title: Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.
abstract: OBJECTIVE
  Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.
  
  
  METHODS
  We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.
  
  
  RESULTS
  We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.
  
  
  CONCLUSIONS
  Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. tracy.briggs@manchester.ac.uk.|St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. tracy.briggs@manchester.ac.uk.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Briggs
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: Department of Rheumatology, The Lady Cilento Children's Hospital, Brisbane, Australia.
authors.forename: Navid
authors.initials: N
authors.lastname: Adib
authors.affiliation: Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paedatrics and Child Health, The University of Sydney, Sydney, Australia.
authors.forename: Lesley
authors.initials: L
authors.lastname: Ades
authors.affiliation: Dermatology Department, Pitie-Salpetriere Hospital, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Barete
authors.affiliation: Creighton University, 2500 California Plaza, NE 68178, Omaha, USA.
authors.forename: Kannan
authors.initials: K
authors.lastname: Baskar
authors.affiliation: Pediatric Nephrology Department, Robert Debré University Hospital - APHP, 48 boulevard Sérurier, 75019, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Baudouin
authors.affiliation: Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye.
authors.forename: Ayse N
authors.initials: AN
authors.lastname: Cebeci
authors.affiliation: Pediatric Imaging Unit, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clapuyt
authors.affiliation: Neuroscience Department, The Lady Cilento Children's Hospital, Brisbane, Australia.|School of Medicine, Griffith University, Gold Coast, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Coman
authors.affiliation: Pediatric Rheumatology, Department of Pediatrics, University Hospitals Leuven, B-3000, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: De Somer
authors.affiliation: Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Finezilber
authors.affiliation: Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel.|Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Frydman
authors.affiliation: Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye.|Amasya University Medical Faculty, Department of Pediatric Endocrinology, Istanbul, Türkiye.
authors.forename: Ayla
authors.initials: A
authors.lastname: Guven
authors.affiliation: Department of Pediatric Hematology and Oncology, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Heritier
authors.affiliation: Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Karall
authors.affiliation: J. J. M. Medical College, Davangere, Karnataka, 577004, India.
authors.forename: Muralidhar L
authors.initials: ML
authors.lastname: Kulkarni
authors.affiliation: Service de Virologie, AP-HP Hôpital Cochin, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebon
authors.affiliation: Department of Paediatrics, The Lady Cilento Children's Hospital, Brisbane, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Levitt
authors.affiliation: Centre de Référence des Maladies Osseuses Constitutionnelles et Institut Imagine, Hopital Necker 149 rue de Sevres, 75015, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.affiliation: APHP, Bicêtre Paris Sud, Department of Pediatric Endocrinology and Diabetology for Children, 94270, Le Kremlin Bicêtre, France.|Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d'expertise Paris Sud Maladies Rares, APHP, 94270, Le Kremlin Bicêtre, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Linglart
authors.affiliation: Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
authors.forename: John H
authors.initials: JH
authors.lastname: Livingston
authors.affiliation: Epilepsy Unit, Pitie-Salpetriere Hospital, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Navarro
authors.affiliation: Kaiser Permanente - Genetics, 1650 Response Rd, Sacramento, CA, 95815, USA.
authors.forename: Ericka
authors.initials: E
authors.lastname: Okenfuss
authors.affiliation: Génétique Humaine des Maladies Infectieuses, INSERM UMR 1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Pièce 421-B1, 24 boulevard du Montparnasse, 75015, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.affiliation: Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nicole
authors.initials: N
authors.lastname: Revencu
authors.affiliation: Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Scholl-Bürgi
authors.affiliation: Division of Nephrology, IRCCS Bambino Gesu' Pediatric Hospital, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Vivarelli
authors.affiliation: Department of Microbiology and Immunology, Pediatric Immunology, KU Leuven, University of Leuven, Leuven, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.affiliation: Pediatric Immunology and Rheumatology Unit, Hôpital Necker, APHP, Paris, France.|Institut Imagine, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bader-Meunier
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.|Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, 24 boulevard du Montparnasse, 75015, Paris, France.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001842:Bone and Bones / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000071681:Tartrate-Resistant Acid Phosphatase / Q000172:deficiency / Q000235:genetics* / Q000276:immunology
chemical_list: D001323:Autoantibodies; D007370:Interferon Type I; C000605510:ACP5 protein, human; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: ACP5; SPENCD/SPENCDI; Spondyloenchondrodysplasia; interferon signature; tartrate-resistant acid phosphatase (TRAP); type I interferon