Delphine Sterlin1, Guillaume Velasco2, Despina Moshous3,4, Fabien Touzot3,4,5,6, Nizar Mahlaoui3,7, Alain Fischer3,4,8,7, Felipe Suarez9,7,10, Claire Francastel2, Capucine Picard11,12,13,14. 1. Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), University Paris Descartes, 149 rue de Sevres, 75015, Paris, France. 2. CNRS UMR7216, Epigenetics and Cell Fate, Sorbonne Paris Cité, Université Paris Diderot, Paris, France. 3. Pediatric Immuno-Hematology Unit, Necker Children's Hospital, APHP, Université Paris Descartes, Paris, France. 4. INSERM UMR1163, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France. 5. Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes, Paris, France. 6. Biotherapy Department, Necker-Enfants Malades Hospital, APHP, University Paris Descartes, Paris, France. 7. French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker - Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. 8. College de France, Paris, France. 9. Adult Hematology Unit, Necker Children's Hospital, APHP, University Paris Descartes, Paris, France. 10. INSERM UMR1163 and CNRS ERL8254, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France. 11. Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), University Paris Descartes, 149 rue de Sevres, 75015, Paris, France. capucine.picard@inserm.fr. 12. Pediatric Immuno-Hematology Unit, Necker Children's Hospital, APHP, Université Paris Descartes, Paris, France. capucine.picard@inserm.fr. 13. Laboratory of the Human Genetics of Infectious Diseases, INSERM UMR1163, Imagine Institute, Necker Medical School, Sorbonne Paris Cité, University Paris Descartes, Paris, France. capucine.picard@inserm.fr. 14. French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker - Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. capucine.picard@inserm.fr.
Abstract
PURPOSE: Autosomal recessive deficiencies of DNMT3B or ZBTB24 account for two-thirds of cases of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). This primary immunodeficiency (PID) is characterized mainly by an antibody deficiency, facial abnormalities and centromeric instability. We analyzed the national cohort of patients with ICF syndrome with the aim of providing a more detailed description of the phenotype and management of patients with ICF syndrome. METHODS: Demographic, genetic, immunological, and clinical features were recorded for each patient. RESULTS: In the French cohort, seven of the nine patients carried DNMT3B mutations, six of which had never been described before. One patient had compound heterozygous ZBTB24 mutations. All patients were found to lack CD19(+)CD27(+) memory B cells. This feature is a major diagnostic criterion for both ICF1 and ICF2. Patients suffered both bacterial and viral infections, and three patients developed bronchiectasis. Autoimmune manifestations (hepatitis, nephritis and thyroiditis) not previously reported in ICF1 patients were also detected in two of our ICF1 patients. The mode of treatment and outcome of the French patients are reported, by genetic defect, and compared with those for 68 previously reported ICF patients. Immunoglobulin (Ig) replacement treatment was administered to all nine French patients. One ICF1 patient presented severe autoimmune manifestations and pancytopenia and underwent allogeneic hematopoietic stem cell transplantation (HSCT), but she died from unknown causes 6 years post-transplant. CONCLUSION: Autoimmune signs are uncommon in ICF syndrome, but, when present, they affect patient outcome and require immunosuppressive treatment. The long-term outcome of ICF patients has been improved by the combination of IgG replacement and antibiotic prophylaxis.
PURPOSE:Autosomal recessive deficiencies of DNMT3B or ZBTB24 account for two-thirds of cases of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). This primary immunodeficiency (PID) is characterized mainly by an antibody deficiency, facial abnormalities and centromeric instability. We analyzed the national cohort of patients with ICF syndrome with the aim of providing a more detailed description of the phenotype and management of patients with ICF syndrome. METHODS: Demographic, genetic, immunological, and clinical features were recorded for each patient. RESULTS: In the French cohort, seven of the nine patients carried DNMT3B mutations, six of which had never been described before. One patient had compound heterozygous ZBTB24 mutations. All patients were found to lack CD19(+)CD27(+) memory B cells. This feature is a major diagnostic criterion for both ICF1 and ICF2. Patients suffered both bacterial and viral infections, and three patients developed bronchiectasis. Autoimmune manifestations (hepatitis, nephritis and thyroiditis) not previously reported in ICF1patients were also detected in two of our ICF1patients. The mode of treatment and outcome of the French patients are reported, by genetic defect, and compared with those for 68 previously reported ICFpatients. Immunoglobulin (Ig) replacement treatment was administered to all nine French patients. One ICF1patient presented severe autoimmune manifestations and pancytopenia and underwent allogeneic hematopoietic stem cell transplantation (HSCT), but she died from unknown causes 6 years post-transplant. CONCLUSION: Autoimmune signs are uncommon in ICF syndrome, but, when present, they affect patient outcome and require immunosuppressive treatment. The long-term outcome of ICFpatients has been improved by the combination of IgG replacement and antibiotic prophylaxis.
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