Asena Pinar Sefer1,2,3, Hassan Abolhassani4,5,6, Franziska Ober7, Basak Kayaoglu8, Sevgi Bilgic Eltan1,2,3, Altan Kara9, Baran Erman10,11, Naz Surucu Yilmaz8, Cigdem Aydogmus12, Sezin Aydemir13, Louis-Marie Charbonnier14, Burcu Kolukisa1,2,3, Gholamreza Azizi15, Samaneh Delavari4, Tooba Momen16, Simuzar Aliyeva17, Yasemin Kendir Demirkol18, Saban Tekin19, Ayca Kiykim13, Omer Faruk Baser20, Haluk Cokugras13, Mayda Gursel8, Elif Karakoc-Aydiner1,2,3, Ahmet Ozen1,2,3, Daniel Krappmann7, Talal A Chatila14, Nima Rezaei4,21, Safa Baris22,23,24. 1. Division of Pediatric Allergy/Immunology, Marmara University, Istanbul, Turkey. 2. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. 3. Marmara University, The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey. 4. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 5. Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden. 6. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. 7. Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany. 8. Department of Biological Sciences, Middle East Technical University, Ankara, Turkey. 9. TUBITAK Marmara Research Center, Gene Engineering and Biotechnology Institute, Gebze, Turkey. 10. Institute of Child Health, Hacettepe University, Ankara, Turkey. 11. Can Sucak Research Laboratory for Translational Immunology, Center for Genomics and Rare Diseases, Hacettepe University, Ankara, Turkey. 12. Division of Pediatric Allergy and Immunology, University of Health Sciences, Basaksehir Cam Sakura City Hospital, Istanbul, Turkey. 13. Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey. 14. Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Division of Immunology, Boston, MA, USA. 15. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran. 16. Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran. 17. Faculty of Medicine, Department of Pediatrics, Marmara University, Istanbul, Turkey. 18. Division of Pediatric Genetics, University of Health Sciences, Umraniye Education and Research Hospital, Istanbul, Turkey. 19. Hamidiye Faculty of Medicine, Department of Basic Medical Sciences, Division of Medical Biology, University of Health Sciences, Istanbul, Turkey. 20. Faculty of Medicine, Pediatric Gastroenterology, Hepatology and Nutrition, Istanbul University-Cerrahpasa, Istanbul, Turkey. 21. Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran. 22. Division of Pediatric Allergy/Immunology, Marmara University, Istanbul, Turkey. safabaris@hotmail.com. 23. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey. safabaris@hotmail.com. 24. Marmara University, The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey. safabaris@hotmail.com.
Abstract
PURPOSE: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. METHODS: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. RESULTS: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). CONCLUSION: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.
PURPOSE: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. METHODS: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. RESULTS: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). CONCLUSION: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.
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