Jocelyn R Farmer1, Zsofia Foldvari2, Boglarka Ujhazi3, Suk See De Ravin4, Karin Chen5, Jack J H Bleesing6, Catharina Schuetz7, Waleed Al-Herz8, Roshini S Abraham9, Avni Y Joshi10, Beatriz T Costa-Carvalho11, David Buchbinder12, Claire Booth13, Andreas Reiff14, Polly J Ferguson15, Asghar Aghamohammadi16, Hassan Abolhassani16, Jennifer M Puck17, Mehdi Adeli18, Caterina Cancrini19, Paolo Palma20, Alice Bertaina21, Franco Locatelli22, Gigliola Di Matteo19, Raif S Geha23, Maria G Kanariou24, Lilia Lycopoulou25, Marianna Tzanoudaki24, John W Sleasman26, Suhag Parikh27, Gloria Pinero26, Bernard M Fischer26, Ghassan Dbaibo28, Ekrem Unal29, Turkan Patiroglu30, Musa Karakukcu29, Khulood Khalifa Al-Saad31, Meredith A Dilley32, Sung-Yun Pai33, Cullen M Dutmer34, Erwin W Gelfand35, Christoph B Geier36, Martha M Eibl37, Hermann M Wolf38, Lauren A Henderson39, Melissa M Hazen39, Carmem Bonfim40, Beata Wolska-Kuśnierz41, Manish J Butte42, Joseph D Hernandez43, Sarah K Nicholas44, Polina Stepensky45, Shanmuganathan Chandrakasan46, Maurizio Miano47, Emma Westermann-Clark48, Vera Goda49, Gergely Kriván49, Steven M Holland50, Olajumoke Fadugba51, Sarah E Henrickson52, Ahmet Ozen53, Elif Karakoc-Aydiner53, Safa Baris53, Ayca Kiykim54, Robbert Bredius55, Birgit Hoeger56, Kaan Boztug57, Olga Pashchenko58, Benedicte Neven59, Despina Moshous60, Jean-Pierre de Villartay61, Ahmed Aziz Bousfiha62, Harry R Hill63, Luigi D Notarangelo47, Jolan E Walter64. 1. Massachusetts General Hospital, Harvard Medical School, Boston, Mass. 2. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. 3. University of South Florida and Johns Hopkins All Children's Hospital, Saint Petersburg, Fla. 4. Laboratory of Host Defenses, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Md. 5. Division of Allergy and Immunology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah. 6. Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 7. Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 8. Faculty of Medicine, Pediatrics Department, Kuwait University, Kuwait City, Kuwait; Allergy and Clinical Immunology Unit, Pediatrics Department, Alsabah Hospital, Kuwait City, Kuwait. 9. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn. 10. Division of Pediatric Allergy/Immunology, Mayo Clinic Children's Center Rochester, Rochester, Minn. 11. Department of Pediatrics, UNIFESP-EPM, São Paulo, Brazil. 12. Pediatrics/Hematology, CHOC Children's Hospital - UC Irvine, Irvine, Calif. 13. Department of Paediatric Immunology, Great Ormond Street Hospital, London, United Kingdom. 14. Division of Rheumatology, Children's Hospital Los Angeles, Keck School of Medicine, USC, Los Angeles, Calif. 15. Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa. 16. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 17. Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, Calif. 18. Sidra Medicine, Weill Cornell Medicine, and Hamad Medical Corporation, Doha, Qatar. 19. Academic Department of Pediatrics (DPUO), Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. 20. Academic Department of Pediatrics (DPUO), Research Unit in Congenital and Perinatal Infection, Children's Hospital Bambino Gesù, Rome, Italy. 21. Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Bambino Gesù, Rome, Italy. 22. Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS, Ospedale Bambino Gesù, Rome, Italy; Department of Pediatrics, Sapienza, University of Rome, Rome, Italy. 23. Immunology Division, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 24. Department of Immunology - Histocompatibility, Specialized Center & Referral Center for Primary Immunodeficiencies - Paediatric Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece. 25. 1st Department of Pediatrics, University of Athens, Aghia Sofia Children's Hospital, Athens, Greece. 26. Division of Allergy, Immunology and Pulmonary Medicine, Duke University School of Medicine, Durham, NC. 27. Division of Pediatric Blood and Marrow Transplantation, Duke University School of Medicine, Durham, NC. 28. Department of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon. 29. Division of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey. 30. Division of Pediatric Hematology and Oncology & HCST Unit, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey; Division of Pediatric Immunology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey. 31. Salmanyia Medical Complex, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Manama, Bahrain. 32. Department of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 33. Division of Hematology-Oncology, Boston Children's Hospital, Boston, Mass; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Mass; Harvard Medical School, Boston, Mass. 34. Division of Allergy & Immunology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colo. 35. Department of Pediatrics, National Jewish Health, Denver, Colo. 36. Immunology Outpatient Clinic, Vienna, Austria. 37. Immunology Outpatient Clinic, Vienna, Austria; Biomedizinische Forschungs GmbH, Vienna, Austria. 38. Immunology Outpatient Clinic, Vienna, Austria; Sigmund Freud Private University-Medical School, Vienna, Austria. 39. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 40. Hospital Infantil Pequeno Principe, Curitiba, Brazil. 41. Immunology Department, Children's Memorial Health Institute, Warsaw, Poland. 42. Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and Jeffrey Modell Diagnostic and Research Center, University of California, Los Angeles, Los Angeles, Calif. 43. Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford University, Stanford, Calif. 44. Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas. 45. Department of Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel. 46. Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga. 47. Haematology Unit, Department of Pediatric Haematology-Oncology, IRCCS Istituto Giannina Gaslini, Genova, Italy. 48. Department of Internal Medicine, Division of Allergy/Immunology, University of South Florida Morsani College of Medicine, Tampa, Fla. 49. Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest- National Institute of Hematology and Infectious Diseases, Budapest, Hungary. 50. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Md. 51. Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa. 52. Allergy Immunology Division, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pa; Institute for Immunology, the University of Pennsylvania, Philadelphia, Pa. 53. Marmara University School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkey. 54. Ministry of Health, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey. 55. Department of Pediatrics, Section Pediatric Immunology, Infections and Stem Cell Transplantation, Leiden University Medical Center, Leiden, the Netherlands. 56. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. 57. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; St Anna Kinderspital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 58. Department of Immunology, Pirogov Russian National Research Medical University, Russian Clinical Children's Hospital, Moscow, Russia. 59. Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory "Immunogenetics of Pediatric Autoimmune Diseases", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France. 60. Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Laboratory "Genome Dynamics in The Immune System", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France. 61. Laboratory "Genome Dynamics in The Immune System", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France. 62. Laboratoire d'Immunologie Clinique, d'Inflammation et d'Allergie LICIA, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco; Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, Hassan II University, Casablanca, Morocco. 63. Division of Clinical Immunology, Departments of Pathology, Pediatrics and Medicine, University of Utah, Salt Lake City, Utah. 64. University of South Florida and Johns Hopkins All Children's Hospital, Saint Petersburg, Fla; Division of Allergy and Immunology, Massachusetts General Hospital for Children, Boston, Mass. Electronic address: jolanwalter@health.usf.edu.
Abstract
BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.
BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS:Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.
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