.Z.), Department of Radiology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Amal Al-Hashem
- Division of Genetics (A.A.-H.), Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - David M. Mirsky
- Department of Radiology (D.M.M.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
| | - Rajan Patel
- Texas Children's Hospital (R.P.), Baylor College of Medicine, Houston, Texas
| | - Rupa Radhakrishnan
- Department of Radiology and Imaging Sciences (R.R.), Indiana University School of Medicine, Indianapolis, Indiana
| | - Karuna Shekdar
- Department of Radiology (K.S., M.T.W.), Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Matthew T. Whitehead
- Department of Radiology (K.S., M.T.W.), Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
- Perelman School of Medicine (M.T.W.), University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kshitij Mankad
- Department of Radiology (S.S., A.B., F.D., U.L., K.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
- Developmental Biology and Cancer Section (J.S., K.M.), University College London Great Ormond Street Institute of Child Health, London, UK
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Hasan HA, Johnstone LS, Benedetti DJ. A case of pancreatoblastoma in a child with Simpson-Golabi-Behmel syndrome: Highlighting the importance of alpha fetoprotein monitoring. Pediatr Blood Cancer 2024; 71:e31097. [PMID: 38773720 DOI: 10.1002/pbc.31097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/04/2024] [Accepted: 05/12/2024] [Indexed: 05/24/2024]
Affiliation(s)
- Hira A Hasan
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lindsey S Johnstone
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Daniel J Benedetti
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Division of Pediatric Hematology Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Perotti D, Williams RD, Wegert J, Brzezinski J, Maschietto M, Ciceri S, Gisselsson D, Gadd S, Walz AL, Furtwaengler R, Drost J, Al-Saadi R, Evageliou N, Gooskens SL, Hong AL, Murphy AJ, Ortiz MV, O'Sullivan MJ, Mullen EA, van den Heuvel-Eibrink MM, Fernandez CV, Graf N, Grundy PE, Geller JI, Dome JS, Perlman EJ, Gessler M, Huff V, Pritchard-Jones K. Hallmark discoveries in the biology of Wilms tumour. Nat Rev Urol 2024; 21:158-180. [PMID: 37848532 DOI: 10.1038/s41585-023-00824-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2023] [Indexed: 10/19/2023]
Abstract
The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions.
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Affiliation(s)
- Daniela Perotti
- Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Richard D Williams
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Section of Genetics and Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Jenny Wegert
- Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany
| | - Jack Brzezinski
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Mariana Maschietto
- Research Center, Boldrini Children's Hospital, Campinas, São Paulo, Brazil
| | - Sara Ciceri
- Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - David Gisselsson
- Cancer Cell Evolution Unit, Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Skåne, Sweden
| | - Samantha Gadd
- Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Amy L Walz
- Division of Hematology,Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Rhoikos Furtwaengler
- Division of Pediatric Oncology and Hematology, Department of Pediatrics, Inselspital Bern University, Bern, Switzerland
| | - Jarno Drost
- Princess Máxima Center for Paediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Reem Al-Saadi
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Histopathology, Great Ormond Street Hospital for Children, London, UK
| | - Nicholas Evageliou
- Divisions of Hematology and Oncology, Children's Hospital of Philadelphia, CHOP Specialty Care Center, Vorhees, NJ, USA
| | - Saskia L Gooskens
- Princess Máxima Center for Paediatric Oncology, Utrecht, Netherlands
| | - Andrew L Hong
- Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Andrew J Murphy
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Michael V Ortiz
- Department of Paediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maureen J O'Sullivan
- Histology Laboratory, Children's Health Ireland at Crumlin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College, Dublin, Ireland
| | - Elizabeth A Mullen
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
| | | | - Conrad V Fernandez
- Division of Paediatric Hematology Oncology, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Norbert Graf
- Department of Paediatric Oncology and Hematology, Saarland University Hospital, Homburg, Germany
| | - Paul E Grundy
- Department of Paediatrics Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Jeffrey S Dome
- Division of Oncology, Center for Cancer and Blood Disorders, Children's National Hospital and the Department of Paediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Elizabeth J Perlman
- Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Manfred Gessler
- Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany
- Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany
| | - Vicki Huff
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kathy Pritchard-Jones
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
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Connolly GK, Harris RD, Shumate C, Rednam SP, Canfield MA, Plon SE, Nguyen J, Schraw JM, Lupo PJ. Pediatric cancer incidence among individuals with overgrowth syndromes and overgrowth features: A population-based assessment in seven million children. Cancer 2024; 130:467-475. [PMID: 37788149 DOI: 10.1002/cncr.35041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 10/05/2023]
Abstract
BACKGROUND Overgrowth syndromes (e.g., Beckwith-Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population-based estimates of risk. There are also limited studies describing associations between other overgrowth features (e.g., hepatosplenomegaly) and pediatric cancer. Therefore, cancer risk among children with these conditions was evaluated with data from a large, diverse population-based registry linkage study. METHODS This study includes all live births in Texas during the years 1999-2017. Children with overgrowth features and syndromes were identified from the Texas Birth Defects Registry; children with cancer were identified by linkage to the Texas Cancer Registry. Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between each overgrowth syndrome/feature and cancer, which were adjusted for infant sex and maternal age. RESULTS In the total birth cohort (n = 6,997,422), 21,207 children were identified as having an overgrowth syndrome or feature. Children with Beckwith-Wiedemann syndrome were 42 times more likely to develop pediatric cancer (95% CI, 24.20-71.83), with hepatoblastoma being the most common, followed by Wilms tumor. The presence of any isolated overgrowth feature was associated with increased cancer risk (HR, 4.70; 95% CI, 3.83-5.77); associations were strongest for hepatosplenomegaly (HR, 23.04; 95% CI, 13.37-39.69) and macroglossia (HR, 11.18; 95% CI, 6.35-19.70). CONCLUSIONS This population-based assessment confirmed prior findings that children with either overgrowth syndromes or features were significantly more likely to develop cancer. Overall, this study supports recommendations for cancer surveillance in children with these conditions and may also inform future research into cancer etiology.
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Affiliation(s)
- Gillean K Connolly
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Rachel D Harris
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Charles Shumate
- Environmental Epidemiology and Disease Registries Section, Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
| | - Surya P Rednam
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Mark A Canfield
- Environmental Epidemiology and Disease Registries Section, Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
| | - Sharon E Plon
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Joanne Nguyen
- Environmental Epidemiology and Disease Registries Section, Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
| | - Jeremy M Schraw
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Philip J Lupo
- Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
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10
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Mirnia K, Saeedi M, Sangsari R, Kazemzadeh K. A five-day-old child with lipid hemihypertrophy: A case report. Clin Case Rep 2024; 12:e8476. [PMID: 38333663 PMCID: PMC10849986 DOI: 10.1002/ccr3.8476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/18/2023] [Accepted: 01/21/2024] [Indexed: 02/10/2024] Open
Abstract
Key Clinical Message Lipid hemihypertrophy should be considered in the differential diagnosis of neonatal asymmetry. Early recognition and further evaluation for associated disorders are important for appropriate management and surveillance of potential complications. Abstract We present the case of a 5-day-old female neonate who presented with a visibly enlarged right thigh, right labia majora, and below the right mandible. This case report highlights the importance of early identification, comprehensive evaluation, and multidisciplinary management in neonates with lipid hemihypertrophy to optimize their long-term outcomes and quality of life.
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Affiliation(s)
- Kayvan Mirnia
- Division of Neonatology, Department of Pediatrics, Children's Medical Center, Pediatric Center of Excellence, Faculty of MedicineTehran University of Medical SciencesTehranIran
| | - Maryam Saeedi
- Division of Neonatology, Department of Pediatrics, Children's Medical Center, Pediatric Center of Excellence, Faculty of MedicineTehran University of Medical SciencesTehranIran
| | - Razieh Sangsari
- Division of Neonatology, Department of Pediatrics, Children's Medical Center, Pediatric Center of Excellence, Faculty of MedicineTehran University of Medical SciencesTehranIran
| | - Kimia Kazemzadeh
- Students' Scientific Research CenterTehran University of Medical SciencesTehranIran
- Network of Neurosurgery and Artificial Intelligence (NONAI)Universal Scientific Education and Research Network (USERN)TehranIran
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11
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Bozzarelli I, Orsini A, Isidori F, Mastracci L, Malvi D, Lugaresi M, Fittipaldi S, Gozzellino L, Astolfi A, Räsänen J, D’Errico A, Rosati R, Fiocca R, Seri M, Krishnadath KK, Bonora E, Mattioli S. miRNA-221 and miRNA-483-3p Dysregulation in Esophageal Adenocarcinoma. Cancers (Basel) 2024; 16:591. [PMID: 38339342 PMCID: PMC10854562 DOI: 10.3390/cancers16030591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/25/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Alterations in microRNA (miRNA) expression have been reported in different cancers. We assessed the expression of 754 oncology-related miRNAs in esophageal adenocarcinoma (EAC) samples and evaluated their correlations with clinical parameters. We found that miR-221 and 483-3p were consistently upregulated in EAC patients vs. controls (Wilcoxon signed-rank test: miR-221 p < 0.0001; miR-483-3p p < 0.0001). Kaplan-Meier analysis showed worse cancer-related survival among all EAC patients expressing high miR-221 or miR-483-3p levels (log-rank p = 0.0025 and p = 0.0235, respectively). Higher miR-221 or miR-483-3p levels also correlated with advanced tumor stages (Mann-Whitney p = 0.0195 and p = 0.0085, respectively), and overexpression of miR-221 was associated with worse survival in low-risk EAC patients. Moreover, a significantly worse outcome was associated with the combined overexpression of miR-221 and miR-483-3p (log-rank p = 0.0410). To identify target genes affected by miRNA overexpression, we transfected the corresponding mimic RNA (miRVANA) for either miR-221 or miR-483-3p in a well-characterized esophageal adenocarcinoma cell line (OE19) and performed RNA-seq analysis. In the miRNA-overexpressing cells, we discovered a convergent dysregulation of genes linked to apoptosis, ATP synthesis, angiogenesis, and cancer progression, including a long non-coding RNA associated with oncogenesis, i.e., MALAT1. In conclusion, dysregulated miRNA expression, especially overexpression of miR-221 and 483-3p, was found in EAC samples. These alterations were connected with a lower cancer-specific patient survival, suggesting that these miRNAs could be useful for patient stratification and prognosis.
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Affiliation(s)
- Isotta Bozzarelli
- Gastrointestinal Genetics Lab, CIC bioGUNE—BRTA, 48160 Derio, Spain;
| | - Arianna Orsini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, via Massarenti 9, 40138 Bologna, Italy (L.G.); (M.S.)
| | - Federica Isidori
- Dipartimento di Genetica Medica, IRCCS Azienda Ospedaliero–Universitaria di Bologna, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; (F.I.); (D.M.); (M.L.); (S.F.); (A.D.)
| | - Luca Mastracci
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16100 Genoa, Italy; (L.M.); (R.F.)
- IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Deborah Malvi
- Dipartimento di Genetica Medica, IRCCS Azienda Ospedaliero–Universitaria di Bologna, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; (F.I.); (D.M.); (M.L.); (S.F.); (A.D.)
- Institute of Oncology and Transplant Pathology, University of Bologna, 40126 Bologna, Italy
| | - Marialuisa Lugaresi
- Dipartimento di Genetica Medica, IRCCS Azienda Ospedaliero–Universitaria di Bologna, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; (F.I.); (D.M.); (M.L.); (S.F.); (A.D.)
| | - Silvia Fittipaldi
- Dipartimento di Genetica Medica, IRCCS Azienda Ospedaliero–Universitaria di Bologna, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; (F.I.); (D.M.); (M.L.); (S.F.); (A.D.)
| | - Livia Gozzellino
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, via Massarenti 9, 40138 Bologna, Italy (L.G.); (M.S.)
| | - Annalisa Astolfi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, via Massarenti 9, 40138 Bologna, Italy (L.G.); (M.S.)
| | - Jari Räsänen
- Department of Cardiothoracic Surgery, University of Helsinki and Helsinki University Hospital, 00100 Helsinki, Finland;
| | - Antonia D’Errico
- Dipartimento di Genetica Medica, IRCCS Azienda Ospedaliero–Universitaria di Bologna, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; (F.I.); (D.M.); (M.L.); (S.F.); (A.D.)
- Institute of Oncology and Transplant Pathology, University of Bologna, 40126 Bologna, Italy
| | - Riccardo Rosati
- Department of Gastrointestinal Surgery, San Raffaele Hospital, Vita–Salute San Raffaele University, 20132 Milan, Italy;
| | - Roberto Fiocca
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16100 Genoa, Italy; (L.M.); (R.F.)
- IRCCS Ospedale Policlinico San Martino, 16100 Genoa, Italy
| | - Marco Seri
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, via Massarenti 9, 40138 Bologna, Italy (L.G.); (M.S.)
- Dipartimento di Genetica Medica, IRCCS Azienda Ospedaliero–Universitaria di Bologna, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; (F.I.); (D.M.); (M.L.); (S.F.); (A.D.)
| | - Kausilia K. Krishnadath
- Laboratory of Experimental Medicine and Pediatrics (LEMP), Department of Gastroenterology and Hepatology, University Hospital Antwerp, University of Antwerp, 2180 Antwerp, Belgium;
| | - Elena Bonora
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, via Massarenti 9, 40138 Bologna, Italy (L.G.); (M.S.)
- Dipartimento di Genetica Medica, IRCCS Azienda Ospedaliero–Universitaria di Bologna, University of Bologna, via Massarenti 9, 40138 Bologna, Italy; (F.I.); (D.M.); (M.L.); (S.F.); (A.D.)
| | - Sandro Mattioli
- Division of Thoracic Surgery, Maria Cecilia Hospital, 48010 Cotignola, Italy;
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12
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Faivre L, Crépin JC, Réda M, Nambot S, Carmignac V, Abadie C, Mirault T, Faure-Conter C, Mazereeuw-Hautier J, Maza A, Puzenat E, Collonge-Rame MA, Bursztejn AC, Philippe C, Thauvin-Robinet C, Chevarin M, Abasq-Thomas C, Amiel J, Arpin S, Barbarot S, Baujat G, Bessis D, Bourrat E, Boute O, Chassaing N, Coubes C, Demeer B, Edery P, El Chehadeh S, Goldenberg A, Hadj-Rabia S, Haye D, Isidor B, Jacquemont ML, Van Kien PK, Lacombe D, Lehalle D, Lambert L, Martin L, Maruani A, Morice-Picard F, Petit F, Phan A, Pinson L, Rossi M, Touraine R, Vanlerberghe C, Vincent M, Vincent-Delorme C, Whalen S, Willems M, Marle N, Verkarre V, Devalland C, Devouassoux-Shisheboran M, Abad M, Rioux-Leclercq N, Bonniaud B, Duffourd Y, Martel J, Binquet C, Kuentz P, Vabres P. Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations. Clin Genet 2023; 104:554-563. [PMID: 37580112 DOI: 10.1111/cge.14410] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 07/07/2023] [Accepted: 07/19/2023] [Indexed: 08/16/2023]
Abstract
The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.
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Affiliation(s)
- Laurence Faivre
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- Centre de Génétique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
| | - Jean-Charles Crépin
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- Service de Dermatologie, CHU Dijon Bourgogne, Dijon, France
- Centre de référence Maladies Rares Génétiques à Expression Cutanée (MAGEC), CHU Dijon, Dijon, France
| | - Manon Réda
- Oncogénétique, Centre de lutte contre le cancer Georges François Leclerc, Dijon, France
| | - Sophie Nambot
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- Centre de Génétique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
- Oncogénétique, Centre de lutte contre le cancer Georges François Leclerc, Dijon, France
| | - Virginie Carmignac
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- Centre de référence Maladies Rares Génétiques à Expression Cutanée (MAGEC), CHU Dijon, Dijon, France
| | | | - Tristan Mirault
- Université Paris Cité, PARCC INSERM U970, Centre de référence des maladies vasculaires rares, Hôpital européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | | | | | - Aude Maza
- Service de Dermatologie, CHU Toulouse, Toulouse, France
| | - Eve Puzenat
- Service de Dermatologie, CHU Besançon, Besançon, France
| | | | | | - Christophe Philippe
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- UF6254 Innovation en Diagnostic Génomique des Maladies Rares, Plate-forme de Biologie Hospitalo-Universitaire, CHU Dijon-Bourgogne, Dijon, France
| | - Christel Thauvin-Robinet
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- Centre de Référence Déficiences Intellectuelles de Causes Rares, CHU Dijon Bourgogne, Dijon, France
| | - Martin Chevarin
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- UF6254 Innovation en Diagnostic Génomique des Maladies Rares, Plate-forme de Biologie Hospitalo-Universitaire, CHU Dijon-Bourgogne, Dijon, France
| | - Claire Abasq-Thomas
- Département de Pédiatrie et Génétique Médicale, CHU Brest Morvan, Brest, France
| | - Jeanne Amiel
- Service de Médecine Génomique des Maladies Rares et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Stéphanie Arpin
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHRU de Tours, Tours, France
| | | | - Geneviève Baujat
- Service de Médecine Génomique des Maladies Rares et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Didier Bessis
- Département de Dermatologie, CHRU de Montpellier, Montpellier, France
| | - Emmanuelle Bourrat
- Service de dermatologie, centre de référence maladies génétiques à expression cutanée MAGEC, CHU St-Louis, Service de pédiatrie générale, CHU Robert Debré, Paris, France
| | - Odile Boute
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Lille, Lille, France
| | - Nicolas Chassaing
- Service de Génétique Médicale et Centre de Compétence Anomalies du Développement et Syndromes Malformatifs, CHU Toulouse, Toulouse, France
| | - Christine Coubes
- Département de Génétique Médicale, Maladies rares et Médecine Personnalisée, et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHRU de Montpellier, Montpellier, France
| | - Bénédicte Demeer
- Centre d'Activité de Génétique Clinique et Oncogénétique, CHU d'Amiens, Amiens, France
| | - Patrick Edery
- Service de génétique, Centre de Référence Anomalies du Développement, Hospices Civils de Lyon, Bron, France
- INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Université Claude Bernard Lyon 1, Bron, France
| | - Salima El Chehadeh
- Service de Génétique Médicale, Centre de Référence Déficiences Intellectuelles de Causes Rares, Institut de Génétique Médicale d'Alsace (IGMA), CHRU de Strasbourg, Strasbourg, France
| | - Alice Goldenberg
- Service de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Rouen et Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France
| | - Smail Hadj-Rabia
- Service de Dermatologie et Centre de Référence des Maladies Rares Génétiques à Expression Cutanée (MAGEC), Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Universitaire Necker Enfants Malades, Paris, France
| | - Damien Haye
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHRU de Tours, Tours, France
| | - Bertrand Isidor
- Service de Génétique Médicale et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Nantes, Nantes, France
| | - Marie-Line Jacquemont
- Unité de Génétique Médicale et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de la Réunion, Saint-Pierre, France
| | - Philippe Khau Van Kien
- Unité de Génétique Médicale et Cytogénétique, Centre de Compétence Anomalies du Développement et Syndromes Malformatifs, CHU de Nîmes, Nîmes, France
| | - Didier Lacombe
- Service de Génétique Médicale et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Bordeaux, Bordeaux, France
| | - Daphné Lehalle
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
| | - Laetitia Lambert
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Nancy, Nancy, France
| | | | | | - Fanny Morice-Picard
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Nancy, Nancy, France
- Service de Dermatologie, CHU de Bordeaux, Bordeaux, France
| | - Florence Petit
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Lille, Lille, France
| | - Alice Phan
- Service de Dermatologie, CHU de Lyon, Lyon, France
| | - Lucile Pinson
- Département de Génétique Médicale, Maladies rares et Médecine Personnalisée, et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHRU de Montpellier, Montpellier, France
| | - Massimiliano Rossi
- Service de génétique, Centre de Référence Anomalies du Développement, Hospices Civils de Lyon, Bron, France
- INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Université Claude Bernard Lyon 1, Bron, France
| | - Renaud Touraine
- Service de Génétique Clinique et Centre de Compétence Anomalies du Développement et Syndromes Malformatifs, CHU de Saint-Etienne, Saint-Etienne, France
| | - Clémence Vanlerberghe
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Lille, Lille, France
| | - Marie Vincent
- Service de Génétique Médicale et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU de Nantes, Nantes, France
| | - Catherine Vincent-Delorme
- Service de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Lille, Lille, France
| | - Sandra Whalen
- Unité Fonctionnelle de Génétique Clinique, Hôpital Armand-Trousseau, Paris, France
| | - Marjolaine Willems
- Département de Génétique Médicale, Maladies rares et Médecine Personnalisée, et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHRU de Montpellier, Montpellier, France
| | - Nathalie Marle
- UF6254 Innovation en Diagnostic Génomique des Maladies Rares, Plate-forme de Biologie Hospitalo-Universitaire, CHU Dijon-Bourgogne, Dijon, France
| | - Virginie Verkarre
- Service d'Anatomie Pathologique, Hôpital Européen Georges Pompidou, Paris, France et INSERM UMR 970, Equipe 13, PARCC Université de Paris Cité, Paris, France
| | - Christine Devalland
- Service d'Anatomie Pathologique, Hôpital Nord Franche Comté, Trevenans, France
| | | | - Marine Abad
- Service d'Anatomie Pathologique, CHU Besançon, Besançon, France
| | | | | | - Yannis Duffourd
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
| | - Jehanne Martel
- Centre de référence Maladies Rares Génétiques à Expression Cutanée (MAGEC), CHU Dijon, Dijon, France
| | - Christine Binquet
- INSERM, Université de Bourgogne, CHU Dijon Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Paul Kuentz
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- Oncobiologie Génétique Bioinformatique, PCBio, CHU Besançon, Besançon, France
| | - Pierre Vabres
- Equipe INSERM UMR1231, Génétique des Anomalies du Développement, FHU TRANSLAD, Université Bourgogne Franche-Comté, Dijon, France
- Service de Dermatologie, CHU Dijon Bourgogne, Dijon, France
- Centre de référence Maladies Rares Génétiques à Expression Cutanée (MAGEC), CHU Dijon, Dijon, France
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Kim JK, Hansen A, Peard L, Newsome M, Saltzman AF. Bilateral Wilms Tumor in CLOVES Syndrome. Urology 2023; 177:178-180. [PMID: 36804444 DOI: 10.1016/j.urology.2023.01.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 01/22/2023] [Indexed: 02/18/2023]
Abstract
Wilms tumor is the most common pediatric renal mass and occurs in up to 10% of predisposition syndromes. One such syndrome is CLOVES syndrome, an extremely rare disorder within the umbrella of PIK3CA-related overgrowth spectrum disorders. This case presents the management of a bilateral Wilms tumor in a patient with CLOVES syndrome and highlights the many intricacies in caring for complex oncology patients. Particularly highlighted in this case is the delicate line in balancing the risks of treatment-related morbidity against the risks of recurrence in predisposed patients, while still abiding by established treatment guidelines.
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Affiliation(s)
- Joon Kyung Kim
- Department of Urology, University of Kentucky, Lexington, KY
| | - Anna Hansen
- College of Medicine, University of Kentucky, Lexington, KY
| | - Leslie Peard
- Department of Urology, University of Kentucky, Lexington, KY
| | - Matthew Newsome
- Department of Urology, University of Kentucky, Lexington, KY
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14
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Mehawej C, Chouery E, Al Hage Chehade G, Bejaoui Y, Mahfoud D, Gerges M, Delague V, El Hajj N, Megarbane A. Report on a Case with Moreno-Nishimura-Schmidt Overgrowth Syndrome: A Clinically Delineated Disease Yet of an Unknown Origin! Mol Syndromol 2023; 14:219-224. [PMID: 37323196 PMCID: PMC10267562 DOI: 10.1159/000527215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/23/2022] [Indexed: 12/03/2023] Open
Abstract
Introduction Overgrowth syndromes are a heterogeneous group of genetic disorders characterized by excessive growth, often accompanied by additional clinical features, such as facial dysmorphism, hormonal imbalances, cognitive impairment, and increased risk for neoplasia. Moreno-Nishimura-Schmidt (M-N-S) overgrowth syndrome is a very rare overgrowth syndrome characterized by severe pre- and postnatal overgrowth, dysmorphic facial features, kyphoscoliosis, large hands and feet, inguinal hernia, and distinctive skeletal features. The clinical and radiological features of the disorder have been well delineated, yet its molecular pathogenesis remains unclear. Case Presentation We report on a Lebanese boy with M-N-S syndrome, whose clinical manifestations were compared with those of previously reported 5 affected individuals. Whole-exome sequencing combined with comparative genome hybridization analysis failed to delineate the molecular basis of the phenotype. However, epigenetic studies revealed a different methylation status of several CpG sites between him and healthy controls, with methyltransferase activity showing the most significant enrichment. Conclusion An additional case of M-N-S syndrome recapitulated the clinical and radiological manifestations described in the previous reports. The data in the epigenetic studies implicated that abnormal methylations might play an essential role in development of the disease phenotype. However, additional studies in a clinically homogeneous cohort of patients are crucial to confirm this hypothesis.
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Affiliation(s)
- Cybel Mehawej
- Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - Eliane Chouery
- Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - Ghada Al Hage Chehade
- Pediatric Endocrinology and Diabetology, Pediatrics Department, Hammoud Hospital University Medical Center, Saida, Lebanon
- Pediatric Endocrinology and Diabetology, Pediatric Division, Saint George Hospital University Medical Center, Beirut, Lebanon
| | - Yosra Bejaoui
- College of Health and Life Sciences, Qatar Foundation, Education City, Hamad Bin Khalifa University, Doha, Qatar
| | - Daniel Mahfoud
- Department of Radiology, Gilbert and Rose-Marie Ghagoury School of Medicine, Lebanese American University, Byblos, Lebanon
| | - Maya Gerges
- Genetic Laboratory, American University of Science and Technology, Beirut, Lebanon
| | - Valérie Delague
- Inserm, MMG, U 1251, Institut Marseille Maladies Rares (MarMaRa), Aix Marseille University, Marseille, France
| | - Nady El Hajj
- College of Health and Life Sciences, Qatar Foundation, Education City, Hamad Bin Khalifa University, Doha, Qatar
| | - Andre Megarbane
- Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, Lebanon
- Institut Jérôme Lejeune, Paris, France
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15
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Parra A, Rabin R, Pappas J, Pascual P, Cazalla M, Arias P, Gallego-Zazo N, Santana A, Arroyo I, Artigas M, Pachajoa H, Alanay Y, Akgun-Dogan O, Ruaud L, Couque N, Levy J, Porras-Hurtado GL, Santos-Simarro F, Ballesta-Martinez MJ, Guillén-Navarro E, Muñoz-Hernández H, Nevado J, Tenorio-Castano J, Lapunzina P. Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature. Genes (Basel) 2023; 14:1179. [PMID: 37372360 DOI: 10.3390/genes14061179] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 05/25/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.
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Affiliation(s)
- Alejandro Parra
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Rachel Rabin
- Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA
| | - John Pappas
- Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA
- Clinical Genetics, NYU Orthopedic Hospital, New York, NY 10010, USA
| | - Patricia Pascual
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Mario Cazalla
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
| | - Pedro Arias
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Natalia Gallego-Zazo
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Alfredo Santana
- Clinical Genetics Unit, Complejo Hospitalario Universitario Insular-Materno Infantil de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain
| | - Ignacio Arroyo
- Pediatrics Department, San Pedro de Alcántara Hospital, 10003 Cáceres, Spain
| | - Mercè Artigas
- Genetics Unit, Hospital de Navarra, 31008 Pamplona, Spain
| | - Harry Pachajoa
- Fundación Valle del Lili, Universidad Icesi, 760032 Cali, Colombia
| | - Yasemin Alanay
- Division of Pediatric Genetics, Department of Pediatrics, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
- Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
| | - Ozlem Akgun-Dogan
- Division of Pediatric Genetics, Department of Pediatrics, Faculty of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
- Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey
| | - Lyse Ruaud
- Department of Genetics, APHP-Robert Debré University Hospital, 75019 Paris, France
- INSERM UMR1141, Neurodiderot, University of Paris Cité, 75019 Paris, France
| | - Nathalie Couque
- Department of Genetics, APHP-Robert Debré University Hospital, 75019 Paris, France
- Laboratoire de Biologie Médicale Multisites Seqoia-FMG2025, 75014 Paris, France
| | - Jonathan Levy
- Department of Genetics, APHP-Robert Debré University Hospital, 75019 Paris, France
- Laboratoire de Biologie Médicale Multisites Seqoia-FMG2025, 75014 Paris, France
| | | | - Fernando Santos-Simarro
- Unidad de Diagnóstico Molecular y Genética Clínica, Hospital Universitario Son Espases, Idisba, 07120 Palma de Mallorca, Spain
| | - Maria Juliana Ballesta-Martinez
- Sección de Genética Médica, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain
| | - Encarna Guillén-Navarro
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain
| | - Hugo Muñoz-Hernández
- Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8092 Zurich, Switzerland
| | - Julián Nevado
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Jair Tenorio-Castano
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Pablo Lapunzina
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28046 Madrid, Spain
- INGEMM-Idipaz, Institute of Medical and Molecular Genetics, 28046 Madrid, Spain
- ITHACA, European Reference Network, Hospital Universitario La Paz, 28046 Madrid, Spain
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Sedlack AJH, Hatfield SJ, Kumar S, Arakawa Y, Roper N, Sun NY, Nilubol N, Kiseljak-Vassiliades K, Hoang CD, Bergsland EK, Hernandez JM, Pommier Y, del Rivero J. Preclinical Models of Adrenocortical Cancer. Cancers (Basel) 2023; 15:2873. [PMID: 37296836 PMCID: PMC10251941 DOI: 10.3390/cancers15112873] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 06/12/2023] Open
Abstract
Adrenocortical cancer is an aggressive endocrine malignancy with an incidence of 0.72 to 1.02 per million people/year, and a very poor prognosis with a five-year survival rate of 22%. As an orphan disease, clinical data are scarce, meaning that drug development and mechanistic research depend especially on preclinical models. While a single human ACC cell line was available for the last three decades, over the last five years, many new in vitro and in vivo preclinical models have been generated. Herein, we review both in vitro (cell lines, spheroids, and organoids) and in vivo (xenograft and genetically engineered mouse) models. Striking leaps have been made in terms of the preclinical models of ACC, and there are now several modern models available publicly and in repositories for research in this area.
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Affiliation(s)
- Andrew J. H. Sedlack
- Medical Scientist Training Program, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Samual J. Hatfield
- Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Suresh Kumar
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Yasuhiro Arakawa
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Nitin Roper
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Nai-Yun Sun
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Naris Nilubol
- Surgical Oncology Program National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Katja Kiseljak-Vassiliades
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO 80016, USA
| | - Chuong D. Hoang
- Thoracic Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Emily K. Bergsland
- University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | | | - Yves Pommier
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Jaydira del Rivero
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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17
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Abstract
Adrenal cortical carcinoma (ACC) is a rare and aggressive malignancy that poses challenging issues regarding the diagnostic workup. Indeed, no presurgical technique or clinical parameters can reliably distinguish between adrenal cortical adenomas, which are more frequent and have a favorable outcome, and ACC, and the final diagnosis largely relies on histopathologic analysis of the surgical specimen. However, even the pathologic assessment of malignancy in an adrenal cortical lesion is not straightforward and requires a combined evaluation of multiple histopathologic features. Starting from the Weiss score, which was developed in 1984, several histopathologic scoring systems have been designed to tackle the difficulties of ACC diagnosis. Dealing with specific histopathologic variants (eg, Liss-Weiss-Bisceglia scoring system for oncocytic ACC) or patient characteristics (eg, Wieneke index in the pediatric setting), these scores remarkably improved the diagnostic workup of ACC and its subtypes. Nevertheless, cases with misleading features or discordant correlations between pathologic findings and clinical behavior still occur. Owing to multicentric collaborative studies integrating morphologic features with ancillary immunohistochemical markers and molecular analysis, ACC has eventually emerged as a multifaceted, heterogenous malignancy, and, while innovative and promising approaches are currently being tested, the future clinical management of patients with ACC will mainly rely on personalized medicine and target-therapy protocols. At the dawn of the new Fifth World Health Organization classification of endocrine tumors, this review will tackle ACC from the pathologist's perspective, thus focusing on the main available diagnostic, prognostic, and predictive tissue-tethered features and biomarkers and providing relevant clinical and molecular correlates.
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18
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Nussbaumer G, Benesch M. Hepatoblastoma in molecularly defined, congenital diseases. Am J Med Genet A 2022; 188:2527-2535. [PMID: 35478319 PMCID: PMC9545988 DOI: 10.1002/ajmg.a.62767] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 03/21/2022] [Accepted: 04/09/2022] [Indexed: 01/24/2023]
Abstract
Beckwith-Wiedemann spectrum, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18 are the most common congenital conditions associated with an increased incidence of hepatoblastoma (HB). In patients with these genetic disorders, screening protocols for HB are proposed that include periodic abdominal ultrasound and measurement of alpha-fetoprotein levels. Surveillance in these children may contribute to the early detection of HB and possibly improve their chances of overall survival. Therefore, physicians must be aware of the high HB incidence in children with certain predisposing genetic diseases.
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Affiliation(s)
- Gunther Nussbaumer
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent MedicineMedical University of GrazGrazAustria
| | - Martin Benesch
- Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent MedicineMedical University of GrazGrazAustria
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19
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Marques P, Korbonits M. Approach to the Patient With Pseudoacromegaly. J Clin Endocrinol Metab 2022; 107:1767-1788. [PMID: 34792134 DOI: 10.1210/clinem/dgab789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Indexed: 11/19/2022]
Abstract
Pseudoacromegaly encompasses a heterogeneous group of conditions in which patients have clinical features of acromegaly or gigantism, but no excess of GH or IGF-1. Acromegaloid physical features or accelerated growth in a patient may prompt referral to endocrinologists. Because pseudoacromegaly conditions are rare and heterogeneous, often with overlapping clinical features, the underlying diagnosis may be challenging to establish. As many of these have a genetic origin, such as pachydermoperiostosis, Sotos syndrome, Weaver syndrome, or Cantú syndrome, collaboration is key with clinical geneticists in the diagnosis of these patients. Although rare, awareness of these uncommon conditions and their characteristic features will help their timely recognition.
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Affiliation(s)
- Pedro Marques
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
- Endocrinology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisboa, Portugal
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK
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20
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Colafati GS, Piccirilli E, Marrazzo A, Carboni A, Diociaiuti A, El Hachem M, Esposito F, Zama M, Rollo M, Gandolfo C, Tomà P. Vascular lesions of the pediatric orbit: A radiological walkthrough. Front Pediatr 2022; 10:734286. [PMID: 36533238 PMCID: PMC9748295 DOI: 10.3389/fped.2022.734286] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/03/2022] [Indexed: 12/05/2022] Open
Abstract
Vascular anomalies of the pediatric orbit represent a heterogeneous group that include both vascular tumors and vascular malformations. The disorder may initially be silent and then associated with symptoms and/or function damage, depending on the type of vascular anomaly and its extension. Vascular tumors include benign, locally aggressive (or borderline) and malignant forms while vascular malformations are divided into "simple", "combined" and syndromic, or "low flow" or "high flow". Both entities can arise in isolation or as part of syndromes. In this review, we describe the imaging findings of the vascular lesions of the orbit in the pediatric population, which are key to obtain a correct diagnosis and to guide the appropriate treatment in the light of the new genetic and molecular discoveries, and the role of the radiologist in their multidisciplinary management. We will also touch upon the main syndromes associated with orbital vascular abnormalities.
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Affiliation(s)
| | - Eleonora Piccirilli
- Department of Neuroscience, Imaging and Clinical Science, University "G. d'Annunzio" of Chieti, Chieti, Italy
| | - Antonio Marrazzo
- Neuroradiology Unit, Department of Imaging, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Alessia Carboni
- Neuroradiology Unit, Department of Imaging, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Andrea Diociaiuti
- Dermatology Unit and Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - May El Hachem
- Dermatology Unit and Genodermatosis Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Francesco Esposito
- Department of Radiology, Santobono-Pausilipon Children Hospital, Naples, Italy
| | - Mario Zama
- Craniofacial Centre-Plastic and Maxillofacial Surgery Unit, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Massimo Rollo
- Department of Imaging, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Carlo Gandolfo
- Neuroradiology Unit, Department of Imaging, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Paolo Tomà
- Department of Imaging, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
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21
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Pitsava G, Maria AG, Faucz FR. Disorders of the adrenal cortex: Genetic and molecular aspects. Front Endocrinol (Lausanne) 2022; 13:931389. [PMID: 36105398 PMCID: PMC9465606 DOI: 10.3389/fendo.2022.931389] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
Adrenal cortex produces glucocorticoids, mineralocorticoids and adrenal androgens which are essential for life, supporting balance, immune response and sexual maturation. Adrenocortical tumors and hyperplasias are a heterogenous group of adrenal disorders and they can be either sporadic or familial. Adrenocortical cancer is a rare and aggressive malignancy, and it is associated with poor prognosis. With the advance of next-generation sequencing technologies and improvement of genomic data analysis over the past decade, various genetic defects, either from germline or somatic origin, have been unraveled, improving diagnosis and treatment of numerous genetic disorders, including adrenocortical diseases. This review gives an overview of disorders associated with the adrenal cortex, the genetic factors of these disorders and their molecular implications.
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Affiliation(s)
- Georgia Pitsava
- Division of Intramural Research, Division of Population Health Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States
| | - Andrea G. Maria
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States
| | - Fabio R. Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States
- Molecular Genomics Core (MGC), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States
- *Correspondence: Fabio R. Faucz,
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22
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Maciaszek JL, Oak N, Nichols KE. Recent advances in Wilms' tumor predisposition. Hum Mol Genet 2021; 29:R138-R149. [PMID: 32412586 DOI: 10.1093/hmg/ddaa091] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/01/2020] [Accepted: 05/12/2020] [Indexed: 12/13/2022] Open
Abstract
Wilms' tumor (WT), the most common childhood kidney cancer, develops in association with an underlying germline predisposition in up to 15% of cases. Germline alterations affecting the WT1 gene and epigenetic alterations affecting the 11p15 locus are associated with a selective increase in WT risk. Nevertheless, WT also occurs in the context of more pleiotropic cancer predispositions, such as DICER1, Li-Fraumeni and Bloom syndrome, as well as Fanconi anemia. Recent germline genomic investigations have increased our understanding of the host genetic factors that influence WT risk, with sequencing of rare familial cases and large WT cohorts revealing an expanding array of predisposition genes and associated genetic conditions. Here, we describe evidence implicating WT1, the 11p15 locus, and the recently identified genes CTR9, REST and TRIM28 in WT predisposition. We discuss the clinical features, mode of inheritance and biological aspects of tumorigenesis, when known. Despite these described associations, many cases of familial WT remain unexplained. Continued investigations are needed to fully elucidate the landscape of germline genetic alterations in children with WT. Establishing a genetic diagnosis is imperative for WT families so that individuals harboring a predisposing germline variant can undergo surveillance, which should enable the early detection of tumors and use of less intensive treatments, thereby leading to improved overall outcomes.
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Affiliation(s)
- Jamie L Maciaszek
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Ninad Oak
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Kim E Nichols
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
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23
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Pediatric onco-nephrology: time to spread the word : Part I: early kidney involvement in children with malignancy. Pediatr Nephrol 2021; 36:2227-2255. [PMID: 33245421 DOI: 10.1007/s00467-020-04800-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/28/2020] [Accepted: 09/25/2020] [Indexed: 12/29/2022]
Abstract
Onco-nephrology has been a growing field within the adult nephrology scope of practice. Even though pediatric nephrologists have been increasingly involved in the care of children with different forms of malignancy, there has not been an emphasis on developing special expertise in this area. The fast pace of discovery in this field, including the development of new therapy protocols with their own kidney side effects and the introduction of the CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy, has introduced new challenges for general pediatric nephrologists because of the unique effects of these treatments on the kidney. Moreover, with the improved outcomes in children receiving cancer therapy come an increased number of survivors at risk for chronic kidney disease related to both their cancer diagnosis and therapy. Therefore, it is time for pediatric onco-nephrology to take its spot on the expanding subspecialties map in pediatric nephrology.
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Hol JA, Jewell R, Chowdhury T, Duncan C, Nakata K, Oue T, Gauthier-Villars M, Littooij AS, Kaneko Y, Graf N, Bourdeaut F, van den Heuvel-Eibrink MM, Pritchard-Jones K, Maher ER, Kratz CP, Jongmans MCJ. Wilms tumour surveillance in at-risk children: Literature review and recommendations from the SIOP-Europe Host Genome Working Group and SIOP Renal Tumour Study Group. Eur J Cancer 2021; 153:51-63. [PMID: 34134020 DOI: 10.1016/j.ejca.2021.05.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/02/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022]
Abstract
Since previous consensus-based Wilms tumour (WT) surveillance guidelines were published, novel genes and syndromes associated with WT risk have been identified, and diagnostic molecular tests for previously known syndromes have improved. In view of this, the International Society of Pediatric Oncology (SIOP)-Europe Host Genome Working Group and SIOP Renal Tumour Study Group hereby present updated WT surveillance guidelines after an extensive literature review and international consensus meetings. These guidelines are for use by clinical geneticists, pediatricians, pediatric oncologists and radiologists involved in the care of children at risk of WT. Additionally, we emphasise the need to register all patients with a cancer predisposition syndrome in national or international databases, to enable the development of better tumour risk estimates and tumour surveillance programs in the future.
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Affiliation(s)
- Janna A Hol
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Rosalyn Jewell
- Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
| | - Tanzina Chowdhury
- Great Ormond Street Hospital for Children, London, United Kingdom; University College London Great Ormond Street Institute of Child Health, University College London, United Kingdom
| | - Catriona Duncan
- Great Ormond Street Hospital for Children, London, United Kingdom
| | - Kayo Nakata
- Cancer Control Center, Osaka International Cancer Institute, Osaka, Japan
| | - Takaharu Oue
- Department of Pediatric Surgery, Hyōgo College of Medicine, Nishinomiya, Hyōgo, Japan
| | | | - Annemieke S Littooij
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Yasuhiko Kaneko
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan
| | - Norbert Graf
- Department of Pediatric Oncology & Hematology, Saarland University, Homburg, Germany
| | - Franck Bourdeaut
- SIREDO Pediatric Oncology Center, Institut Curie Hospital, Paris, France
| | | | - Kathy Pritchard-Jones
- Great Ormond Street Hospital for Children, London, United Kingdom; University College London Great Ormond Street Institute of Child Health, University College London, United Kingdom
| | - Eamonn R Maher
- Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Christian P Kratz
- Department of Pediatric Hematology and Oncology & Rare Disease Program, Hannover Medical School, Center for Pediatrics and Adolescent Medicine, Hannover, Germany
| | - Marjolijn C J Jongmans
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht / Wilhelmina Children's Hospital, Utrecht, the Netherlands.
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Affiliation(s)
- John S Fuqua
- Indiana University School of Medicine, 705 Riley Hospital Drive, Room 5960, Indianapolis, IN 46202, USA.
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26
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Tenorio-Castaño JA, Arias P, Fernández-Jaén A, Lay-Son G, Bueno-Lozano G, Bayat A, Faivre L, Gallego N, Ramos S, Butler KM, Morel C, Hadjiyannakis S, Lespinasse J, Tran-Mau-Them F, Santos-Simarro F, Pinson L, Martínez-Monseny AF, O'Callaghan Cord MDM, Álvarez S, Stolerman ES, Washington C, Ramos FJ, The S O G R I Consortium, Lapunzina P. Tenorio syndrome: Description of 14 novel cases and review of the clinical and molecular features. Clin Genet 2021; 100:405-411. [PMID: 34196401 DOI: 10.1111/cge.14020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 11/28/2022]
Abstract
Tenorio syndrome (TNORS) (OMIM #616260) is a relatively recent disorder with very few cases described so far. Clinical features included macrocephaly, intellectual disability, hypotonia, enlarged ventricles and autoimmune diseases. Molecular underlying mechanism demonstrated missense variants and a large deletion encompassing RNF125, a gene that encodes for an U3 ubiquitin ligase protein. Since the initial description of the disorder in six patients from four families, several new patients were diagnosed, adding more evidence to the clinical spectrum. In this article, we described 14 additional cases with deep phenotyping and make an overall review of all the cases with pathogenic variants in RNF125. Not all patients presented with overgrowth, but instead, most patients showed a common pattern of neurodevelopmental disease, macrocephaly and/or large forehead. Segregation analysis showed that, though the variant was inherited in some patients from an apparently asymptomatic parent, deep phenotyping suggested a mild form of the disease in some of them. The mechanism underlying the development of this disease is not well understood yet and the report of further cases will help to a better understanding and clinical characterization of the syndrome.
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Affiliation(s)
- Jair Antonio Tenorio-Castaño
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Overgrowth Syndromes Laboratory, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Ithaca, European Reference Network, Brussels, Belgium
| | - Pedro Arias
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Overgrowth Syndromes Laboratory, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | | | - Guillermo Lay-Son
- Unidad de Genética, División de Pediatría, Facultad de Medicina, Pontificia Universidad Católica de, Chile
| | - Gloria Bueno-Lozano
- Unit of Clinical Genetics, Service of Paediatrics, School of Medicine, University Hospital 'Lozano Blesa, University of Zaragoza, CIBERER-GCV02 and ISS-Aragón, Zaragoza, Spain
| | - Allan Bayat
- Department of Pediatrics, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Laurence Faivre
- Ithaca, European Reference Network, Brussels, Belgium.,Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.,UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
| | - Natalia Gallego
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Overgrowth Syndromes Laboratory, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Ithaca, European Reference Network, Brussels, Belgium
| | - Sergio Ramos
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Overgrowth Syndromes Laboratory, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Kameryn M Butler
- Cytogenetics Laboratory, Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Chantal Morel
- University Health Network, Fred A. Litwin Family Centre in Genetic Medicine, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Stasia Hadjiyannakis
- Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
| | - James Lespinasse
- Service de Cytogenetique, Centre Hospitalier de Chambéry, Chambéry, France
| | - Frederic Tran-Mau-Them
- UF6254 Innovation en Diagnostic Genomique des Maladies Rares Bat, Pôle de Biologie, CHU, Dijon, France
| | - Fernando Santos-Simarro
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Ithaca, European Reference Network, Brussels, Belgium.,Clinical Genetics section, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Lucile Pinson
- Départment de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Montpellier, France
| | - Antonio Federico Martínez-Monseny
- Clinical Genetics section, Department of Genetic and Molecular Medicine and Pediatric Institute of Rare Diseases (IPER), Hospital Sant Joan de Déu, Barcelona, Spain.,Department of Pediatric Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
| | - María Del Mar O'Callaghan Cord
- Clinical Genetics section, Department of Genetic and Molecular Medicine and Pediatric Institute of Rare Diseases (IPER), Hospital Sant Joan de Déu, Barcelona, Spain
| | - Sara Álvarez
- NIMGENETICS, Calle de Anabel Segura, Madrid, Spain
| | - Elliot S Stolerman
- Cytogenetics Laboratory, Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Camerun Washington
- Cytogenetics Laboratory, Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Feliciano J Ramos
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Unit of Clinical Genetics, Service of Paediatrics, School of Medicine, University Hospital 'Lozano Blesa, University of Zaragoza, CIBERER-GCV02 and ISS-Aragón, Zaragoza, Spain.,Unit of Pediatric Endocrinology, Service of Paediatrics, University Hospital Lozano Blesa, Zaragoza, Spain
| | - The S O G R I Consortium
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Overgrowth Syndromes Laboratory, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Pablo Lapunzina
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.,Overgrowth Syndromes Laboratory, INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.,Ithaca, European Reference Network, Brussels, Belgium
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Dangles MT, Davous D, Vialle G, Auvrignon A, Angellier E, Bourdeaut F. [Intellectual disability and cancer in children: An analysis of the decision-making process]. Bull Cancer 2021; 108:813-826. [PMID: 34176585 DOI: 10.1016/j.bulcan.2021.02.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/21/2021] [Accepted: 02/26/2021] [Indexed: 11/25/2022]
Abstract
AIM The aim was to describe and to analyze the ethics of decision-making in situations involving children with intellectual disability and cancer, from the referent-doctor's point-of-view, in pediatric oncology units in France. METHODS Pediatricians working in pediatric oncology units were interviewed through an online questionnaire and a semi-directive interview was systematically proposed. We analyzed the ethical issues that arose during the process of decision-making and we made suggestions in order to address them. RESULTS Sixteen doctors reported twenty-one clinical cases. Of these cases, one third of the children had a change in their oncologic treatment, with a risk of pejorative outcome on the prognosis. Despite the fact that ethical issues appeared in 80 % of the cases, there were few consultations with ethical committees. Decision-making process showed no difference compared to children without intellectual disability, thus raising ethical issues in the medical team. Our study showed discrepancy between frequently reported ethical issues, high consensus rate regarding treatment decision and lack of consultation with ethical committees. DISCUSSION We propose three steps to guide the decision-making process in situations involving children with intellectual disability and cancer: 1/deeper understanding of the child through reinforced interactions with their caregivers, 2/better cross-boundary discussions, to improve the effectiveness of the multidisciplinary staff, and 3/more systematic ethical committees consultation.
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Affiliation(s)
- Marie-Thérèse Dangles
- Hôpital Necker-Enfants-Malades, service de neurologie pédiatrique, 149, rue de Sèvres, 75015 Paris, France; Université de Paris, Paris, France.
| | - Dominique Davous
- Hôpital Saint-Louis, groupe de réflexion et de recherche au sein de l'espace éthique région Île-de-France : parents et soignants face à l'éthique en pédiatrie, 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Guénola Vialle
- Chargée de mission PALIPED-RIFHOP, réseau d'Île-de-France pour l'hématologie, l'oncologie et les soins palliatifs pédiatrique, 3-5, rue de Metz, 75010 Paris, France
| | - Anne Auvrignon
- Hôpital Armand-Trousseau, service d'hématologie pédiatrique, 26, avenue du Dr Arnold-Netter, 75012 Paris, France
| | - Elisabeth Angellier
- Institut Curie, département interdisciplinaire de soins de support pour le patient en oncologie (DISSPO), 35, rue Dailly, 92210 Saint-Cloud, France
| | - Franck Bourdeaut
- Institut Curie, service d'oncologie pédiatrique, SIREDO, 26, rue d'Ulm, 75005 Paris, France
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Farid Aql MM, Bahget SAEG, Kholoussi N, Abdel-Salam GMEH, Abdel Raouf H, Mohamed Eid M, Esmail REB. Telomerase Dysfunction in the Tumorigenesis of Genetic Disorders. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2021; 10:56-68. [PMID: 34268254 PMCID: PMC8256828 DOI: 10.22088/ijmcm.bums.10.1.56] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/25/2021] [Indexed: 12/03/2022]
Abstract
Telomeres are nucleoprotein complexes present at the ends of chromosome to maintain its integrity. Telomere length is maintained by an enzyme called "telomerase". Thus, telomerase activity and telomere length are crucial for the initiation of cancer and tumors survival. Also, oxidative stress will cause DNA, protein, and/or lipid damage, which end with changes in chromosome instability, genetic mutation, and may affect cell growth and lead to cancer. Some genetic diseases such as chromosomal instability syndrome, overgrowth syndrome, and neurofibromatosis make the patients at higher risk for developing different types of cancers. Therefore, we aimed to estimate telomerase activity and oxidative stress in these patients. Blood samples were collected from 31 patients (10 with neurofibromatosis, 11 with chromosomal breakage, and 10 with overgrowth syndrome) and 12 healthy subjects. Blood hTERT mRNA was detected by real time quantitative reverse-transcription PCR (RT-qPCR). All patients were subjected to chromosomal examination and chromosome breakage study using diepoxybutane method. Moreover, serum glutathione (GSH), glutathione-s-transferase (GST) activity and nitric oxide (NO) levels were measured among the control and patients groups. Receiver operating characteristic (ROC) curve was drawn to evaluate the efficiency of telomerase activity as a biomarker for the prediction of cancer occurrence. The relative telomerase activity in neurofibromatosis patients was significantly higher than controls (P = 0.014), while it was non-significantly higher in chromosomal breakage and overgrowth patients (P = 0.424 and 0.129, respectively). NO levels in neurofibromatosis, chromosomal breakage and overgrowth patients significantly increased with respect to control (P = 0.021, 0.002, 0.050, respectively). GSH levels were non-significantly lower in neurofibromatosis and chromosomal breakage patients in comparison with the control group, while it remained unchanged in overgrowth patients. The GST activity was significantly upregulated in neurofibromatosis, chromosomal breakage and overgrowth groups in comparison with the control group (P = 0.001, 0.009, and 0.025, respectively). Chromosomal examination revealed normal karyotype in all four chromosomal breakage patients with positive diepoxybutane test. The results of the present study revealed altered telomerase activity and oxidative stress in the studied genetic disorders. More research studies with a larger number of patients are required to confirm whether this alteration is related to cancer occurrence risk or not.
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Affiliation(s)
| | | | - Naglaa Kholoussi
- Immunogenetic Department, National Research Centre, Cairo, Egypt
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Martínez-Glez V, Tenorio J, Nevado J, Gordo G, Rodríguez-Laguna L, Feito M, de Lucas R, Pérez-Jurado LA, Ruiz Pérez VL, Torrelo A, Spinner NB, Happle R, Biesecker LG, Lapunzina P. A six-attribute classification of genetic mosaicism. Genet Med 2020; 22:1743-1757. [PMID: 32661356 PMCID: PMC8581815 DOI: 10.1038/s41436-020-0877-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/12/2020] [Accepted: 06/12/2020] [Indexed: 01/23/2023] Open
Abstract
Mosaicism denotes an individual who has at least two populations of cells with distinct genotypes that are derived from a single fertilized egg. Genetic variation among the cell lines can involve whole chromosomes, structural or copy-number variants, small or single-nucleotide variants, or epigenetic variants. The mutational events that underlie mosaic variants occur during mitotic cell divisions after fertilization and zygote formation. The initiating mutational event can occur in any types of cell at any time in development, leading to enormous variation in the distribution and phenotypic effect of mosaicism. A number of classification proposals have been put forward to classify genetic mosaicism into categories based on the location, pattern, and mechanisms of the disease. We here propose a new classification of genetic mosaicism that considers the affected tissue, the pattern and distribution of the mosaicism, the pathogenicity of the variant, the direction of the change (benign to pathogenic vs. pathogenic to benign), and the postzygotic mutational mechanism. The accurate and comprehensive categorization and subtyping of mosaicisms is important and has potential clinical utility to define the natural history of these disorders, tailor follow-up frequency and interventions, estimate recurrence risks, and guide therapeutic decisions.
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Affiliation(s)
- Víctor Martínez-Glez
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
- Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain.
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium.
| | - Jair Tenorio
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium
| | - Julián Nevado
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium
| | - Gema Gordo
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain
| | - Lara Rodríguez-Laguna
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain
| | - Marta Feito
- Department of Pediatric Dermatology, Hospital Universitario La Paz-UAM, Madrid, Spain
| | - Raúl de Lucas
- Department of Pediatric Dermatology, Hospital Universitario La Paz-UAM, Madrid, Spain
| | - Luis A Pérez-Jurado
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- Genetics Unit, Universitat Pompeu Fabra and Hospital del Mar Research Institute (IMIM), Barcelona, Spain
- Women's and Children's Hospital, South Australia Medical and Health Research Institute (SAHMRI) and University of Adelaide, Adelaide, SA, Australia
| | - Víctor L Ruiz Pérez
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium
- Instituto de Investigaciones Biomédicas de Madrid (CSIC-UAM), Madrid, Spain
| | - Antonio Torrelo
- Department of Pediatrics, Hospital Universitario Niño Jesús, Madrid, Spain
| | - Nancy B Spinner
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicines at The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Rudolf Happle
- Department of Dermatology, Medical Center-University of Freiburg, Freiburg, Germany
| | - Leslie G Biesecker
- Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD, USA
| | - Pablo Lapunzina
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
- Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM, Madrid, Spain.
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Brussels, Belgium.
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Semmes EC, Shen E, Cohen JL, Zhang C, Wei Q, Hurst JH, Walsh KM. Genetic variation associated with childhood and adult stature and risk of MYCN-amplified neuroblastoma. Cancer Med 2020; 9:8216-8225. [PMID: 32945147 PMCID: PMC7643638 DOI: 10.1002/cam4.3458] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/07/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
Background Neuroblastoma is the most common pediatric solid tumor. MYCN‐amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes. Methods We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN‐amplification status, and compared to 3390 European‐ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature. Results An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre‐pubertal height, was associated with greater risk of MYCN‐amplified neuroblastoma (OR = 1.14, P = .047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN‐amplified neuroblastoma (OR = 0.87, P = .047). These associations persisted in case‐case analyses comparing MYCN‐amplified to MYCN‐unamplified neuroblastoma. No polygenic height scores were associated with MYCN‐unamplified neuroblastoma risk. Previously identified genome‐wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10−3) and adult height (P = 8.9 × 10−3) in >250 000 UK Biobank study participants. Conclusions Genetic propensity to taller childhood height and shorter adult height were associated with MYCN‐amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN‐amplified neuroblastoma etiology.
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Affiliation(s)
- Eleanor C Semmes
- Medical Scientist Training Program, Duke University, Durham, NC, USA.,Department of Pediatrics, Children's Health and Discovery Institute, Duke University, Durham, NC, USA
| | - Erica Shen
- Division of Neuro-epidemiology, Department of Neurosurgery, Duke University, Durham, NC, USA
| | - Jennifer L Cohen
- Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC, USA
| | - Chenan Zhang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
| | - Qingyi Wei
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA.,Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
| | - Jillian H Hurst
- Department of Pediatrics, Children's Health and Discovery Institute, Duke University, Durham, NC, USA
| | - Kyle M Walsh
- Department of Pediatrics, Children's Health and Discovery Institute, Duke University, Durham, NC, USA.,Division of Neuro-epidemiology, Department of Neurosurgery, Duke University, Durham, NC, USA.,Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.,Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA.,Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
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31
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Papulino C, Chianese U, Nicoletti MM, Benedetti R, Altucci L. Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome. Front Genet 2020; 11:563718. [PMID: 33101381 PMCID: PMC7522569 DOI: 10.3389/fgene.2020.563718] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 08/26/2020] [Indexed: 12/26/2022] Open
Abstract
Epigenetics has achieved a profound impact in the biomedical field, providing new experimental opportunities and innovative therapeutic strategies to face a plethora of diseases. In the rare diseases scenario, Beckwith-Wiedemann syndrome (BWS) is a pediatric pathological condition characterized by a complex molecular basis, showing alterations in the expression of different growth-regulating genes. The molecular origin of BWS is associated with impairments in the genomic imprinting of two domains at the 11p15.5 chromosomal region. The first domain contains three different regions: insulin growth like factor gene (IGF2), H19, and abnormally methylated DMR1 region. The second domain consists of cell proliferation and regulating-genes such as CDKN1C gene encoding for cyclin kinase inhibitor its role is to block cell proliferation. Although most cases are sporadic, about 5-10% of BWS patients have inheritance characteristics. In the 11p15.5 region, some of the patients have maternal chromosomal rearrangements while others have Uniparental Paternal Disomy UPD(11)pat. Defects in DNA methylation cause alteration of genes and the genomic structure equilibrium leading uncontrolled cell proliferation, which is a typical tumorigenesis event. Indeed, in BWS patients an increased childhood tumor predisposition is observed. Here, we summarize the latest knowledge on BWS and focus on the impact of epigenetic alterations to an increased cancer risk development and to metabolic disorders. Moreover, we highlight the correlation between assisted reproductive technologies and this rare disease. We also discuss intriguing aspects of BWS in twinning. Epigenetic therapies in clinical trials have already demonstrated effectiveness in oncological and non-oncological diseases. In this review, we propose a potential "epigenetic-based" approaches may unveil new therapeutic options for BWS patients. Although the complexity of the syndrome is high, patients can be able to lead a normal life but tumor predispositions might impair life expectancy. In this sense epigenetic therapies should have a supporting role in order to guarantee a good prognosis.
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Affiliation(s)
- Chiara Papulino
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Ugo Chianese
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Maddalena Nicoletti
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Rosaria Benedetti
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Lucia Altucci
- Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
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Chehade M, Bullock M, Glover A, Hutvagner G, Sidhu S. Key MicroRNA's and Their Targetome in Adrenocortical Cancer. Cancers (Basel) 2020; 12:E2198. [PMID: 32781574 PMCID: PMC7465134 DOI: 10.3390/cancers12082198] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 12/23/2022] Open
Abstract
Adrenocortical Carcinoma (ACC) is a rare but aggressive malignancy with poor prognosis and limited response to available systemic therapies. Although complete surgical resection gives the best chance for long-term survival, ACC has a two-year recurrence rate of 50%, which poses a therapeutic challenge. High throughput analyses focused on characterizing the molecular signature of ACC have revealed specific micro-RNAs (miRNAs) that are associated with aggressive tumor phenotypes. MiRNAs are small non-coding RNA molecules that regulate gene expression by inhibiting mRNA translation or degrading mRNA transcripts and have been generally implicated in carcinogenesis. This review summarizes the current insights into dysregulated miRNAs in ACC tumorigenesis, their known functions, and specific targetomes. In addition, we explore the possibility of particular miRNAs to be exploited as clinical biomarkers in ACC and as potential therapeutics.
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Affiliation(s)
- Marthe Chehade
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
| | - Martyn Bullock
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
| | - Anthony Glover
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
- Endocrine Surgery Unit, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St. Leonards, Sydney, NSW 2007, Australia
| | - Gyorgy Hutvagner
- School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Stan Sidhu
- Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia; (M.C.); (M.B.); (A.G.)
- Sydney Medical School Northern, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia
- Endocrine Surgery Unit, Royal North Shore Hospital, Northern Clinical School, Faculty of Medicine and Health, The University of Sydney, St. Leonards, Sydney, NSW 2007, Australia
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Abstract
Advances in genomics over the past two decades have allowed for elucidation of the genetic alterations leading to the development of adrenocortical tumors and/or hyperplasias. These molecular changes were initially discovered through the study of rare familial tumor syndromes such as McCune-Albright Syndrome, Carney complex, Li-Fraumeni syndrome, and Beckwith-Wiedemann syndrome, with the identification of alterations in genes and molecular pathways that subsequently led to the discovery of aberrations in these or related genes and pathways in sporadic tumors. Genetic alterations in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B, that lead to aberrant cyclic adenosine monophosphate-protein (cAMP) kinase A signaling, were found to play a major role in the development of benign cortisol-producing adrenocortical tumors and/or hyperplasias, whereas genetic defects in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2 were implicated in the development of benign aldosterone-producing tumors and/or hyperplasias through modification of intracellular calcium signaling. Germline ARMC5 defects were found to cause the development of primary bilateral macronodular adrenocortical hyperplasia with glucocorticoid and/or mineralocorticoid oversecretion. Adrenocortical carcinoma was linked primarily to aberrant p53 signaling and/or Wnt-β-catenin signaling, as well as IGF2 overexpression, with frequent genetic alterations in TP53, ZNRF3, CTNNB1, and 11p15. This review focuses on the genetic underpinnings of benign cortisol- and aldosterone-producing adrenocortical tumors/hyperplasias and adrenocortical carcinoma.
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Affiliation(s)
- Crystal D C Kamilaris
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Fellowship Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Fady Hannah-Shmouni
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Fellowship Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Fellowship Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
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Griff JR, Duffy KA, Kalish JM. Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth. Front Pediatr 2020; 8:613260. [PMID: 33392121 PMCID: PMC7773942 DOI: 10.3389/fped.2020.613260] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/03/2020] [Indexed: 12/26/2022] Open
Abstract
Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of the body. Some overgrowth syndromes, characterized by both generalized and lateralized overgrowth, have been associated with an increased risk of tumor development. This may be due to the underlying genetic and epigenetic defects that lead to disrupted cell growth and proliferation pathways resulting in the overgrowth and tumor phenotypes. This chapter focuses on the four most common syndromes characterized by LO: Beckwith-Wiedemann spectrum (BWSp), PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome (PS), and PTEN hamartoma tumor syndrome (PHTS). These syndromes demonstrate variable risks for tumor development in patients affected by LO, and we provide a comprehensive literature review of all common tumors reported in patients diagnosed with an LO-related disorder. This review summarizes the current data on tumor risk among these disorders and their associated tumor screening guidelines. Furthermore, this chapter highlights the importance of an accurate diagnosis when a patient presents with LO as similar phenotypes are associated with different tumor risks, thereby altering preventative screening protocols.
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Affiliation(s)
- Jessica R Griff
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Kelly A Duffy
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jennifer M Kalish
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Departments of Genetics and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Abstract
Vascular tumors in pediatric patients are an important entity for the clinician to recognize and correctly diagnose. They may present at birth or develop at any point during infancy, childhood, or adolescence. Most are benign, but even benign lesions may have significant morbidity without proper intervention. Malignant vascular tumors are also rarely seen in the pediatric population, and may be associated with various syndromes.
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Affiliation(s)
- Harriet Bagnal Hinen
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, United States
| | - Cameron C Trenor
- Division of Hematology/Oncology, Vascular Anomalies Center, Boston Children's Hospital, Boston, MA, United States
| | - Lara Wine Lee
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, United States
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Elnaw EAA, Abdalla AR, Abdullah MA. Adrenocortical adenoma in a Sudanese girl with Beckwith-Wiedemann syndrome. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2019; 2019:6. [PMID: 31768183 PMCID: PMC6873727 DOI: 10.1186/s13633-019-0068-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 10/16/2019] [Indexed: 11/10/2022]
Abstract
Background We report a case of right adrenocortical adenoma in a girl with features suggestive of Beckwith Wiedemann syndrome to show the importance of tumor surveillance in patients with Beckwith Wiedemann syndrome. Case presentation A 4-years-old female with features suggestive of Beckwith-Wiedemann syndrome presented with 9 months history of virilization. Hormonal investigations results showed high levels of testosterone (2.3 ng/ml, normal values 0.1-0.4 ng/ml), and DHEAS (73 ng/ml normal values 1-6 ng/ml) with normal cortisol level. Computed tomography revealed a right adrenal mass. She underwent right adrenalectomy. Histopathological examination of the resected adrenal gland showed adrenocortical adenoma. Her postoperative evaluation showed a normal testosterone level. Conclusion Adrenocortical neoplasms though rare in children are well documented in Beckwith-Wiedemann syndrome patients. So tumor surveillance protocol should be employed, even in a resource-limited setting for early tumor detection and a better outcome.
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Affiliation(s)
- Eman Abdalla Ali Elnaw
- 1Endocrine Division, Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum, P.O.Box:102, Khartoum, Sudan
| | | | - Mohamed Ahmed Abdullah
- 1Endocrine Division, Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum, P.O.Box:102, Khartoum, Sudan
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Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients. Eur J Hum Genet 2019; 28:469-479. [PMID: 31685998 DOI: 10.1038/s41431-019-0485-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 06/20/2019] [Accepted: 07/02/2019] [Indexed: 12/14/2022] Open
Abstract
Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.
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Sznewajs A, Pon E, Matthay KK. Congenital malformation syndromes associated with peripheral neuroblastic tumors: A systematic review. Pediatr Blood Cancer 2019; 66:e27901. [PMID: 31264798 DOI: 10.1002/pbc.27901] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 04/16/2019] [Accepted: 05/04/2019] [Indexed: 12/13/2022]
Abstract
Malformation syndromes with predisposition to peripheral neuroblastic tumors (pNT), including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, may provide clues to critical mutations influencing pNT development. Our objective was to identify and characterize features of pNT associated with specific malformation syndromes. A systematic review of the literature was performed using MEDLINE, Scopus, and Web of Science. We identified 154 of 1014 papers that met eligibility, comprising 207 cases. The patient's age, tumor histology, and frequency of multiple primary tumors varied by malformation syndrome. Genomic studies and systematized reporting are necessary to elucidate cancer risk and the distinct clinical and biological pNT patterns within syndromes.
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Affiliation(s)
- Aimee Sznewajs
- Department of Pediatrics, The University of California San Francisco School of Medicine and UCSF Benioff Children's Hospital, San Francisco, California
| | - Elizabeth Pon
- Department of Pediatrics, The University of California San Francisco School of Medicine and UCSF Benioff Children's Hospital, San Francisco, California
| | - Katherine K Matthay
- Department of Pediatrics, The University of California San Francisco School of Medicine and UCSF Benioff Children's Hospital, San Francisco, California
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Foster A, Zachariou A, Loveday C, Ashraf T, Blair E, Clayton‐Smith J, Dorkins H, Fryer A, Gener B, Goudie D, Henderson A, Irving M, Joss S, Keeley V, Lahiri N, Lynch SA, Mansour S, McCann E, Morton J, Motton N, Murray A, Riches K, Shears D, Stark Z, Thompson E, Vogt J, Wright M, Cole T, Tatton‐Brown K. The phenotype of Sotos syndrome in adulthood: A review of 44 individuals. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2019; 181:502-508. [PMID: 31479583 DOI: 10.1002/ajmg.c.31738] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/09/2019] [Accepted: 07/10/2019] [Indexed: 11/08/2022]
Affiliation(s)
- Alison Foster
- University of Birmingham, Institution of Cancer and Genomic Sciences Birmingham UK
- West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women and Children's NHS Foundation Trust Birmingham UK
| | - Anna Zachariou
- Division of Genetics and EpidemiologyInstitute of Cancer Research London UK
| | - Chey Loveday
- Division of Genetics and EpidemiologyInstitute of Cancer Research London UK
| | - Tazeen Ashraf
- Department of Clinical GeneticsGuy's and St Thomas' NHS Foundation Trust London UK
| | - Edward Blair
- Oxford Centre for Genomic MedicineOxford University Hospitals NHS Foundation Trust Oxford UK
| | - Jill Clayton‐Smith
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of BiologyMedicine and Health, University of Manchester Manchester UK
- Manchester Centre for Genomic MedicineSt Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester Manchester UK
| | - Huw Dorkins
- Leicester Royal InfirmaryUniversity Hospitals of Leicester NHS Trust Leicester UK
| | - Alan Fryer
- Department of Clinical GeneticsLiverpool Women's NHS Foundation Trust Liverpool UK
| | - Blanca Gener
- Department of GeneticsCruces University Hospital, Biocruces Bizkaia Health Research Institute Barakaldo Spain
| | - David Goudie
- East of Scotland Regional Genetics ServiceNinewells Hospital and Medical School Dundee UK
| | - Alex Henderson
- Northern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK
| | - Melita Irving
- Department of Clinical GeneticsGuy's and St Thomas' NHS Foundation Trust London UK
| | - Shelagh Joss
- West of Scotland Regional Genetics Service, Laboratory Medicine BuildingQueen Elizabeth University Hospital Glasgow UK
| | - Vaughan Keeley
- University Hospitals of Derby and Burton NHS Foundation Trust Derby UK
| | - Nayana Lahiri
- South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust London UK
| | - Sally Ann Lynch
- Department of Clinical GeneticsTemple Street Children's University Hospital Dublin Ireland
| | - Sahar Mansour
- South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust London UK
- St George's University of London London UK
| | - Emma McCann
- Department of Clinical GeneticsLiverpool Women's NHS Foundation Trust Liverpool UK
| | - Jenny Morton
- West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women and Children's NHS Foundation Trust Birmingham UK
| | - Nicole Motton
- West Midlands Regional Genetics ServiceBirmingham Women's Hospital Birmingham UK
| | - Alexandra Murray
- All Wales Medical Genomics ServiceUniversity Hospital of Wales Cardiff UK
| | - Katie Riches
- University Hospitals of Derby and Burton NHS Foundation Trust Derby UK
| | - Deborah Shears
- Oxford Centre for Genomic MedicineOxford University Hospitals NHS Foundation Trust Oxford UK
| | - Zornitza Stark
- Victorian Clinical Genetics ServicesMurdoch Children's Research Institute Melbourne Australia
- Department of PaediatricsUniversity of Melbourne Melbourne Australia
| | - Elizabeth Thompson
- SA Clinical Genetics ServiceWomen's and Children's Hospital Adelaide South Australia Australia
- Faculty of Health and Medical SciencesUniversity of Adelaide Adelaide South Australia
| | - Julie Vogt
- West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women and Children's NHS Foundation Trust Birmingham UK
| | - Michael Wright
- Northern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK
| | - Trevor Cole
- West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women and Children's NHS Foundation Trust Birmingham UK
| | - Katrina Tatton‐Brown
- Division of Genetics and EpidemiologyInstitute of Cancer Research London UK
- South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust London UK
- St George's University of London London UK
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Gravino R, Limongelli G, Petraio A, Masarone D, Russo MG, Maiello C, Verrengia M, De Paulis D, Pacileo G. Berlin Heart EXCOR® pediatric ventricular assist device in a patient with Sotos syndrome: a case report. J Med Case Rep 2019; 13:286. [PMID: 31470900 PMCID: PMC6717362 DOI: 10.1186/s13256-019-2190-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 07/04/2019] [Indexed: 12/02/2022] Open
Abstract
INTRODUCTION Berlin Heart EXCOR® pediatric ventricular assist device is a mechanical circulatory support device currently used in pediatric patients. Sotos syndrome is a well-described multiple anomaly syndrome characterized by overgrowth, distinctive craniofacial appearance, cardiac abnormalities, and variable learning disabilities. CASE PRESENTATION We describe a 7-year-old female Caucasian child with classic Sotos syndrome features subjected to implantation of Berlin Heart EXCOR® pediatric biventricular assist device mechanical support. A heart transplant was carried out after a support time of 459 days. After 5 years of follow-up, our patient is clinically stable and the performance of the transplanted heart is excellent. CONCLUSION This case confirms that Berlin Heart EXCOR® pediatric ventricular assist device can provide satisfactory and safe circulatory support for children with end-stage heart diseases, even in those with Sotos syndrome. The syndrome is not a contraindication to implantation, since the complications are the same as those observed in patients without the syndrome and the prognosis is not affected by the disease.
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Affiliation(s)
- Rita Gravino
- Department of Heart Failure Unit, Monaldi Hospital, via Leonardo Bianchi, 80131 Naples, Italy
| | - Giuseppe Limongelli
- Department of Pediatric Cardiology Unit, Second University of Naples, Monaldi Hospital, Naples, Italy
| | - Andrea Petraio
- Department of Cardiac Transplant Unit, Monaldi Hospital, Naples, Italy
| | - Daniele Masarone
- Department of Heart Failure Unit, Monaldi Hospital, via Leonardo Bianchi, 80131 Naples, Italy
| | - Maria Giovanna Russo
- Department of Pediatric Cardiology Unit, Second University of Naples, Monaldi Hospital, Naples, Italy
| | - Ciro Maiello
- Department of Cardiac Transplant Unit, Monaldi Hospital, Naples, Italy
| | - Marina Verrengia
- Department of Heart Failure Unit, Monaldi Hospital, via Leonardo Bianchi, 80131 Naples, Italy
| | - Danilo De Paulis
- Department of Neurosurgery, San Anna & San Sebastiano City Hospital Caserta, Caserta, Italy
| | - Giuseppe Pacileo
- Department of Heart Failure Unit, Monaldi Hospital, via Leonardo Bianchi, 80131 Naples, Italy
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Mahat U, Dermawan JKT, Herman R, Mamoun I, Flagg A. Ovarian Torsion in an Adolescent with Beckwith-Wiedemann Syndrome and Unilateral Tubo-ovarian Hyperplasia. J Pediatr Adolesc Gynecol 2019; 32:446-449. [PMID: 30981832 DOI: 10.1016/j.jpag.2019.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 04/02/2019] [Accepted: 04/06/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Beckwith-Wiedemann syndrome (BWS) is the most common pediatric overgrowth syndrome. BWS has a broad phenotypic presentation along with an increased propensity to develop various embryonal tumors. There are very few reported cases of gonadal hyperplasia in BWS patients in the existing literature. CASE We describe a 13-year-old girl with BWS who presented with an episode of abdominal pain and was found to have torsion and necrosis of a markedly hyperplastic right ovary and fallopian tube. We present a brief literature review on ovarian hyperplasia in BWS patients for which we used an online search of the databases PubMed, Embase, Ovid Medline, and Cochrane. RESULTS AND CONCLUSION Through an extensive literature search, we only found 3 previous reports of ovarian hyperplasia in BWS patients, all in postmortem specimens. Our case highlights a potentially important aspect of visceral organ hyperplasia in patients with BWS that could remain indolent until adolescence and might present as an abrupt-onset abdominopelvic catastrophe.
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Affiliation(s)
- Upendra Mahat
- Department of Pediatric Hematology Oncology and BMT, Cleveland Clinic Children's, Cleveland, Ohio.
| | | | - Richard Herman
- Department of Pediatric Surgery, Cleveland Clinic Children's, Cleveland, Ohio
| | - Ihsan Mamoun
- Department of Pediatric Radiology, Cleveland Clinic, Cleveland, Ohio
| | - Aron Flagg
- Department of Pediatric Hematology Oncology and BMT, Cleveland Clinic Children's, Cleveland, Ohio
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Abstract
Large offspring syndrome (LOS) is a fetal overgrowth condition in bovines most often observed in offspring conceived with the use of assisted reproductive technologies (ART). Phenotypes observed in LOS include, overgrowth, enlarged tongues, umbilical hernias, muscle and skeleton malformations, abnormal organ growth and placental development. Although LOS cases have only been reported to be associated with ART, fetal overgrowth can occur spontaneously in cattle (S-LOS). S-LOS refers to oversized calves that are born at normal gestation lengths. ART-induced LOS has been characterized as an epigenetic syndrome, more specifically, a loss-of-imprinting condition. We propose that S-LOS is also a loss-of-imprinting condition.
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Brioude F, Toutain A, Giabicani E, Cottereau E, Cormier-Daire V, Netchine I. Overgrowth syndromes - clinical and molecular aspects and tumour risk. Nat Rev Endocrinol 2019; 15:299-311. [PMID: 30842651 DOI: 10.1038/s41574-019-0180-z] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.
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Affiliation(s)
- Frédéric Brioude
- Sorbonne Université, INSERM UMR_S938, Centre de Recherche Saint Antoine, AP-HP Hôpital Trousseau, Paris, France.
| | - Annick Toutain
- CHU de Tours, Hôpital Bretonneau, Service de Génétique, INSERM UMR1253, iBrain, Université de Tours, Faculté de Médecine, Tours, France
| | - Eloise Giabicani
- Sorbonne Université, INSERM UMR_S938, Centre de Recherche Saint Antoine, AP-HP Hôpital Trousseau, Paris, France
| | - Edouard Cottereau
- CHU de Tours, Hôpital Bretonneau, Service de Génétique, Tours, France
| | - Valérie Cormier-Daire
- Service de génétique clinique, Université Paris Descartes-Sorbonne Paris Cité, INSERM UMR1163, Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France
| | - Irene Netchine
- Sorbonne Université, INSERM UMR_S938, Centre de Recherche Saint Antoine, AP-HP Hôpital Trousseau, Paris, France
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Brzezinski J, Michaeli O, Wasserman JD. Tumor risk and surveillance for children with hereditary disorders affecting growth. Curr Opin Endocrinol Diabetes Obes 2019; 26:66-76. [PMID: 30516551 DOI: 10.1097/med.0000000000000459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Hereditary disorders affecting growth (both overgrowth and growth retardation) are frequently associated with heightened risk of neoplastic disease. This review summarizes the tumor spectra associated with these conditions and identifies disease-specific screening approaches. RECENT FINDINGS An understanding of the molecular events underlying many of these growth disorders has evolved significantly over the past several years. Recognition of genotype-phenotype associations, in many cases, informs the cancer risk profile. Additionally, accumulating data suggest a benefit of rational presymptomatic surveillance for at-risk individuals, with a reduction in tumor-associated morbidity. Recent clinical practice recommendations have established risk-driven paradigms for tumor surveillance in the context of hereditary tumor predisposition syndromes, including those affecting growth. SUMMARY Clinicians caring for children with growth disorders should be aware of syndromic associations and the associated cancer risks. Knowledge of tumor spectra and recommended surveillance strategies may facilitate tumor diagnosis at an early stage and reduce morbidity of the disease and associated treatments.
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Affiliation(s)
- Jack Brzezinski
- Division of Haematology/Oncology, The Hospital for Sick Children
- Institute of Medical Science, The University of Toronto
| | - Orli Michaeli
- Division of Haematology/Oncology, The Hospital for Sick Children
| | - Jonathan D Wasserman
- Division of Endocrinology, The Hospital for Sick Children
- Department of Paediatrics, University of Toronto
- Genetics & Genome Biology Program, SickKids Research Institute, Toronto, Ontario, Canada
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45
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Shibui Y, Miyoshi K, Kohashi K, Kinoshita Y, Kuda M, Yamamoto H, Taguchi T, Oda Y. Glypican-3 expression in malignant small round cell tumors. Oncol Lett 2019; 17:3523-3528. [PMID: 30867793 DOI: 10.3892/ol.2019.9976] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 12/12/2018] [Indexed: 12/15/2022] Open
Abstract
Malignant small round cell tumors usually progress rapidly and show resistance to chemotherapy, and it is often difficult to make a definitive diagnosis based on their histological morphology. Glypican-3 (GPC3) is a highly tumor-specific antigen, and the overexpression of GPC3 was reported in many pediatric and adult malignancies. In the present study, we investigated the GPC3 expression in pediatric malignant small round cell tumors to assess its role in the differential diagnosis of the tumors. Immunohistochemistry was performed to assess the expression of GPC3 in samples from 84 rhabdomyosarcomas (RMSs; 44 alveolar and 40 embryonal RMSs), 62 Ewing sarcomas (EWSs), 35 neuroblastomas (NBs) and two desmoplastic small round cell tumors (DSRCTs). We performed a reverse transcription-quantitative polymerase chain reaction for GPC3 to determine the GPC3 mRNA expression in samples from 66 frozen tumors (23 RMSs, 28 EWSs and 15 NBs). The serum expression levels of GPC3 were analyzed in pre-operative blood samples from two RMS and eight NB patients. In total, 25% (21/84) of the RMSs and 3% (1/35) of the NBs exhibited a focal expression of GPC3, whereas, the other specimens showed no GPC3 expression. The GPC3 mRNA expression level of the RMSs with positive GPC3 expression (n=6) was significantly higher compared with the RMSs without such expression (n=17). A total of two cases of NB showed high serum levels of GPC3, but neither tumor showed immunoreactivity for GPC3. The immunohistochemical overexpression of GPC3 may be a candidate ancillary parameter in the differential diagnosis of RMS from EWS and DSRCT.
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Affiliation(s)
- Yuichi Shibui
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kina Miyoshi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshiaki Kinoshita
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masaaki Kuda
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
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Lin28 and let-7 regulate the timing of cessation of murine nephrogenesis. Nat Commun 2019; 10:168. [PMID: 30635573 PMCID: PMC6329821 DOI: 10.1038/s41467-018-08127-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 12/12/2018] [Indexed: 01/10/2023] Open
Abstract
In humans and in mice the formation of nephrons during embryonic development reaches completion near the end of gestation, after which no new nephrons are formed. The final nephron complement can vary 10-fold, with reduced nephron number predisposing individuals to hypertension, renal, and cardiovascular diseases in later life. While the heterochronic genes lin28 and let-7 are well-established regulators of developmental timing in invertebrates, their role in mammalian organogenesis is not fully understood. Here we report that the Lin28b/let-7 axis controls the duration of kidney development in mice. Suppression of let-7 miRNAs, directly or via the transient overexpression of LIN28B, can prolong nephrogenesis and enhance kidney function potentially via upregulation of the Igf2/H19 locus. In contrast, kidney-specific loss of Lin28b impairs renal development. Our study reveals mechanisms regulating persistence of nephrogenic mesenchyme and provides a rationale for therapies aimed at increasing nephron mass. Nephrogenesis ceases after postnatal day 2 in the mouse or after the 36th week of gestation in humans, but how this is regulated is unclear. Here, the authors identify a role for the RNA-binding protein Lin28 and suppression of let-7 microRNA in regulating the duration of nephrogenesis.
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De Paepe ME, Young L, Jones JR, Tantravahi U. Ovotesticular Disorder of Sex Development (Ovotestis) in Simpson-Golabi-Behmel Syndrome: Expansion of the Clinical Spectrum. Pediatr Dev Pathol 2019; 22:70-74. [PMID: 29652239 DOI: 10.1177/1093526618770327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Simpson-Golabi-Behmel syndrome type I (SGBS, OMIM312870), caused by defects of the GPC3 and GPC4 genes on chromosome Xq26, is an X-linked recessive macrosomia/multiple congenital anomaly disorder characterized by somatic overgrowth, coarse facial features, variable congenital anomalies, increased tumor risk, and mild-to-moderate neurodevelopmental anomalies. We report the postmortem findings in 3 second-trimester male siblings with SGBS who displayed ambiguous genitalia (in all 3) and gonadal dysgenesis (ovotestis) (in 1), thus expanding the SGBS spectrum to include these disorders of sex development.
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Affiliation(s)
- Monique E De Paepe
- 1 Department of Pathology, Women and Infants Hospital, Providence, Rhode Island.,2 Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Providence, Rhode Island
| | - Lawrence Young
- 1 Department of Pathology, Women and Infants Hospital, Providence, Rhode Island
| | - Julie R Jones
- 3 Greenwood Genetic Center, Greenwood, South Carolina
| | - Umadevi Tantravahi
- 1 Department of Pathology, Women and Infants Hospital, Providence, Rhode Island.,2 Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Providence, Rhode Island
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Marques P, Korbonits M. Pseudoacromegaly. Front Neuroendocrinol 2019; 52:113-143. [PMID: 30448536 DOI: 10.1016/j.yfrne.2018.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/30/2018] [Accepted: 11/14/2018] [Indexed: 01/19/2023]
Abstract
Individuals with acromegaloid physical appearance or tall stature may be referred to endocrinologists to exclude growth hormone (GH) excess. While some of these subjects could be healthy individuals with normal variants of growth or physical traits, others will have acromegaly or pituitary gigantism, which are, in general, straightforward diagnoses upon assessment of the GH/IGF-1 axis. However, some patients with physical features resembling acromegaly - usually affecting the face and extremities -, or gigantism - accelerated growth/tall stature - will have no abnormalities in the GH axis. This scenario is termed pseudoacromegaly, and its correct diagnosis can be challenging due to the rarity and variability of these conditions, as well as due to significant overlap in their characteristics. In this review we aim to provide a comprehensive overview of pseudoacromegaly conditions, highlighting their similarities and differences with acromegaly and pituitary gigantism, to aid physicians with the diagnosis of patients with pseudoacromegaly.
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Affiliation(s)
- Pedro Marques
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
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Gupta N, Rivera M, Novotny P, Rodriguez V, Bancos I, Lteif A. Adrenocortical Carcinoma in Children: A Clinicopathological Analysis of 41 Patients at the Mayo Clinic from 1950 to 2017. Horm Res Paediatr 2018; 90:8-18. [PMID: 29804118 DOI: 10.1159/000488855] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 03/26/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Adrenocortical carcinoma (ACC) is an aggressive childhood cancer. Limited evidence exists on a definite histopathological criterion to differentiate ACC from adrenocortical adenoma. The aim of this study was to investigate the clinicopathological data of children with ACC, identify prognostic factors, and validate a histopathological criterion to differentiate ACC from adrenocortical adenoma. METHODS This retrospective cohort included 41 children, followed at the Mayo Clinic from 1950 to 2017 (onset of symptoms ≤21 years). Outcomes of interest were: alive with no evidence of disease, alive with evidence of disease, and dead of disease. RESULTS Median age at onset of symptoms was 15.7 years (n = 41; range, 0.2-21 years). Female:male ratio was 3.6: 1. Mixed symptomatology (> 1 hormone abnormality) was the most common presentation (54%, n = 22). Sixty-six percent of patients (n = 27 out of 41) underwent total adrenalectomy. Metastatic disease was more common in children aged > 12 years (p = 0.002 compared to < 4 years). The most common sites of metastases were the liver and lungs. Overall 2-year and 5-year survival rates were 61% (95% CI 45-77) and 46% (95% CI 30-62), respectively. Metastasis at the time of diagnosis was independently associated with poor prognosis (risk ratio 13.7%; 95% CI 3.9-87.7). Weiss criteria (29%) and modified Weiss criteria (33%) were less accurate in younger patients (< 12 years), compared to the Wieneke index (100%). CONCLUSION The presence of metastases was an independent prognostic factor. The Wieneke index was the most accurate in predicting clinical outcomes in younger children.
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Affiliation(s)
- Nidhi Gupta
- Division of Pediatric Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Rivera
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Paul Novotny
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Vilmarie Rodriguez
- Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Aida Lteif
- Division of Pediatric Endocrinology and Metabolism, Mayo Clinic, Rochester, Minnesota, USA
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Goudie C, Cullinan N, Villani A, Mathews N, van Engelen K, Malkin D, Irwin MS, Foulkes WD. Retrospective evaluation of a decision-support algorithm (MIPOGG) for genetic referrals for children with neuroblastic tumors. Pediatr Blood Cancer 2018; 65:e27390. [PMID: 30117275 DOI: 10.1002/pbc.27390] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/06/2018] [Accepted: 07/17/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Neuroblastoma is the most common pediatric extracranial solid tumor. Germline pathogenic variants in ALK and PHOX2B, as well as other cancer predisposition genes, are increasingly implicated in the pathogenesis of neuroblastic tumors. A challenge for clinicians is the identification of children with neuroblastoma who require genetics evaluation for underlying cancer predisposition syndromes (CPS). PROCEDURE We developed a decisional algorithm (MIPOGG) to identify which patients with neuroblastic tumors have an increased likelihood of an underlying CPS. This algorithm, comprising 11 Yes/No questions, evaluates features in the tumor, personal and family history that are suggestive of an underlying CPS. We assessed the algorithm's performance in a retrospective cohort. RESULTS Two hundred and nine of 278 consecutive patients with neuroblastic tumors at The Hospital for Sick Children (2007-2016) had sufficient clinical data for retrospective application of the decisional algorithm. Fifty-one of 209 patients had been referred to genetics for CPS evaluation; 6/51 had a genetic or clinical confirmation of a CPS. The algorithm correctly identified all six children (Beckwith-Wiedemann (n = 2), Fanconi anemia, RB1, PHOX2B, chromosome duplication involving ALK) as requiring a genetic evaluation by using clinical features present at diagnosis. The level of agreement between the algorithm and physicians was 83.9%, with 15 more patients identified by the algorithm than by physicians as requiring a genetics referral. CONCLUSIONS This decisional algorithm appropriately detected all patients who, following genetic evaluation, were confirmed to have a CPS and may improve the detection of CPS in patients with neuroblastic tumors compared with current practice.
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Affiliation(s)
- Catherine Goudie
- Division of Haematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Noelle Cullinan
- Division of Haematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Anita Villani
- Division of Haematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Natalie Mathews
- Department of Pediatrics, McGill University Health Centre, Montreal, Quebec, Canada
| | - Kalene van Engelen
- Department of Clinical and Metabolic Genetics, The Hospital for Sick Children, Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - David Malkin
- Division of Haematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Meredith S Irwin
- Division of Haematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Canada
| | - William D Foulkes
- Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada
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