Latifa Al Shekaili1, Farrukh Sheikh2, Sulaiman Al Gazlan3, Hasan Al Dhekri4, Hamoud Al Mousa5, Abdulaziz Al Ghonaium6, Bander Al Saud7, Saleh Al Mohsen8, Agha M Rehan Khaliq9, Safiah Al Sumayli10, Mufarreh Al Zahrani11, Anas Dababo12, Ammar AlKawi13, Abbas Hawwari14, Rand Arnaout15. 1. King Faisal Specialist Hospital and Research Center, Department of Medicine, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 46, Saudi Arabia. Electronic address: latifaalshukeili@hotmail.com. 2. King Faisal Specialist Hospital and Research Center, Department of Medicine, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 46, Saudi Arabia. Electronic address: fsheikh96@kfshrc.edu.sa. 3. King Faisal Specialist Hospital and Research Center, Department of Medicine, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 46, Saudi Arabia. Electronic address: gazlan@kfshrc.edu.sa. 4. King Faisal Specialist Hospital and Research Center, Department of Pediatric, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 58, Saudi Arabia. Electronic address: haldhekri@kfshrc.edu.sa. 5. King Faisal Specialist Hospital and Research Center, Department of Pediatric, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 58, Saudi Arabia. Electronic address: hamoudalmousa@kfshrc.edu.sa. 6. King Faisal Specialist Hospital and Research Center, Department of Pediatric, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 58, Saudi Arabia. Electronic address: ghonaium@kfshrc.edu.sa. 7. King Faisal Specialist Hospital and Research Center, Department of Pediatric, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 58, Saudi Arabia. Electronic address: balsaud@kfshrc.edu.sa. 8. King Faisal Specialist Hospital and Research Center, Department of Pediatric, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 58, Saudi Arabia. Electronic address: smohsen@kfshrc.edu.sa. 9. King Faisal Specialist Hospital and Research Center, Department of Medicine, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 46, Saudi Arabia; Alfaisal University, Saudi Arabia. Electronic address: rehankhaliq@kfshrc.edu.sa. 10. King Faisal Specialist Hospital and Research Center, Department of Medicine, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 46, Saudi Arabia. Electronic address: ssumayli@kfshrc.edu.sa. 11. King Fahad medical city, Department of Medicine, Riyadh 11525, P.O. Box 59046, Saudi Arabia. Electronic address: rarnaut@kfshrc.edu.sa. 12. King Faisal Specialist Hospital and Research Center, Department of Pathology and Lab Medicine, P.O Box 3354, Riyadh 11211, MBC 10, Saudi Arabia. Electronic address: mdababo@kfshrc.edu.sa. 13. King Faisal Specialist Hospital and Research Center, Department of Neuroscience, P.O Box 3354, Riyadh 11211, MBC 76, Saudi Arabia. Electronic address: aalkawi@kfshrc.edu.sa. 14. King Faisal Specialist Hospital and Research Center, Department of genetics, P.O Box 3354, Riyadh 11211, MBC 3, Saudi Arabia. Electronic address: ahawwari@kfshrc.edu.sa. 15. King Faisal Specialist Hospital and Research Center, Department of Medicine, Allergy and Immunology section, P.O Box 3354, Riyadh 11211, MBC 46, Saudi Arabia; Alfaisal University, Saudi Arabia. Electronic address: rarnaout@kfshrc.edu.sa.
Abstract
BACKGROUND: Hyper-IgE syndrome (HIES) due to DOCK8 deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease. OBJECTIVE: We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution. METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected. RESULTS: All patients had a severe course of the disease with rarely reported severe complications in HIES. One patient died with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations. CONCLUSION: We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.
BACKGROUND:Hyper-IgE syndrome (HIES) due to DOCK8deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease. OBJECTIVE: We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution. METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected. RESULTS: All patients had a severe course of the disease with rarely reported severe complications in HIES. One patientdied with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations. CONCLUSION: We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.
Authors: Bethany A Pillay; Danielle T Avery; Joanne M Smart; Theresa Cole; Sharon Choo; Damien Chan; Paul E Gray; Katie Frith; Richard Mitchell; Tri Giang Phan; Melanie Wong; Dianne E Campbell; Peter Hsu; John B Ziegler; Jane Peake; Frank Alvaro; Capucine Picard; Jacinta Bustamante; Benedicte Neven; Andrew J Cant; Gulbu Uzel; Peter D Arkwright; Jean-Laurent Casanova; Helen C Su; Alexandra F Freeman; Nirali Shah; Dennis D Hickstein; Stuart G Tangye; Cindy S Ma Journal: JCI Insight Date: 2019-04-25
Authors: Alexandra F Freeman; Nada Yazigi; Nirali N Shah; David E Kleiner; Mark Parta; Prescott Atkinson; Theo Heller; Steven M Holland; Stuart S Kaufman; Khalid M Khan; Dennis D Hickstein Journal: Transplantation Date: 2019-10 Impact factor: 4.939