Reza Yazdani1, Hassan Abolhassani2, Fatemeh Kiaee1, Sima Habibi1, Gholamreza Azizi3, Marzieh Tavakol3, Zahra Chavoshzadeh4, Seyed Alireza Mahdaviani5, Tooba Momen6, Mohammad Gharagozlou7, Masoud Movahedi7, Amir Ali Hamidieh8, Nasrin Behniafard9, Mohammamd Nabavi10, Mohammad Hassan Bemanian10, Saba Arshi10, Rasol Molatefi11, Roya Sherkat12, Afshin Shirkani13, Reza Amin14, Soheila Aleyasin14, Reza Faridhosseini15, Farahzad Jabbari-Azad15, Iraj Mohammadzadeh16, Javad Ghaffari17, Alireza Shafiei18, Arash Kalantari19, Mahboubeh Mansouri20, Mehrnaz Mesdaghi20, Delara Babaie3, Hamid Ahanchian15, Maryam Khoshkhui15, Habib Soheili21, Mohammad Hossein Eslamian22, Taher Cheraghi23, Abbas Dabbaghzadeh16, Mahmoud Tavassoli24, Rasoul Nasiri Kalmarzi25, Seyed Hamidreza Mortazavi26, Sara Kashef14, Hossein Esmaeilzadeh14, Javad Tafaroji27, Abbas Khalili28, Fariborz Zandieh18, Mahnaz Sadeghi-Shabestari29, Sepideh Darougar4, Fatemeh Behmanesh14, Hedayat Akbari14, Mohammadreza Zandkarimi15, Farhad Abolnezhadian30, Abbas Fayezi31, Mojgan Moghtaderi14, Akefeh Ahmadiafshar31, Behzad Shakerian24, Vahid Sajedi32, Behrang Taghvaei33, Mojgan Safari22, Marzieh Heidarzadeh34, Babak Ghalebaghi23, Seyed Mohammad Fathi35, Behzad Darabi36, Saeed Bazregari13, Nasrin Bazargan37, Morteza Fallahpour10, Alireza Khayatzadeh38, Naser Javahertrash10, Bahram Bashardoust4, Mohammadali Zamani39, Azam Mohsenzadeh40, Sarehsadat Ebrahimi7, Samin Sharafian7, Ahmad Vosughimotlagh7, Mitra Tafakoridelbari7, Maziar Rahim7, Parisa Ashournia7, Anahita Razaghian7, Arezou Rezaei1, Ashraf Samavat41, Setareh Mamishi42, Hossein Ali Khazaei43, Javad Mohammadi44, Babak Negahdari45, Nima Parvaneh1, Nima Rezaei1, Vassilios Lougaris46, Silvia Giliani47, Alessandro Plebani46, Hans D Ochs48, Lennart Hammarström49, Asghar Aghamohammadi50. 1. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Primary Immunodeficiencies Network (IPIN), Tehran University of Medical Sciences, Tehran, Iran. 2. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Primary Immunodeficiencies Network (IPIN), Tehran University of Medical Sciences, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. 3. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran. 4. Pediatric Infections Research Center, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6. 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. 7. Division of Allergy and Clinical Immunology, Department of Pediatrics, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 8. Hematology, Oncology and Stem Cell Transplantation Research Centre, Tehran University of Medical Sciences, Tehran, Iran. 9. Department of Allergy and Clinical Immunology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. 10. Department of Allergy and Clinical Immunology, Rasool e Akram Hospital, Iran University of Medical Sciences, Tehran, Iran. 11. Department of Pediatrics, Bo-Ali Children's Hospital of Ardabil University of Medical Sciences, Ardabil, Iran. 12. Acquired Immunodeficiency Research Center, lsfahan University of Medical Sciences, Isfahan, Iran. 13. Allergy and Clinical Immunology Department, Bushehr University of Medical Science, School of Medicine, Bushehr, Iran. 14. Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 15. Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. 16. Department of Allergy and Clinical Immunology, Pediatric Infectious Diseases Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. 17. Department of Pediatrics, Mazandaran University of Medical Sciences, Sari, Iran. 18. Department of Immunology, Bahrami Hospital, Tehran University of Medical Sciences, Tehran, Iran. 19. Department of Immunology and Allergy, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran. 20. Immunology and Allergy Department, Mofid Children's Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran. 21. Department of Pediatrics, School of Medicine, Arak University of Medical Sciences, Arak, Iran. 22. Department of Pediatrics, Hamadan University of Medical Sciences, Hamadan, Iran. 23. Department of Pediatrics, 17th Shahrivar Children's Hospital, Guilan University of Medical Sciences, Rasht, Iran. 24. Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. 25. Cellular & Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. 26. Department of Pediatrics, Kermanshah University of Medical Sciences, Kermanshah, Iran. 27. Department of Pediatrics, Qom University of Medical Sciences, Qom, Iran. 28. Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. 29. Department of Immunology and Allergy, Tabriz University of Medical Sciences, Tabriz, Iran. 30. Department of Immunology and Allergy, Ahvaz University of Medical Sciences, Ahvaz, Iran. 31. Mousavi Hospital, Zanjan University of Medical Sciences, Zanjan, Iran. 32. Department of Immunology and Allergy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 33. Department of Immunology and Allergy, Semnan University of Medical Sciences, Semnan, Iran. 34. Department of Immunology and Allergy, Kashan University of Medical Sciences, Kashan, Iran. 35. Department of Immunology and Allergy, Qazvin University of Medical Sciences, Qazvin, Iran. 36. Department of Immunology and Allergy, Ilam University of Medical Sciences, Ilam, Iran. 37. Department of Immunology and Allergy, Kerman University of Medical Sciences, Kerman, Iran. 38. Department of Allergy and Clinical Immunology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 39. Department of Immunology and Allergy, Shahrekord University of Medical Sciences, Shahrekord, Iran. 40. Department of Pediatrics, Lorestan University of Medical Sciences, Khorramabad, Iran. 41. Genetics Office, Centers for Disease Control and Prevention (CDC), Ministry of Health of Iran, Tehran, Iran. 42. Pediatric Infectious Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran. 43. Clinical Immunology Research Center, Zahedan University of Medical Sciences, Zahedan, Iran. 44. Department of Life Science, Faculty of New Science and Technology, University of Tehran, Tehran, Iran. 45. School of Advanced Technologies in Medicine, Department of Medical Biotechnology, Tehran University of Medical Sciences, Tehran, Iran. 46. Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy. 47. Nocivelli Institute for Molecular Medicine and Pediatric Clinic, University of Brescia, Brescia, Italy. 48. Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Wash. 49. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden. 50. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Primary Immunodeficiencies Network (IPIN), Tehran University of Medical Sciences, Tehran, Iran. Electronic address: aghamohammadi@tums.ac.ir.
Abstract
BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. OBJECTIVE: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. METHODS: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 μ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with μ heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008). CONCLUSIONS: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.
BACKGROUND:Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. OBJECTIVE: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. METHODS: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 μ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with μ heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008). CONCLUSIONS: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.
Authors: Frederik V Ilkjær; Line D Rasmussen; Raquel Martin-Iguacel; Lena Westh; Terese L Katzenstein; Ann-Brit E Hansen; Thyge L Nielsen; Carsten S Larsen; Isik S Johansen Journal: J Clin Immunol Date: 2019-08-01 Impact factor: 8.317
Authors: Waleed Al-Herz; Janet Chou; Ottavia Maria Delmonte; Michel J Massaad; Wayne Bainter; Riccardo Castagnoli; Christoph Klein; Yenan T Bryceson; Raif S Geha; Luigi D Notarangelo Journal: Front Immunol Date: 2019-01-15 Impact factor: 7.561
Authors: Susana L Silva; Mariana Fonseca; Marcelo L M Pereira; Sara P Silva; Rita R Barbosa; Ana Serra-Caetano; Elena Blanco; Pedro Rosmaninho; Martin Pérez-Andrés; Ana Berta Sousa; Alexandre A S F Raposo; Margarida Gama-Carvalho; Rui M M Victorino; Lennart Hammarstrom; Ana E Sousa Journal: Front Immunol Date: 2019-11-22 Impact factor: 7.561