1. Inherited IL-12p40 Deficiency Genetic, Immunologic, and Clinical Features of 49 Patients From 30 Kindreds
- Author
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Prando, C, Samarina, A, Bustamante, J, Boisson-Dupuis, S, Cobat, A, Picard, C, AlSum, Z, Al-Jumaah, S, Al-Hajjar, S, Frayha, H, Alangari, A, Al-Mousa, H, Mobaireek, KF, Ben-Mustapha, I, Adimi, P, Feinberg, J, de Suremain, M, Jannière, L, Filipe-Santos, O, Mansouri, N, Stephan, JL, Nallusamy, R, Kumararatne, DS, Bloorsaz, MR, Ben-Ali, M, Elloumi-Zghal, H, Chemli, J, Bouguila, J, Bejaoui, M, Alaki, E, AlFawaz, TS, Al Idrissi, E, ElGhazali, G, Pollard, AJ, Murugasu, B, Wah Lee, B, Halwani, R, Al-Zahrani, M, Al Shehri, MA, Bin-Hussain, I, Mahdaviani, SA, Parvaneh, N, Abel, L, Mansouri, D, Barbouche, R, Al-Muhsen, S, Casanova, JL, Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], King Saud University [Riyadh] (KSU), King Faisal Specialist Hospital and Research Center, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pediatrie, Université de St Etienne, Department of Pediatrics, Penang Medical College, Addenbrookes Hospital, Sahloul Hospital, Farhat Hached Hospital, Bone Marrow Transplantation Center, King Fahad Med City, Dept Pediat, Univ Oxford, NIHR Oxford Biomed Res Ctr, Childrens Hosp, Dept Paediat, Natl Univ Singapore, Dept Pediat, Secur Forces Hosp, Dept Pediat, King Fahad Medical City, Univ Tehran Med Sci, Pediat Infect Dis Res Ctr, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), The Laboratory of Human Genetics of Infectious Diseases is supported by institutional grants to INSERM and The Rockefeller University, and grants from the Agence Nationale de la Recherche (ANR), the European Union HOMITB (E08153KK) and NEOTIM (018736), the St. Giles Foundation, the Thrasher Research Fund, the Jeffrey Modell Foundation, Talecris Biotherapeutics, National Institutes of Health (1R01AI089970-01), European Project: 200732,EC:FP7:HEALTH,FP7-HEALTH-2007-A,HOMITB(2008), European Project: 33419,NEOTIM, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Shahid Beheshti University of Medical Sciences, King Saud Univ, Coll Med, Dept Pediat, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet - Saint-Étienne (UJM), and National University of Singapore (NUS)
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MESH: Asia, Western ,MESH: Age of Onset ,[SDV]Life Sciences [q-bio] ,MESH: Founder Effect ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Genetic etiology ,MESH: Penetrance ,MESH: Child ,Medicine ,MESH: DNA Mutational Analysis ,MESH: Cohort Studies ,Survival analysis ,030304 developmental biology ,Genetics ,MESH: Adolescent ,0303 health sciences ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Salmonella Infections ,MESH: Humans ,business.industry ,Il 12p40 ,MESH: Child, Preschool ,MESH: Genetic Predisposition to Disease ,Interleukin ,MESH: Adult ,General Medicine ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,MESH: Mycobacterium Infections, Nontuberculous ,Penetrance ,MESH: Infant ,MESH: Male ,3. Good health ,MESH: Young Adult ,MESH: Interleukin-12 Subunit p40 ,MESH: Survival Analysis ,Immunology ,Mendelian inheritance ,symbols ,Age of onset ,business ,MESH: Tunisia ,MESH: Female ,030215 immunology ,Founder effect - Abstract
International audience; 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-gamma). The clinical features are characterized by childhood onset of bacille Calmette-Guerin (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 beta 1 (IL-12R beta 1) 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. (Medicine 2013; 92: 109-122)
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- 2013
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