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Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds
Carolina Prando1, Arina Samarina, Jacinta Bustamante
1From the St. Giles Laboratory of Human Genetics of Infectious Diseases (C. Prando, SBD, LA, JLC), Rockefeller Branch, The Rockefeller University, New York, New York; Laboratory of Human Genetics of Infectious Diseases (AS, J. Bustamante, SBD, C. Picard, JF, MdS, LJ, OFS, LA, JLC) Necker Branch, Institut National de la Santé et de la Recherche Médicale, U980, Necker Branch, Paris, France; University Paris Descartes (AS, J. Bustamante, SBD, C. Picard, JF, MdS, LJ, OFS, JLC) Paris Cité Sorbonne, Necker Medical School, Paris, France; Center for the Study of Primary Immunodeficiencies (J. Bustamante, C. Picard) and Pediatric Hematology-Immunology Unit (C. Picard, JLC), Assistance Publique-Hôpitaux de Paris, Necker Hospital, Paris, France; McGill Centre for the Study of Host Resistance (AC), Research Institute of McGill University Health Centre, and Departments of Human Genetics and Medicine, McGill University, Montreal, Quebec, Canada; Prince Naif Center for Immunology Research (ZAS, RH, S. Al-Muhsen, JLC) and Department of Pediatrics (ZAS, S. Al-Muhsen), College of Medicine, KingSaud University, Riyadh, Saudi Arabia; Department of Pediatrics (SAJ, SAH, HF, HAM, Mofareh Al-Zahrani, S. Al-Muhsen, IBH) King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; King Saud Medical City (EA), Riyadh, Saudi Arabia; Laboratory of Cytoimmunology (IBM, MBA, HEZ, RB), Pasteur Institut of Tunis, Tunis-Belvédère, Tunisia; Department of Clinical Immunology and Infectious Disease (PA, NM, DM) and Pediatric Respiratory Disease Research Center (MRB S.A Mahdaviani), National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Pediatrics (JLS), University of Saint Etienne, Hôpital Nord, Saint Etienne, France; Department of Pediatrics (RN), Penang Medical College, Penang, Malaysia; Department of Clinical Biochemistry and Immunology (DSK), Addenbrookes Hospital, Cambridge, United Kingdom; Department of Pediatrics (JC), Sahloul Hospital, Sousse, Tunisia; Department of Pediatrics (J. Bouguila), Farhat Hached Hospital, Sousse, Tunisia; Department of Pediatrics (MB), Bone Marrow Transplantation Center, Tunis, Tunisia; Department of Pediatrics (TSAF, EAI, GEG, MAAS, Mofareh Al-Zahrani), King Fahad Medical City, Riyadh, Saudi Arabia; Department of Paediatrics (AJP), University of Oxford, NIHR Oxford Biomedical Research Centre, Children's Hospital, Oxford, United Kingdom; Department of Pediatrics (BM, BWL), National University of Singapore, Singapore; Department of Pediatrics (Mohammed Al-Zahrani), Security Forces Hospital, Riyadh, Saudi Arabia; and Pediatric Infectious Disease Research Center (NP), Tehran University of Medical Sciences, Tehran, Iran.
Abstract:
Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.
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