2. Academic Validation
  3. Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey

Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey

  • J Clin Immunol. 2016 Apr;36(3):220-34. doi: 10.1007/s10875-016-0252-y.
Tracy A Briggs 1 2,  Gillian I Rice 3,  Navid Adib 4,  Lesley Ades 5 6,  Stephane Barete 7,  Kannan Baskar 8,  Veronique Baudouin 9,  Ayse N Cebeci 10,  Philippe Clapuyt 11,  David Coman 12 13,  Lien De Somer 14,  Yael Finezilber 15,  Moshe Frydman 15 16,  Ayla Guven 10 17,  Sébastien Heritier 18,  Daniela Karall 19,  Muralidhar L Kulkarni 20,  Pierre Lebon 21,  David Levitt 22,  Martine Le Merrer 23,  Agnes Linglart 24 25,  John H Livingston 26,  Vincent Navarro 27,  Ericka Okenfuss 28,  Anne Puel 29,  Nicole Revencu 30,  Sabine Scholl-Bürgi 19,  Marina Vivarelli 31,  Carine Wouters 32,  Brigitte Bader-Meunier 33 34,  Yanick J Crow 3 35
Affiliations

Affiliations

  • 1 Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK. [email protected].
  • 2 St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. [email protected].
  • 3 Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
  • 4 Department of Rheumatology, The Lady Cilento Children's Hospital, Brisbane, Australia.
  • 5 Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia.
  • 6 Discipline of Paedatrics and Child Health, The University of Sydney, Sydney, Australia.
  • 7 Dermatology Department, Pitie-Salpetriere Hospital, Paris, France.
  • 8 Creighton University, 2500 California Plaza, NE 68178, Omaha, USA.
  • 9 Pediatric Nephrology Department, Robert Debré University Hospital - APHP, 48 boulevard Sérurier, 75019, Paris, France.
  • 10 Goztepe Educational and Research Hospital Pediatric Endocrinology Clinic, Istanbul, Türkiye.
  • 11 Pediatric Imaging Unit, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
  • 12 Neuroscience Department, The Lady Cilento Children's Hospital, Brisbane, Australia.
  • 13 School of Medicine, Griffith University, Gold Coast, Australia.
  • 14 Pediatric Rheumatology, Department of Pediatrics, University Hospitals Leuven, B-3000, Leuven, Belgium.
  • 15 Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Aviv, Israel.
  • 16 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 17 Amasya University Medical Faculty, Department of Pediatric Endocrinology, Istanbul, Türkiye.
  • 18 Department of Pediatric Hematology and Oncology, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
  • 19 Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstr. 35, A-6020, Innsbruck, Austria.
  • 20 J. J. M. Medical College, Davangere, Karnataka, 577004, India.
  • 21 Service de Virologie, AP-HP Hôpital Cochin, Paris, France.
  • 22 Department of Paediatrics, The Lady Cilento Children's Hospital, Brisbane, Australia.
  • 23 Centre de Référence des Maladies Osseuses Constitutionnelles et Institut Imagine, Hopital Necker 149 rue de Sevres, 75015, Paris, France.
  • 24 APHP, Bicêtre Paris Sud, Department of Pediatric Endocrinology and Diabetology for Children, 94270, Le Kremlin Bicêtre, France.
  • 25 Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d'expertise Paris Sud Maladies Rares, APHP, 94270, Le Kremlin Bicêtre, France.
  • 26 Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
  • 27 Epilepsy Unit, Pitie-Salpetriere Hospital, Paris, France.
  • 28 Kaiser Permanente - Genetics, 1650 Response Rd, Sacramento, CA, 95815, USA.
  • 29 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.
  • 30 Centre for Human Genetics, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
  • 31 Division of Nephrology, IRCCS Bambino Gesu' Pediatric Hospital, Rome, Italy.
  • 32 Department of Microbiology and Immunology, Pediatric Immunology, KU Leuven, University of Leuven, Leuven, Belgium.
  • 33 Pediatric Immunology and Rheumatology Unit, Hôpital Necker, APHP, Paris, France.
  • 34 Institut Imagine, Paris, France.
  • 35 Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, 24 boulevard du Montparnasse, 75015, Paris, France.
PMID: 26951490 DOI: 10.1007/s10875-016-0252-y
Abstract

Purpose: 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.

Keywords

ACP5; SPENCD/SPENCDI; Spondyloenchondrodysplasia; interferon signature; tartrate-resistant acid phosphatase (TRAP); type I interferon.

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