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1. Atypical Bacterial Pathogens and Small-Vessel Leukocytoclastic Vasculitis of the Skin in Children: Systematic Literature Review

Author

Céline Betti, Pietro Camozzi, Viola Gennaro, Mario G. Bianchetti, Martin Scoglio, Giacomo D. Simonetti, Gregorio P. Milani, Sebastiano A. G. Lava, and Alessandra Ferrarini

Subjects
leukocytoclastic small-vessel vasculitis, atypical pathogens, Mycoplasma pneumoniae, Legionella pneumophila, Chlamydophila pneumoniae, Chlamydophila psittaci, Medicine
Abstract

Leukocytoclastic small-vessel vasculitis of the skin (with or without systemic involvement) is often preceded by infections such as common cold, tonsillopharyngitis, or otitis media. Our purpose was to document pediatric (≤18 years) cases preceded by a symptomatic disease caused by an atypical bacterial pathogen. We performed a literature search following the Preferred Reporting of Systematic Reviews and Meta-Analyses guidelines. We retained 19 reports including 22 cases (13 females and 9 males, 1.0 to 17, median 6.3 years of age) associated with a Mycoplasma pneumoniae infection. We did not find any case linked to Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Francisella tularensis, or Legionella pneumophila. Patients with a systemic vasculitis (N = 14) and with a skin-limited (N = 8) vasculitis did not significantly differ with respect to gender and age. The time to recovery was ≤12 weeks in all patients with this information. In conclusion, a cutaneous small-vessel vasculitis with or without systemic involvement may occur in childhood after an infection caused by the atypical bacterial pathogen Mycoplasma pneumoniae. The clinical picture and the course of cases preceded by recognized triggers and by this atypical pathogen are indistinguishable.

Published
2021
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2. Pathologic fracture revealed a rare syndromic form of genetic lipodystrophy

Author

Gabriel Bronz, Corinna F.P. Leoni-Foglia, Giacomo D. Simonetti, Alessandra Ferrarini, and Sebastiano G. Lava

Subjects
Male, Pathology, medicine.medical_specialty, Adolescent, Lipodystrophy, Pathologic fracture, business.industry, Genetic lipodystrophy, Point mutation, MEDLINE, Lipid metabolism, General Medicine, Lamin Type A, medicine.disease, Lipid Metabolism, Inborn Errors, Pathology and Forensic Medicine, Pediatrics, Perinatology and Child Health, medicine, Humans, Point Mutation, Anatomy, business, Femoral Fractures, Genetics (clinical)
Published
2020

3. Immune deposits in skin vessels of patients with acute hemorrhagic edema of young children: A systematic literature review

Author

Gregorio P. Milani, Giorgia Pellanda, Sebastiano A. G. Lava, Alessandra Ferrarini, Mario G. Bianchetti, and Federica Vanoni

Subjects
Immunoglobulin A, medicine.medical_specialty, IgA Vasculitis, Immunoglobulins, Dermatology, Immunoglobulin G, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Edema, medicine, Humans, Child, Skin, biology, medicine.diagnostic_test, business.industry, medicine.disease, Purpura, Immunoglobulin M, Child, Preschool, 030220 oncology & carcinogenesis, Acute Disease, Pediatrics, Perinatology and Child Health, Skin biopsy, biology.protein, Vasculitis, Leukocytoclastic, Cutaneous, medicine.symptom, Antibody, Vasculitis, business
Abstract

BACKGROUND Acute hemorrhagic edema of young children is a benign skin-limited vasculitis mainly affecting children 2 to 24 months of age, which is often considered the infantile variant of immunoglobulin A vasculitis (Henoch-Schonlein purpura). In most cases, the diagnosis is made on a clinical basis without a skin biopsy. METHODS A systematic review of the literature was performed to examine the reported prevalence of vascular immune deposits in skin biopsies of patients with acute hemorrhagic edema of young children. RESULTS Testing for vascular immune deposits was performed in 75 cases (64 boys and 11 girls aged from 3.5 to 72, median 11 months) published between 1970 and 2018. Vessel wall deposition of complement C3 was seen in 40 cases. Immunoglobulin M (N = 24), immunoglobulin A (N = 21), immunoglobulin G (N = 13), and immunoglobulin E (N = 3) were less frequently detected. Gender, age, clinical features, and disease duration were not statistically different in cases with and without vessel wall deposition of immunoglobulin A. CONCLUSION Immune deposits in skin vessels, most frequently complement C3, are common in subjects with acute hemorrhagic edema of young children, providing furhter evidence that acute hemorrhagic edema, immunoglobulin A vasculitis, and pauci-immune vasculitides are different entities.

Published
2019

4. De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features

Author

Benjamin Navet, Renee Perrier, Kiyotaka Tomiwa, Alexander Pepler, Hui Xi, Adele Schneider, Xiao Mao, Ryan J. Taft, Paul Rollier, Alban Ziegler, Roberto Colombo, Noriko Miyake, Emmanuel Scalais, Katrien Stouffs, Estelle Colin, Denise L. Perry, Adeline Vanderver, Nobuhiko Okamoto, Magalie Barth, Li Shu, Elizabeth Wohler, Louise Amlie-Wolf, Hainan Zhang, Alessandro Serretti, Naomichi Matsumoto, Dominique Bonneau, Hua Wang, Omar Sherbini, Alka Malhotra, Nara Sobreira, Alessandra Ferrarini, Malhotra A., Ziegler A., Shu L., Perrier R., Amlie-Wolf L., Wohler E., Lygia De MacEna Sobreira N., Colin E., Vanderver A., Sherbini O., Stouffs K., Scalais E., Serretti A., Barth M., Navet B., Rollier P., Xi H., Wang H., Zhang H., Perry D.L., Ferrarini A., Colombo R., Pepler A., Schneider A., Tomiwa K., Okamoto N., Matsumoto N., Miyake N., Taft R., Mao X., Bonneau D., Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hunan Agricultural University [Changsha], Department of Neurology, Children's National Medical Center, Universitair Ziekenhuis Brussel, Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Institute of Psychiatry, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Réseau Maladies Métaboliques, Hôpitaux Universitaires du Grand Ouest, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), CHU Pontchaillou [Rennes], Shandong University, Nanjing University of Science and Technology (NJUST), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Università degli Studi di Brescia [Brescia], Genetics Division, Einstein Medical Center, Gifu University Graduate School of Medicine, Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Institute for Molecular Bioscience, University of Queensland [Brisbane], Clinical sciences, Medical Genetics, Reproduction and Genetics, and Faculty of Law and Criminology

Subjects
0301 basic medicine, gain of function mutation, Microcephaly, [SDV]Life Sciences [q-bio], Population, Biology, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Genetics, medicine, Missense mutation, education, Exome, Allele frequency, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, education.field_of_study, mutation, missense, medicine.disease, 030104 developmental biology, genetics, medical, 030217 neurology & neurosurgery
Abstract

ObjectiveTo determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes.MethodsHere we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher.ResultsLMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms.ConclusionThese findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.

Published
2021

5. Author response for '<scp>IQSEC2</scp> disorder: a new disease entity or a Rett spectrum continuum?'

Author

Anna Maria Pinto, Diego Lopergolo, Roberto Canitano, Flavia Privitera, Judith Armstrong, Gian Paolo Ramelli, Caterina Lo Rizzo, Hilde Van Esch, Gerardo Mejia Baltodano, Alessandra Renieri, Sabrina Mueller, Vittoria Lamacchia, Maria Antonietta Mencarelli, Maria Del Carmen Fons-Estupina, Aurora Currò, Mercè Pineda, Lionel Van Maldergem, Damien Lederer, Candy Kumps, Francesca Ariani, Elisabetta Vaghi, Bert Callewaert, Mercedes Serrano, Giuseppe Castello, Alessandra Ferrarini, Jeroen Breckpot, and Francesca Mari

Subjects
Physics, Theoretical physics, Continuum (measurement), New disease, Spectrum (topology)
Published
2020

6. IQSEC2 disorder: A new disease entity or a Rett spectrum continuum?

Author

Anna Maria Pinto, Giuseppe Castello, Lionel Van Maldergem, Caterina Lo Rizzo, Alessandra Ferrarini, Vittoria Lamacchia, Jeroen Breckpot, Candy Kumps, Damien Lederer, Francesca Mari, Alessandra Renieri, Mercè Pineda, Elisabetta Vaghi, Diego Lopergolo, Judith Armstrong, Francesca Ariani, Maria Del Carmen Fons-Estupina, Flavia Privitera, Mercedes Serrano, Sabrina Mueller, Gian Paolo Ramelli, Roberto Canitano, Bert Callewaert, Gerardo Mejia Baltodano, Hilde Van Esch, Maria Antonietta Mencarelli, and Aurora Currò

Subjects
0301 basic medicine, Male, INTELLECTUAL DISABILITY, 030105 genetics & heredity, Bioinformatics, phenotype-genotype, IQSEC2, Rett syndrome, Intellectual disability, Medicine and Health Sciences, Guanine Nucleotide Exchange Factors, Genetics(clinical), intellectual disability, Child, Genetics (clinical), Clinical course, Middle Aged, Phenotype, New disease, Child, Preschool, Phenotype genotype, INACTIVATION, Female, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, PHENOTYPIC VARIABILITY, Diagnosis, Differential, 03 medical and health sciences, Young Adult, Intellectual Disability, Exome Sequencing, Genetics, medicine, Rett Syndrome, Humans, Point Mutation, Genetic Association Studies, LANDSCAPE, MUTATIONS, business.industry, Point mutation, medicine.disease, GENE, 030104 developmental biology, Differential diagnosis, business
Abstract

IQSEC2 mutations are associated with IQSEC2-related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype-phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2-related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype-phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate-to-mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2-associated phenotype delineation.

Published
2020

7. Acute hemorrhagic edema: Uncommon features

Author

Cristina Chelleri, Sebastiano A. G. Lava, Gabriel Bronz, Alessandra Ferrarini, Gregorio P. Milani, Mario G. Bianchetti, Pietro O. Rinoldi, and Cristina Mangas

Subjects
medicine.medical_specialty, business.industry, MEDLINE, Infant, Hemorrhage, Dermatology, Edema, Acute Disease, medicine, Prevalence, Humans, Vasculitis, Leukocytoclastic, Cutaneous, medicine.symptom, business
Published
2020

8. De novo missense variants in

Author

Alka, Malhotra, Alban, Ziegler, Li, Shu, Renee, Perrier, Louise, Amlie-Wolf, Elizabeth, Wohler, Nara, Lygia de Macena Sobreira, Estelle, Colin, Adeline, Vanderver, Omar, Sherbini, Katrien, Stouffs, Emmanuel, Scalais, Alessandro, Serretti, Magalie, Barth, Benjamin, Navet, Paul, Rollier, Hui, Xi, Hua, Wang, Hainan, Zhang, Denise L, Perry, Alessandra, Ferrarini, Roberto, Colombo, Alexander, Pepler, Adele, Schneider, Kiyotaka, Tomiwa, Nobuhiko, Okamoto, Naomichi, Matsumoto, Noriko, Miyake, Ryan, Taft, Xiao, Mao, and Dominique, Bonneau

Subjects
Cohort Studies, Motor Skills Disorders, Nucleocytoplasmic Transport Proteins, Phenotype, Amino Acid Substitution, Genotype, Developmental Disabilities, Mutation, Missense, Humans, Genetic Predisposition to Disease, Nervous System Malformations, Alleles
Abstract

To determine the potential disease association between variants inHere we describe a series of de novo missense variants inThese findings indicate that rare de novo variants in

Published
2020

9. Sporadic acute benign calf myositis: Systematic literature review

Author

Alessandra Ferrarini, Gregorio P. Milani, Mario G. Bianchetti, Sebastiano A. G. Lava, Gioele Capoferri, and Gian Paolo Ramelli

Subjects
Mycoplasma pneumoniae, Pediatrics, medicine.medical_specialty, medicine.disease_cause, Virus, Dengue fever, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Muscle, Skeletal, Genetics (clinical), Myositis, Leg, biology, business.industry, Outbreak, medicine.disease, Systematic review, Neurology, Virus type, Acute Disease, Pediatrics, Perinatology and Child Health, biology.protein, Creatine kinase, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Acute benign calf myositis is a rare infection-associated syndrome presenting with calf pain that occurs in epidemics or sporadically. Epidemic cases are usually associated with influenza virus type B. Sporadic cases, however, might be associated with a large number of microorganisms. Furthermore, during an outbreak there is a great alertness that promotes earlier diagnosis. In contrast, there is likely a lower awareness regarding the sporadic form, compromising early and correct diagnosis. In order to characterize the sporadic form of acute calf myositis and increase the knowledge of this condition, we systematically reviewed the literature reporting sporadic cases. We identified 72 reports, including 451 patients, 325 males and 126 females. Sporadic acute benign calf myositis affected subjects ≤18 years of age (N = 450; 99%), who followed a prodromal flu-like illness (N = 411; 91%), presented with pain and tenderness affecting only the calves for ≤1½ weeks (N = 441; 99%) and was never complicated by kidney involvement. The creatine kinase ratio was ≥10 in 310 (70%) out of 444 cases. Microbiological studies identified an infectious trigger in 181 cases, mostly influenza virus (type B more frequently than type A), Dengue, Ebstein–Barr or Parainfluenza virus and Mycoplasma pneumoniae. Sporadic acute benign calf myositis is a self-limited condition that can usually be diagnosed on a clinical basis. Unlike the epidemic form, many cases are due to microorganisms other than influenza virus B or A.

Published
2018

10. Acute hemorrhagic edema of young children: open questions and perspectives

Author

Gian Paolo Ramelli, Pietro O. Rinoldi, Alessandra Ferrarini, Gregorio P. Milani, and Sebastiano A. G. Lava, and Mario G. Bianchetti

Subjects
business.industry, Edema, Anesthesia, hemorrhagic edema, Medicine, medicine.symptom, business
Abstract

Childhood vasculitis is a challenging group of conditions that are often multisystem in nature and may require integrated care from multiple pediatric subspecialists, including cardiologists, dermatologists, gastroenterologists, nephrologists, neurologists, and rheumatologists. Apart from Henoch Schönlein syndrome, recently renamed immunoglobulin A vasculitis, and Kawasaki disease, which are reltively common, there are a number of important but comparatively rare vasculitides affecting children [1-4]. Acute hemorrhagic edema of young children [5-8] is a skin limited nongranulomatous leukocytoclastic small-vessel vasculitis, which usually develops in previously healthy subjects after a simple, mostly viral, febrile illness (more rarely after a vaccination). The condition was initially reported in 1913 by Irving Snow in the United States and in 1936 by Mario Del Carril in Argentina [5,6]. The most comprehensive descriptions, however, were made in Germany before the Second World War by Heinrich Finkelstein (1865–1942) and later by Hubert Seidlmayer (1910–1965). A significant description was also made in 1942 by Marcel Lelong (1892-1973) in France [5,6]. Acute hemorrhagic edema has been known with a variety of synonyms: acute hemorrhagic edema of young children (or infancy), cockade (or iris-like) purpura and edema of young children, Henoch–Schönlein syndrome of early childhood, Finkelstein-Seidlmayer syndrome, Finkelstein syndrome and Seidlmayer syndrome [5,6,8].

Published
2019

11. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St George’s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)

Subjects
0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

12. Acute hemorrhagic edema of young children: a prospective case series

Author

Mario G. Bianchetti, Sebastiano A. G. Lava, Gregorio P. Milani, Cecilia Benetti, Giacomo D. Simonetti, Alessandro Ostini, Alessandra Ferrarini, and Pietro Camozzi

Subjects
Male, medicine.medical_specialty, 610 Medicine & health, Antibodies, Antineutrophil Cytoplasmic, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Edema, Humans, Medicine, Prospective Studies, skin and connective tissue diseases, Prospective cohort study, business.industry, Autoantibody, Infant, Mucous membrane, Complete resolution, Dermatology, Surgery, medicine.anatomical_structure, Scratch marks, Child, Preschool, Leukocytoclastic vasculitis, Acute Disease, Pediatrics, Perinatology and Child Health, Vasculitis, Leukocytoclastic, Cutaneous, Female, medicine.symptom, Differential diagnosis, business, 030217 neurology & neurosurgery
Abstract

Acute hemorrhagic edema of young children is a rare leukocytoclastic vasculitis that has been reported exclusively in small retrospective cases series, case reports, or quizzes. Considering that retrospective experience deserves confirmation in at least one observational prospective study, we present our experience with 16 children (12 boys and 4 girls, 5-28 months of age) affected by acute hemorrhagic edema. The patients were in good general conditions and with a low-grade or even absent fever. They presented with non-itching red to purpuric targetoid lesions not changing location within hours, with non-pitting and sometimes tender indurative swelling, and without mucous membrane involvement or scratch marks. Signs for articular, abdominal, or kidney involvement were absent. Antinuclear or antineutrophil cytoplasmic autoantibodies were never detected. The cases were managed symptomatically as outpatients and fully resolved within 4 weeks or less. No recurrence or familiarity was noted. CONCLUSION This is the first prospective evaluation of hemorrhagic edema. Our findings emphasize its distinctive tetrad: a well-appearing child; targetoid lesions that do not change location within hours; non-pitting, sometimes tender edema; complete resolution without recurrence. What is known • Acute hemorrhagic edema of young children is considered a benign vasculitis. • There have been ≈100 cases reported in small retrospective case series. What is new • The first prospective evaluation of this condition emphasizes its features: febrile prodrome; well-appearing child; targetoid lesions not changing location within hours; non-pitting, sometimes tender indurative edema; absent extracutaneous involvement; resolution within 3 weeks. • Antineutrophil cytoplasmic autoantibodies do not play a pathogenic role.

Published
2015

13. A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly

Author

Annemarie Haeberli, Alessandra Ferrarini, Luisa Bonafé, Jean-Marc Nuoffer, André Schaller, Sabina Gallati, M F Bauer, Hassib Chehade, Frédéric Barbey, Christel Tran, Christopher B. Jackson, Dagmar Hahn, Sandra Eggimann, Urania Kotzaeridou, Research Programs Unit, and Research Programme for Molecular Neurology

Subjects
Male, 0301 basic medicine, IRON-OVERLOAD, Microcephaly, Mitochondrial Diseases, BCS1L, GRACILE syndrome, PROTEIN, Deafness, DISEASE, Electron Transport Complex III, MITOCHONDRIA, 3123 Gynaecology and paediatrics, Missense mutation, LACTIC-ACIDOSIS, Growth Disorders, Cholestasis, Fetal Growth Retardation, Lactic acidosis, COMPLEX III DEFICIENCY, Homozygote, ENCEPHALOPATHY, Mitochondrial disorder, 3. Good health, Acidosis, Lactic, Electrophoresis, Polyacrylamide Gel, Female, GRACILE SYNDROME, medicine.symptom, Adult, medicine.medical_specialty, Hemosiderosis, Adolescent, Blotting, Western, Mutation, Missense, 610 Medicine & health, Isolated complex III deficiency and assembly, Short stature, Diagnosis, Differential, 03 medical and health sciences, Tubulopathy, Glycosuria, Intellectual Disability, Internal medicine, medicine, Humans, Renal Aminoacidurias, Rieske iron-sulphur protein, business.industry, Infant, Newborn, Fanconi syndrome, Growth retardation, Fanconi Syndrome, medicine.disease, GENE, 030104 developmental biology, Endocrinology, Pediatrics, Perinatology and Child Health, ATPases Associated with Diverse Cellular Activities, Hypoglycaemia, business, Metabolism, Inborn Errors
Abstract

We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. CONCLUSION Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period. What is Known: • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.

Published
2015

14. Acute Hemorrhagic Edema of Infancy With Associated Hemorrhagic Lacrimation

Author

Mario G. Bianchetti, Sebastiano A. G. Lava, Pietro O. Rinoldi, Gregorio P. Milani, and Alessandra Ferrarini

Subjects
Male, medicine.medical_specialty, Databases, Factual, Lacrimal Apparatus Diseases, business.industry, Acute hemorrhagic edema of infancy, Infant, Hemorrhage, General Medicine, medicine.disease, Gastroenterology, Internal medicine, Acute Disease, Pediatrics, Perinatology and Child Health, Emergency Medicine, medicine, Edema, Humans, Vasculitis, Leukocytoclastic, Cutaneous, Female, business
Published
2020

15. Acute hemorrhagic edema of infancy associated with Coxsackie virus infection

Author

Mario G. Bianchetti, Alessandra Ferrarini, Gregorio P. Milani, and Sebastiano A. G. Lava

Subjects
Male, Pathology, medicine.medical_specialty, business.industry, Acute hemorrhagic edema of infancy, Coxsackievirus Infections, Infant, Hemorrhage, medicine.disease, Virus, Enterovirus B, Human, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Pediatrics, Perinatology and Child Health, Acute Disease, medicine, Edema, Humans, Female, 030212 general & internal medicine, business
Published
2018

16. Influenzavirus B-associated acute benign myalgia cruris: An outbreak report and review of the literature

Author

Mario G. Bianchetti, Sebastiano A. G. Lava, Alessandra Ferrarini, Giacomo D. Simonetti, and Gian Paolo Ramelli

Subjects
Male, myalgia, medicine.medical_specialty, Influenzavirus B, Bilateral calf pain, Virus, Disease Outbreaks, Internal medicine, Influenza, Human, Humans, Medicine, Child, Influenza virus B, Genetics (clinical), Nose, Movement Disorders, business.industry, virus diseases, Outbreak, Mean age, Myalgia, Surgery, medicine.anatomical_structure, Italy, Neurology, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), medicine.symptom, business, Switzerland
Abstract

Acute benign myalgia cruris is characterized by transient bilateral calf pain that leads to difficulty walking. A regional outbreak of influenza virus B-associated myalgia cruris was observed during the seasonal influenza outbreak observed in Switzerland from week 1 to 13 of 2013. We performed a prospective case finding among the Swiss-Italian pediatric emergency units and pediatricians. A review of the literature was also performed. The diagnosis of myalgia cruris was made in 49 Swiss-Italian children aged 3.0-14 years (♂:♀=1.7). Flu-like symptoms were resolving when bilateral calf pain began that remitted over ⩽ 7days. The creatine kinase-level, assessed in 28 patients, was elevated in 25. Nose swabs were positive for influenza virus B in 13 out of 14 cases. The blood cell count, measured in 41 cases, disclosed leucopenia in 12 and thrombocytopenia in 3. The review of the literature found 10 outbreaks of ⩾ 10 cases of influenza virus B-associated myalgia cruris, which included a total of 203 patients with a mean age of 7.3 years and a ♂:♀ ratio of 2.0. In conclusion influenza virus B caused a large Swiss-Italian outbreak of myalgia cruris. Our outbreak and the literature indicate that influenza virus B-associated myalgia cruris affects preschool- and school-aged children, primarily boys.

Published
2014

17. Whole Exome Sequencing Revealed a Candidate Gene for Finkelstein-Seidlmayer Disease

Author

Manuel Luedeke, Alessandra Ferrarini, Saskia Biskup, Gabriel Bronz, Heinz Gabriel, Carlo Mainetti, Gian Paolo Ramelli, and Sebastiano A. G. Lava

Subjects
medicine.medical_specialty, Mutation, Candidate gene, business.industry, General Medicine, Disease, medicine.disease_cause, Genetic analysis, Dermatology, Penetrance, medicine, business, Gene, Exome sequencing, Aunt
Abstract

Background: Finkelstein-Seidlmayer disease (FSD) is a benign cutaneous small-vessel leukocytoclastic vasculitis syndrome, which normally affects children between 2-60 months in a male-to-female ratio of 2:1. Skin lesions may appear as papules, erythematous macules, or urticaria. They are symmetric, sharp-edged and favouring the face, ears and extremities. Frequently they are targetoid, annular, medallion-like, or cockade. Fever and extracutaneous involvement are rare and spontaneous resolution occurs in 1-3 weeks. Case Information: In 2015, we reported a familial occurrence of FSD. Patients described in that article were the mother and all her three sons. All of them had a history of recurrent and relapsing non-thrombocytopenic, red-to-purpuric skin lesions, with a neonatal-onset. There was no systemic involvement. Anamnestic data revealed that maternal aunt, cousin and grandmother had also a positive history of neonatal onset of an acute cockade purpura and oedema. At that time, we suspected a genetic form of FSD with an autosomal dominant transmission or X-linked inheritance and incomplete penetrance. Method and Results: Blood samples were obtained from all available family members and a whole exome sequencing (WES) was performed on various affected and non-affected members of this family. The genetic analysis identified a common new mutation in the HCK gene. Conclusion: Up now, FSD is considered a sporadic disease and no genetic researches have been published on affected patients. We performed WES on a previously reported familiar case of FSD and the result was a common mutation in HCK gene. We found out the mutation on all the analysed affected and obligate-carrier members of the family. HCK gene encodes for a hematopoietic cell kinase protein, which is a member of the SRC family of cytoplasmic tyrosine kinases (SFK). We propose that HCK gene could be a candidate gene in the pathophysiology of some types of FSD. We also discuss the autosomal dominant transmission and incomplete penetrance of these specific types of disease.

Published
2019

18. Potocki-shaffer deletion encompassingALX4in a patient with frontonasal dysplasia phenotype

Author

Fodstad Heidi, Jacques S. Beckmann, Frederic Guerry, Gianpaolo Ramelli, Ilse Wieland, Muriel Gaillard, Alessandra Ferrarini, Sébastien Jaquemont, Caroline Verley Keddache, and Danielle Martinet

Subjects
Heterozygote, Potocki–Shaffer syndrome, Chromosome Disorders, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Facial Bones, Craniosynostosis, Craniofacial Abnormalities, Young Adult, Imaging, Three-Dimensional, Genetics, medicine, Humans, Frontonasal dysplasia, Genetics (clinical), Sequence Deletion, Comparative Genomic Hybridization, Mutation, Genetic heterogeneity, Chromosomes, Human, Pair 11, Facies, Exons, medicine.disease, Phenotype, DNA-Binding Proteins, Face, Homeobox, Female, Chromosome Deletion, Exostoses, Multiple Hereditary, Transcription Factors, Comparative genomic hybridization
Abstract

Frontonasal dysplasia (FND) is a genetically heterogeneous malformation spectrum with marked hypertelorism, broad nasal tip and bifid nose. Only a small number of genes have been associated with FND phenotypes until now, the first gene being EFNB1, related to craniofrontonasal syndrome (CFNS) with craniosynostosis in addition, and more recently the aristaless-like homeobox genes ALX3, ALX4, and ALX1, which have been related with distinct phenotypes named FND1, FND2, and FND3 respectively. We here report on a female patient presenting with severe FND features along with partial alopecia, hypogonadism and intellectual disability. While molecular investigations did not reveal mutations in any of the known genes, ALX4, ALX3, ALX1 and EFNB1, comparative genomic hybridization (array CGH) techniques showed a large heterozygous de novo deletion at 11p11.12p12, encompassing the ALX4 gene. Deletions in this region have been described in patients with Potocki–Shaffer syndrome (PSS), characterized by biparietal foramina, multiple exostoses, and intellectual disability. Although the patient reported herein manifests some overlapping features of FND and PPS, it is likely that the observed phenotype maybe due to a second unidentified mutation in the ALX4 gene. The phenotype will be discussed in view of the deleted region encompassing the ALX4 gene. © 2013 Wiley Periodicals, Inc.

Published
2013

19. Primary Hypertension in Childhood

Author

Mario G. Bianchetti, Nico Weber, Barbara S. Bucher, Alessandra Ferrarini, Marina Bullo, and Giacomo D. Simonetti

Subjects
medicine.medical_specialty, Pediatrics, Blood Pressure, Disease, Overweight, Insulin resistance, Risk Factors, Internal medicine, Internal Medicine, medicine, Humans, Salt intake, Child, Sedentary lifestyle, business.industry, Blood Pressure Determination, Sodium, Dietary, medicine.disease, Obesity, Low birth weight, Endocrinology, Blood pressure, Cardiovascular Diseases, Hypertension, medicine.symptom, business
Abstract

There is growing concern about elevated blood pressure in children and adolescents, because of its association with the obesity epidemic. Moreover, cardiovascular function and blood pressure level are determined in childhood and track into adulthood. Primary hypertension in childhood is defined by persistent blood pressure values ≥ the 95th percentile and without a secondary cause. Preventable risk factors for elevated blood pressure in childhood are overweight, dietary habits, salt intake, sedentary lifestyle, poor sleep quality and passive smoking, whereas non-preventable risk factors include race, gender, genetic background, low birth weight, prematurity, and socioeconomic inequalities. Several different pathways are implicated in the development of primary hypertension, including obesity, insulin resistance, activation of the sympathetic nervous system, alterations in sodium homeostasis, renin-angiotensin system and altered vascular function. Prevention of adult cardiovascular disease should begin in childhood by regularly screening for high blood pressure, counseling for healthy lifestyle and avoiding preventable risk factors.

Published
2013

20. Regional differences in symptomatic fever management among paediatricians in Switzerland: the results of a cross-sectional Web-based survey

Author

Gian Paolo Ramelli, Alessandra Ferrarini, Giacomo D. Simonetti, Sebastiano A. G. Lava, and Mario G. Bianchetti

Subjects
Pharmacology, medicine.medical_specialty, Cross-sectional study, business.industry, MEDLINE, language.human_language, Clinical Practice, German, Regimen, Health care, language, medicine, Pharmacology (medical), Psychiatry, business, Web based survey, Regional differences
Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In children antipyretic drugs should be prescribed to treat the general discomfort that accompanies fever. Nonetheless, a gap often exists between available evidence and clinical practice. • Fever is often a cause of fear among both parents and health care providers. • Prescription patterns of several drugs are modulated by socio-cultural factors. WHAT THIS STUDY ADDS • Among the main regions of Switzerland there are significant regional differences in symptomatic fever management as well as in the perceived frequency of fear of fever. • Paediatricians active in the German speaking region less frequently differ from available recommendations than their colleagues active in the French and Italian speaking regions. AIMS In symptomatic fever management, there is often a gap between everyday clinical practice and current evidence. We were interested to see whether the three linguistic regions of Switzerland differ in the management of fever. METHODS A close-ended questionnaire, sent to 900 Swiss paediatricians, was answered by 322 paediatricians. Two hundred and fourteen respondents were active in the German speaking, 78 in the French speaking and 30 in the Italian speaking region. RESULTS Paediatricians from the French and Italian speaking regions identify a lower temperature threshold for initiating a treatment and more frequently reduce it for children with a history of febrile seizures. A reduced general appearance leads more frequently to a lower threshold for treatment in the German speaking than in the French and Italian speaking areas. Among 1.5 and 5-year-old children the preference for the rectal route is more pronounced in the German than in the French speaking region. French speaking respondents more frequently prescribe ibuprofen and an alternating regimen with two drugs than German speaking respondents. Finally, the stated occurrence of exaggerated fear of fever was higher in the German and Italian speaking regions. CONCLUSIONS Switzerland offers the opportunity to compare three different regions with respect to management of febrile children. This inquiry shows regional differences in symptomatic fever management and in the perceived frequency of exaggerated fear of fever. The gap between available evidence and clinical practice is more pronounced in the French and in the Italian speaking regions than in the German speaking region.

Published
2012

21. Familial Henoch-Schönlein Syndrome

Author

Gregorio P. Milani, Alessandra Ferrarini, Giorgia Pellanda, Mario G. Bianchetti, Giacomo D. Simonetti, and Alessandro Ostini

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, IgA Vasculitis, Nephropathy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Age Distribution, Rheumatology, immune system diseases, hemic and lymphatic diseases, medicine, Humans, 030212 general & internal medicine, Young adult, Sex Distribution, Child, 030203 arthritis & rheumatology, business.industry, Infant, Middle Aged, medicine.disease, Purpura, Leukocytoclastic vasculitis, Child, Preschool, HENOCH SCHONLEIN SYNDROME, Age distribution, Female, medicine.symptom, business
Abstract

Little attention has been so far paid to familial cases of Henoch-Schonlein syndrome. We performed a search of the Medical Subject Headings terms (Henoch or Schonlein OR anaphylactoid purpura OR IgA nephropathy OR Berger nephropathy) AND (family OR familial). We identified no more than 19 reports including 47 families with a total of 100 affected cases: their ages ranged from 1.3 to 51 years (median, 11 years), with a male-to-female ratio of 1.4. Familial cases developed simultaneously in 45% and nonsimultaneously in 55% of the families. Age, male-to-female ratio, and clinical findings were not statistically different in cases with simultaneous and nonsimultaneous familial occurrence of Henoch-Schonlein syndrome. Henoch-Schonlein syndrome occurs almost always sporadically. Age at presentation, male-to-female ratio, and findings are similar in familial (both simultaneously and nonsimultaneously occurring) and sporadic Henoch-Schonlein cases.

Published
2016

22. Taste acceptability of pulverized brand-name and generic drugs containing amlodipine or candesartan

Author

Mario G. Bianchetti, Alessandra Ferrarini, Giacomo D. Simonetti, Gregorio P. Milani, Peter Uestuener, Chiara Mardegan, Maristella Santi, and Sebastiano A. G. Lava

Subjects
Adult, Male, Chemistry, Pharmaceutical, Tetrazoles, Pharmaceutical Science, Pharmacology, Irbesartan, Hydrochlorothiazide, medicine, Drugs, Generic, Humans, Single-Blind Method, Amlodipine, Antihypertensive Agents, business.industry, Lercanidipine, Biphenyl Compounds, Taste Perception, Middle Aged, Calcium Channel Blockers, Candesartan, Valsartan, Patient Satisfaction, Bisoprolol, Benzimidazoles, Female, Telmisartan, business, Angiotensin II Type 1 Receptor Blockers, medicine.drug
Abstract

Trials with pulverized brand-name antihypertensive drugs suggest that, from the perspective of taste acceptability, crushed candesartan, chlortalidon, hydrochlorothiazide, lercanidipine and lisinopril should be preferred to pulverized amlodipine, atenolol, bisoprolol, enalapril, irbesartan, losartan, ramipril, telmisartan and valsartan. Brand-name antihypertensive drugs and the corresponding generic medicines have never been compared with respect to their taste acceptability. We therefore investigated among healthy health care workers the taste acceptability of a pulverized 1 mg-test dose of the brand-name and two generics containing either the dihydropyridine calcium-channel blocker amlodipine (Norvasc(®), Amlodipin-Mepha(®) and Amlodipin Pfizer(®)) or the angiotensin receptor antagonist candesartan (Atacand(®), Cansartan-Mepha(®) and Pemzek(®)). For this purpose, a smiley-face scale depicting four degrees of pleasure was used. Between November and December 2013, the taste test was performed among 19 nurses (15 female and 4 male subjects) and 12 physicians (5 female and 7 male subjects) aged between 25 and 49 years. Pulverized brand-names and generics containing either amlodipine or candesartan did not differ with respect to their taste acceptability.

Published
2014

23. Familial occurrence of an association of multiple intestinal atresia and choanal atresia: A new syndrome?

Author

Maria-Chiara Osterheld, Yvan Vial, Jacques S. Beckmann, Florence Fellmann, Pierre A. de Viragh, Jacques Cotting, Danielle Martinet, and Alessandra Ferrarini

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Ectodermal dysplasia, Intestinal Atresia, Choanal atresia, Gastroenterology, Choanal Atresia, Fetus, Pregnancy, Internal medicine, otorhinolaryngologic diseases, Genetics, medicine, Humans, Abnormalities, Multiple, Family, Genetics (clinical), business.industry, Infant, Newborn, Syndrome, medicine.disease, Small intestine, Pedigree, Stenosis, Endocrinology, medicine.anatomical_structure, Atresia, Gestation, Female, business, Hair
Abstract

We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

Published
2009

24. Index of Suspicion

Author

Alessandra Ferrarini, Gian Paolo Ramelli, and Mario G. Bianchetti

Subjects
Pediatrics, Perinatology and Child Health
Published
2009

25. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome

Author

Bregje W.M. van Bon, Tiia Reimand, Berten Ceulemans, Barbara Delle Chiaie, Christine Oley, Anne Destree, Ernie M.H.F. Bongers, Danielle Martinet, Dom McMullan, Rolph Pfund, Bert B.A. de Vries, Jenneke van den Ende, Louise Brueton, Connie Schrander-Stumpel, Corrado Romano, Marco Fichera, Alexander P.A. Stegmann, Edwin Reyniers, Geert Mortier, Suzanna G.M. Frints, Isabelle Maystadt, Katrin Männik, Nathalie Van der Aa, Ants Kurg, Geert Vandeweyer, Björn Menten, Alessandra Ferrarini, R. Frank Kooy, Sébastien Jacquemont, and Liesbeth Rooms

Subjects
Male, Williams Syndrome, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Language delay, Population, Chromosome Disorders, Speech Disorders, Genomic disorders and inherited multi-system disorders [IGMD 3], Communication disorder, Intellectual Disability, Gene duplication, Genetics, medicine, Humans, Abnormalities, Multiple, Diaphragmatic hernia, Child, education, Genetics (clinical), Family Health, education.field_of_study, business.industry, Infant, Syndrome, General Medicine, medicine.disease, Hypotonia, Phenotype, Child, Preschool, Face, Speech delay, Autism, Female, Human medicine, Chromosome Deletion, medicine.symptom, business, Chromosomes, Human, Pair 7
Abstract

Contains fulltext : 80644.pdf (Publisher’s version ) (Closed access) Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.

Published
2009

26. Primary Vesicoureteric Reflux and Reflux Nephropathy - New Insights

Author

Laura Crosazzo, Alessandra Ferrarini, Laura Santoro, and Mario G. Bianchetti

Subjects
Reflux nephropathy, medicine.medical_specialty, business.industry, Pediatrics, Perinatology and Child Health, Urology, Medicine, business, medicine.disease, Primary vesicoureteric reflux
Published
2006

27. A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf–Hirschhorn syndrome

Author

Angelo Selicorni, Giovanni Neri, Giuseppe Zampino, Marcella Zollino, Rosetta Lecce, Alessandra Ferrarini, Livia Garavelli, Mariano Rocchi, John M. Opitz, Giuseppe Marangi, Marina Murdolo, and Irene Mancuso

Subjects
Adult, Male, Adolescent, Genotype, Chromosome Disorders, Chromosomal translocation, Biology, Genome, Translocation, Genetic, Chromosome Painting, Seizures, Chromosomal Instability, Chromosome instability, Genetics, medicine, Humans, Abnormalities, Multiple, Wolf–Hirschhorn syndrome, Genetics (clinical), Infant, Chromosome, Syndrome, medicine.disease, Phenotype, Chromosome 4, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, Muscle Hypotonia, Female, Chromosome Deletion, Chromosomes, Human, Pair 4, Chromosomes, Human, Pair 8, Microsatellite Repeats
Abstract

A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 de novo microdeletion was referred because of genotype-phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter --p16.1::8p23 --pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter --q32::4p15.3 --qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n = 13) or microdeletions (n = 7) and with apparently straightforward genotype-phenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter --4p16.3::8p23 --8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.

Published
2004

28. Chromosomal microarray among children with intellectual disability: a useful diagnostic tool for the clinical geneticist

Author

Alessandra Ferrarini, Danielle Martinet, Gian Paolo Ramelli, Marco Belfiore, Mario G. Bianchetti, Sebastiano A. G. Lava, and Stephanie Capobianco

Subjects
Chromosome Aberrations, Male, medicine.medical_specialty, Microarray, Adolescent, business.industry, Developmental Disabilities, Geneticist, medicine.disease, Young Adult, Developmental Neuroscience, Pediatrics, Perinatology and Child Health, Intellectual disability, Medicine, Humans, Female, Neurology (clinical), 610 Medicine & health, business, Psychiatry, Child, Oligonucleotide Array Sequence Analysis
Published
2013

29. High prevalence of pathologic copy number variants detected by chromosomal microarray in Swiss-Italian children with autism spectrum disorders

Author

Giorgia Pellanda, Sebastiano A. G. Lava, Alessandra Ferrarini, and Gian Paolo Ramelli

Subjects
Chromosome Aberrations, Male, Genetics, High prevalence, Microarray, business.industry, Developmental Disabilities, General Medicine, Microarray Analysis, medicine.disease, Child Development Disorders, Pervasive, Intellectual Disability, Pediatrics, Perinatology and Child Health, Humans, Medicine, Autism, Female, Neurology (clinical), Copy-number variation, 610 Medicine & health, business
Published
2015

30. Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum

Author

Daniela Melis, Lidia Larizza, Anna Cereda, Alessandra Ferrarini, Angelo Selicorni, Silvia Russo, Cristina Gervasini, Teresa Aravena, Maura Masciadri, Ilaria Parenti, Bérénice Doray, Jacopo Azzollini, and Livia Garavelli

Subjects
Male, Cornelia de Lange Syndrome, Adolescent, Chromosomal Proteins, Non-Histone, Molecular Sequence Data, Sequence alignment, Cell Cycle Proteins, Biology, SMC1A, Exon, De Lange Syndrome, Genetics, medicine, Missense mutation, Humans, Amino Acid Sequence, Child, Gene, Peptide sequence, Genetics (clinical), Infant, Newborn, Facies, Infant, Exons, medicine.disease, Phenotype, Child, Preschool, Mutation, Female, Sequence Alignment
Abstract

We report on the clinical and molecular characterization of eight patients, one male and seven females, with clinical diagnosis of Cornelia de Lange syndrome (CdLS), who were found to carry distinct mutations of the SMC1A gene. Five of the eight mutations are novel, with two involving amino acid residues previously described as altered in a different way. The other three have been reported each in a single case. Comparison of pairs of individuals with the same mutation indicates only partial overlap of their clinical phenotypes. The following novel missense mutations, all affecting highly conserved amino acid residues, were found: p.R398G in the N-terminal coiled-coil domain, p.V651M in the C-terminal coiled-coil/hinge junction, p.R693G in the C-terminal coiled-coil, and p.N1166T and p.L1189F in the C-terminal ABC cassette. The latter is localized in the H-loop, and represents the first mutation involving a functional motif of SMC1A protein. The effect of the mutations on SMC1A protein function has been predicted using four bioinformatic tools. All mutations except p.V651M were scored as pathogenic by three or four of the tools. p.V651M was found in the only male individual of our cohort, who presented with the most severe phenotype. This raises the issue of gender effect when addressing mutation-phenotype correlation for genes such as SMC1A, which incompletely escapes X-inactivation. Our clinical and molecular findings expand the total number of characterized SMC1A-mutated patients (from 44 to 52) and the restricted repertoire of SMC1A mutations (from 29 to 34), contributing to the molecular and clinical signature of SMC1A-based CdLS. © 2013 Wiley Periodicals, Inc.

Published
2013

31. What can we do to make antihypertensive medications taste better for children?

Author

Alesandra A. Bianchetti, Mario G. Bianchetti, Giacomo D. Simonetti, Emilio F. Fossali, Pietro B. Faré, Sebastiano A. G. Lava, and Alessandra Ferrarini

Subjects
business.industry, Lercanidipine, Adrenergic beta-Antagonists, Lisinopril, Pharmaceutical Science, Angiotensin-Converting Enzyme Inhibitors, Pharmacology, Calcium Channel Blockers, Candesartan, Irbesartan, Hydrochlorothiazide, Bisoprolol, Taste, Odorants, medicine, Humans, Chlorthalidone, Amlodipine, business, Child, Diuretics, Antihypertensive Agents, circulatory and respiratory physiology, medicine.drug
Abstract

More and more data indicate the importance of palatability when selecting drugs for children. Since hypertension is uncommon in children, no child-friendly palatable formulations of these agents are currently available. As a consequence, in everyday practice available tablets are crushed and administered mixed with food or a sweet drink. We started investigating the issue of palatability of drugs among children in 2004 using smile-face scales. In the first trial we compared taste and smell acceptability of pulverized angiotensin receptor antagonists among nephropathic children and found that the score assigned to candesartan was significantly higher than that assigned to irbesartan, losartan, telmisartan and valsartan. In the second trial we compared the taste of pulverized amlodipine and lercanidipine among children and found that the score assigned to lercanidipine was significantly higher. Our third trial was performed using pulverized β-adrenoceptor blockers, angiotensin-converting enzyme inhibitors, calcium-channel antagonists and diuretics among medical officers and pediatricians. The palatability scores assigned to chlorthalidone, hydrochlorothiazide and lisinopril were significantly higher to those assigned to atenolol, bisoprolol, enalapril and ramipril. In conclusion pulverized amlodipine, atenolol, bisoprolol, enalapril, irbesartan, losartan, ramipril, telmisartan and valsartan are poor tasting. From the child's perspective, lercanidipine, candesartan, chlorthalidone, hydrochlorothiazide and lisinopril are preferable.

Published
2013

32. Ureteral or vesical involvement in Henoch-Schönlein syndrome: a systematic review of the literature

Author

Mario G. Bianchetti, Alessandra Ferrarini, Giacomo D. Simonetti, Mattia Rizzi, Alberto Bettinelli, and Giordano M. Siegenthaler

Subjects
Nephrology, Adult, Male, medicine.medical_specialty, Henoch-Schonlein purpura, Adolescent, IgA Vasculitis, MEDLINE, Young Adult, Internal medicine, medicine, Humans, Ureteral Diseases, Child, business.industry, Urinary Bladder Diseases, Ureteritis, Syndrome, Middle Aged, medicine.disease, Dermatology, Surgery, Purpura, Child, Preschool, Pediatrics, Perinatology and Child Health, HENOCH SCHONLEIN SYNDROME, Female, medicine.symptom, business
Abstract

Little information is available on ureteral or vesical involvement in Henoch-Schönlein syndrome. To determine the features of this condition we performed a formal analysis of peer-reviewed scientific literature on this topic.The US National Library of Medicine database was used as the data source. All articles published as full-length articles or letters were collected. Reports published in languages other than English, French, German, Italian or Spanish were not considered.We analyzed 32 reports describing 35 cases (24 male and 11 female subjects aged between 3.5 and 63, median 7.0 years) with ureteral (n = 30), vesical (n = 4), or both ureteral and vesical involvement (n = 1). The presentation included colicky abdominal pain, macroscopic hematuria (sometimes containing blood clots), urinary tract infection or urinary retention. The diagnosis of ureteral involvement was often fortuitous. Patients with vesical involvement were managed conservatively. However, the majority of those with ureteral involvement were managed surgically.Ureteral or vesical involvement is unusual and likely underappreciated in Henoch-Schönlein syndrome. Improved recognition and wider appreciation of this involvement can help to avoid associated morbidity. Management must be individualized for each patient. A multidisciplinary approach may be of value in planning medical treatment, surgical intervention, and follow-up.

Published
2013

33. Two new cases of Barraquer-Simons syndrome

Author

Giacomo Cagnoli, Alessandra Ferrarini, Donatella Milani, M. Bottigelli, and Angelo Selicorni

Subjects
medicine.medical_specialty, Lipodystrophy, business.industry, Partial Lipodystrophy, Syndrome, medicine.disease, Dermatology, Barraquer–Simons syndrome, Nephropathy, Epilepsy, Endocrinology, Internal medicine, medicine, Humans, Female, medicine.symptom, Child, Myopathy, business, Genetics (clinical), Skin
Abstract

Barraquer-Simons syndrome is a rare form of partial lipodystrophy, mainly characterized by loss of subcutaneous tissue, starting from the face and spreading to the upper part of the body. Occasional functional anomalies such as deafness, epilepsy, and mental retardation can be associated with the condition; nephropathy and myopathy have been observed occasionally. Here we report on two new sporadic cases, who show at the moment only a facial involvement, without any associated anomalies and/or medical complications.

Published
2004

34. Early occurrence of lung adenocarcinoma and breast cancer after radiotherapy of a chest wall sarcoma in a patient with a de novo germline mutation in TP53

Author

Stephan C. Schäfer, Jacques S. Beckmann, Agnes Auteri-Kaczmarek, Alessandra Ferrarini, Christian Monnerat, Viviane Cina, Alessia Pica, Nemya Boesch, Karl Heinimann, and Sara Vesnaver-Megalo

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Breast Neoplasms, Adenocarcinoma, Germline, Germline mutation, Breast cancer, Internal medicine, Genetics, medicine, Humans, Thoracic Wall, neoplasms, Germ-Line Mutation, Genetics (clinical), business.industry, Cancer, Neoplasms, Second Primary, Sarcoma, Thoracic Neoplasms, medicine.disease, Radiation therapy, Li–Fraumeni syndrome, Female, Tumor Suppressor Protein p53, business
Abstract

We report a 26-year-old female patient who was diagnosed within 4 years with chest sarcoma, lung adenocarcinoma, and breast cancer. While her family history was unremarkable, DNA sequencing of TP53 revealed a germline de novo non-sense mutation in exon 6 p.Arg213X. One year later, she further developed a contralateral ductal carcinoma in situ, and 18 months later a jaw osteosarcoma. This case illustrates the therapeutic pitfalls in the care of a young cancer patient with TP53 de novo germline mutations and the complications related to her first-line therapy. Suggestion is made to use the less stringent Chompret criteria for germline TP53 mutation screening. Our observation underlines the possibly negative effect of radiotherapy in generating second tumors in patients with a TP53 mutation. We also present a review of six previously reported cases, comparing their cancer phenotypes with those generally produced by TP53 mutations.

Published
2011

35. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Published
2011

36. [Array CGH: why and to whom]

Author

Alessandra, Ferrarini, Sébastien, Jacquemont, Maja Beck, Popovic, Luisa, Bonafé, and Danielle, Martinet

Subjects
Chromosome Aberrations, Comparative Genomic Hybridization, Genetic Diseases, Inborn, Humans
Abstract

Structural genomic abnormalities play a key role in the pathogenesis of human disorders and represent one of the first causes of mental impairment, complex syndromes and tumors. In order to detect these chromosomal abnormalities, many methodologies have been developed with limits. The new ARRAY based Comparative Genomic Hybridization (ARRAY CGH) is a revolutionary approach which allows to characterize very small genetic abnormalities undetectable by the standard approaches and in the absence of any associated clinical information. The aim of this article is to describe why the application of a new array CGH methodology is necessary in the etiological search for genetic diseases, what the limits of the standard approaches are and to whom arrayCGH analyses can be applied in a pediatric environment. Examples of our practice will be presented.

Published
2010

37. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2

Author

Peter Vollenweider, Leena Peltonen, Audrey Labalme, Jessica L. Buxton, Alessandra Ferrarini, Dawn M. Waterworth, Sven Bergmann, Gérard Waeber, Marie Pigeyre, Sébastien Jacquemont, Vincent Mooser, Audrey Guilmatre, C. Lecoeur, Muriel Holder-Espinasse, Bettina Blaumeiser, Elena G. Bochukova, Ni Huang, Andrew Walley, Danielle Martinet, Peter Jacobson, B. Leheup, Marie-Pierre Lemaitre, A. Brioschi, Julia M. Keogh, Damien Sanlaville, Stephen O'Rahilly, Robert Sladek, Bruno Delobel, Fanny Stutzmann, Sophie Dupuis-Girod, Philippe Froguel, Muriel Gaillard, Anne Philippe, Katrin Männik, Jean-Marie Cuisset, M. Béri-Dexheimer, Lachlan J. M. Coin, Fei Chen, François Pattou, Katrin Õunap, Mari Nelis, A.-L. Hartikainen, Jean-Claude Chèvre, Philippe Jonveaux, Alice Goldenberg, Kay D. MacDermot, Elana Henning, Odile Boute, Sonia Bouquillon, Armand Valsesia, Valérie Malan, Stéphane Lobbens, R. F. Kooy, Alexandra I. F. Blakemore, Marie-Pierre Cordier, Lena M. S. Carlsson, Marjo-Riitta Järvelin, Lars Sjöström, Paul Elliott, C Le Caignec, Florence Fellmann, Nadège Calmels, Dominique Campion, M. M. van Haelst, Vincent Vatin, B. Balkau, Jacques S. Beckmann, Mark I. McCarthy, Robert Caiazzo, Jean-Louis Mandel, Joris Andrieux, Nouchine Hadjikhani, Catherine Vincent-Delorme, David Meyre, Ants Kurg, J. S. El-Sayed Moustafa, Johanna C. Andersson, Jean Chiesa, Michèle Mathieu-Dramard, R. Touraine, Tõnu Esko, Albert David, Alexandre Reymond, Priit Palta, Ghislaine Plessis, Andres Metspalu, Robin G. Walters, Vittorio Giusti, Richard J. Ellis, Bertrand Isidor, Anne-Emmanuelle Ambresin, A J de Smith, I. S. Farooqi, Matthew E. Hurles, Mario Falchi, Medical Research Council (MRC), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), and Other departments

Subjects
Male, Aging, SAMPLE, Inheritance Patterns, Genome-wide association study, Penetrance, MC4R, Body Mass Index, Cohort Studies, 0302 clinical medicine, SH2B1, Missing heritability problem, Age of Onset, Child, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, Sex Characteristics, Multidisciplinary, Mental-Retardation, Adolescent Adult Age of Onset Aging Body Mass Index Case-Control Studies Child *Chromosome Deletion Chromosomes, Human, Pair 16/*genetics Cognition Disorders/complications/genetics Cohort Studies Europe Female Genome-Wide Association Study Heterozygote Humans Inheritance Patterns/genetics Male Mutation/genetics Obesity/complications/*genetics/*physiopathology *Penetrance Reproducibility of Results Sex Characteristics Young Adult, 3. Good health, Multidisciplinary Sciences, Europe, Adolescent, Adult, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Cognition Disorders/complications, Cognition Disorders/genetics, Female, Genome-Wide Association Study, Heterozygote, Humans, Inheritance Patterns/genetics, Mutation/genetics, Obesity/complications, Obesity/genetics, Obesity/physiopathology, Reproducibility of Results, Young Adult, Medical genetics, Science & Technology - Other Topics, CHILDHOOD OBESITY, medicine.medical_specialty, Childhood Obesity, BIRTH, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, Article, Childhood obesity, 03 medical and health sciences, medicine, MICRODELETION, Obesity, GENOME-WIDE ASSOCIATION, AUTISM, education, 030304 developmental biology, COPY NUMBER VARIATION, Science & Technology, MULTIDISCIPLINARY SCIENCES, FRAMESHIFT MUTATION, Individuals, medicine.disease, RISK LOCI, INDIVIDUALS, CIRCULAR BINARY SEGMENTATION, Mutation, Human medicine, Cognition Disorders, MENTAL-RETARDATION, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 16
Abstract

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Published
2010

38. Microduplication 22q11.2 in a child with autism spectrum disorder: clinical and genetic study

Author

Gian Paolo Ramelli, Charlotte Silacci, Graziano Pescia, Alessandra Ferrarini, Claudio Cattaneo, and Paola Visconti

Subjects
Male, medicine.medical_specialty, Pediatrics, Chromosomes, Human, Pair 22, Developmental Disabilities, Buccal swab, Developmental arrest, Cell Cycle Proteins, Diagnosis, Differential, Consanguinity, Genetic Heterogeneity, Developmental Neuroscience, Gene Duplication, Gene duplication, medicine, DiGeorge Syndrome, Humans, Histone Chaperones, Autistic Disorder, Psychiatry, In Situ Hybridization, Fluorescence, Genetic complexity, medicine.disease, Functional development, Phenotype, Autism spectrum disorder, Child, Preschool, Pediatrics, Perinatology and Child Health, Chromosomal region, Autism, Neurology (clinical), Psychology, Transcription Factors
Abstract

Microduplication of the 22q11.2 chromosomal region has been recognized since 1999 and has been associated with a highly variable phenotype. Neurodevelopmental impairment and behavioural problems are very common in patients with 22q11.2 duplication. Autism spectrum disorders (ASDs) have previously been reported in only two patients with 22q11.2 duplication and striking dysmorphic features. We report here on a 4-year-old male of healthy consanguineous parents presenting with ASD according to DSMIV, revised, criteria as a primary manifestation. The child walked at 16 months and started to say one word and some sounds. Parents noticed a subsequent developmental arrest. At 4 years his functional development age, evaluated by the Psychoeducational Profile, was roughly 6 months. Mild non-specific facial dysmorphism was noted. Genetic analyses of the child demonstrated a de novo microduplication of the 22q11.2 chromosomal region. This genetic anomaly was best seen in interphases of blood lymphocytes and in buccal smear nuclei. Our case illustrates once again the clinical heterogeneity of the 22q11.2 duplication as well as the wide genetic complexity of ASD. We suggest that genetic evaluation of ASD should include fluorescence in-situ hybridization analysis of the 22q11.2 chromosomal region.

Published
2008

39. Systemic hypertension and proteinuria in childhood chronic renal parenchymal disease: role of antihypertensive drug management

Author

Laura Crosazzo-Franscini, Giacomo D. Simonetti, Laura Santoro, Mario G. Bianchetti, Emilio F. Fossali, and Alessandra Ferrarini

Subjects
medicine.medical_specialty, Angiotensin receptor, medicine.drug_class, Adrenergic beta-Antagonists, Drug Resistance, Angiotensin-Converting Enzyme Inhibitors, Disease, Pharmacology, Pharmacotherapy, Internal medicine, medicine, Humans, Pharmacology (medical), Antihypertensive drug, Child, Diuretics, Antihypertensive Agents, Proteinuria, business.industry, medicine.disease, Calcium Channel Blockers, Blood pressure, Pediatrics, Perinatology and Child Health, Chronic Disease, Hypertension, Drug Therapy, Combination, Kidney Diseases, medicine.symptom, business, Angiotensin II Type 1 Receptor Blockers, Kidney disease
Abstract

A variety of chronic kidney diseases tend to progress towards end-stage kidney disease. Progression is largely due to factors unrelated to the initial disease, including systemic hypertension and proteinuria. Drugs that block the renin-angiotensin II-aldosterone system, either ACE inhibitors or angiotensin II receptor antagonists, reduce both BP and proteinuria and appear superior to a more conventional antihypertensive treatment regimen in preventing progression to end-stage kidney disease. The most recent recommendations state that the BP goal in children with chronic kidney disease is the corresponding 90th centile for body height, age, and gender. Since satisfactory BP control is often not achieved, the mnemonic acronym DELTAREPROSI was generated to recall the following tips for the practical management of hypertension and proteinuria in childhood chronic renal parenchymal disease: DEfinition of hypertension and Low blood pressure TArget in REnal disease (90th centile calculated by means of simple formulas), potential of drugs inhibiting the REnin-angiotensin II-aldosterone system in hypertension and PROteinuria, advantages of SImplified treatment regimens and escalating the doses every SIx weeks.

Published
2007

40. P132 – 2903: A newborn with poor feeding and a mask-like face

Author

V. Dell'Orto, Gian Paolo Ramelli, Alessandra Ferrarini, and Mario G. Bianchetti

Subjects
medicine.medical_specialty, Möbius syndrome, Pregnancy, business.industry, Sucking Reflex, Cranial nerves, Facial weakness, General Medicine, medicine.disease, Drooling, Surgery, Poor Feeding, medicine.anatomical_structure, Tongue, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), medicine.symptom, business
Abstract

Case presentation A male newborn, the child of nonconsanguineous parents, presents with poor feeding with difficulty in swallowing, drooling of saliva and clubfeet. He had been delivered by cesarean section 3 days earlier at term with normal body weight, length and head circumference. The boy is non-toxic in appearance and without distress. Both feet appear inverted and adducted with an inability to bring them to midline. The extremities are flexed with normal Moro-, Galant-, walking-, palmar- and plantar reflexes. The face appears symmetric and masklike with mimicking features when crying hardly differing from those at rest. The child is not able to follow laterally an object moving horizontally, no blink is noted when a bright light is shone in his eyes, the sucking reflex is weak and the tongue movements are poor. In retrospect the parents reported the use of misoprostol during the first trimester of pregnancy in an attempt to terminate pregnancy. Discussion Non-traumatic congenital bilateral abducens and facial weakness, the most consistent abnormalities noticed in our newborn are essential clinical features of Mobius syndrome, a condition that is diagnosed clinically. This syndrome results from a developmental anomaly of the rhombencephalon that occurs between the 6th and 12th gestational week. The term Mobius syndrome, which was initially used exclusively to define a congenital bilateral facial weakness associated with restriction of horizontal eye movements, has been subsequently expanded to include palsies of other cranial nerves as well as other malformations, such as cranio-facial and oro-facial anomalies and limb malformations that sometimes concurrently occur. The causes of the syndrome include genetic, ischemic, infectious and above all teratogenic factors such as the ingestion of drugs like cocaine, alcohol, ergotamine derivatives, thalidomide, benzodiazepines, and especially, like in our case, the prostaglandin analogue misoprostol (often used for uterine evacuation in pregnancy).

Published
2015

41. False positive dipstick for urinary blood in childhood

Author

Jacopo H, Robbiani, Giacomo D, Simonetti, Laura, Crosazzo, Alessandra, Ferrarini, Fosca, Pronzini, and Mario G, Bianchetti

Subjects
Male, Blood, Adolescent, Child, Preschool, Humans, False Positive Reactions, Female, Reagent Kits, Diagnostic, Child, Hematuria
Abstract

In view of the obvious practical advantages, the most common test for hematuria is currently a reagent strip.A standardized microscopic examination of the sediment was performed in 20 asymptomatic children referred for evaluation of chronic isolated microhematuria detected by means of a reagent strip.In 6 of the 20 children the microscopic examination failed to confirm the result of the dipstick test.Confirmation for the presence of hematuria by microscopy is the most important step in children with a positive dipstick for urinary blood.

Published
2006

42. Poor Adherence to the prophylactic Use of Vitamin D3 in Switzerland

Author

Mario G. Bianchetti, Federica Bartoli, Juan M. Martinez, Elena Recaldini, and Alessandra Ferrarini

Subjects
Vitamin, Poor adherence, medicine.medical_specialty, Pediatrics, chemistry.chemical_compound, Endocrinology, chemistry, business.industry, Endocrinology, Diabetes and Metabolism, Pediatrics, Perinatology and Child Health, Medicine, business, Intensive care medicine
Published
2006

43. Additional case of Tsukahara's syndrome or new syndrome: further delineation of the association of microcephaly and radio-ulnar synostosis

Author

Michaela Bottigelli, Angelo Selicorni, Giacomo Cagnoli, Donatella Milani, Alessandra Ferrarini, and Alessia Fratoni

Subjects
Male, Microcephaly, Ulna, Scoliosis, Short stature, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), In Situ Hybridization, Fluorescence, S syndrome, business.industry, Anatomy, Syndrome, Synostosis, medicine.disease, body regions, Radius, Child, Preschool, Karyotyping, medicine.symptom, Congenital disease, business
Abstract

In 1994, Giuffre et al. reported two unrelated families in which some of the members had microcephaly and radio-ulnar synostosis, suggesting a new condition. Since this first report, Tsukahara et al. and Udler et al. described two distinct patients with a different condition characterized by radio-ulnar synostosis, short stature, microcephaly, scoliosis, and mental retardation. Here we report on a new case of microcephaly and radio-ulnar synostosis and discuss the possible relationship between Tsukahara's syndrome and the phenotype described by Giuffre et al.

Published
2004

44. Severe systemic adverse reaction to proton pump inhibitors in an infant

Author

Mario Mendoza Sagaon, Emanuele Baldassarre, Mario G. Bianchetti, and Alessandra Ferrarini

Subjects
Lung Diseases, Pulmonary and Respiratory Medicine, medicine.drug_class, Proton-pump inhibitor, Esomeprazole, medicine, Humans, Enzyme Inhibitors, Adverse effect, Omeprazole, Respiratory Sounds, Respiratory distress, business.industry, Esophageal disease, digestive, oral, and skin physiology, Respiratory disease, Infant, Proton Pump Inhibitors, medicine.disease, Anesthesia, Pediatrics, Perinatology and Child Health, Gastroesophageal Reflux, Female, business, Anaphylaxis, medicine.drug
Abstract

Episodes of respiratory distress with chest retraction and wheezing, sometimes associated with facial edema, were noted after administering the proton pump inhibitors omeprazole and esomeprazole in an infant with gastroesophageal reflux. The disturbances relieved dramatically after withdrawing the proton pump inhibitor.

Published
2007

45. Intraoperative anaphylaxis to a chlorhexdine polymer in childhood

Author

Alessandra Ferrarini, Marco Baggi, Mario G. Bianchetti, and Rudolph Flückiger

Subjects
Anesthesiology and Pain Medicine, business.industry, Pediatrics, Perinatology and Child Health, medicine, Medical emergency, medicine.disease, business, Anaphylaxis
Published
2006

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