Inherited IL-12p40 Deficiency Genetic, Immunologic, and Clinical Features of 49 Patients From 30 Kindreds

Carolina Prando (1) , Arina Samarina (2) , Jacinta Bustamante (2) , Stephanie Boisson-Dupuis (1, 3, 2) , Aurélie Cobat , Capucine Picard (3, 2, 4) , Zobaida Alsum (5) , Suliman Al-Jumaah (6) , Sami Al-Hajjar (6) , Husn Frayha (6) , Hamoud Al-Mousa (6) , Imen Ben-Mustapha (7) , Parisa Adimi (8) , Jacqueline Feinberg (3, 9) , Maylis De Suremain (3, 9) , Lucile Janniere (3, 9) , Orchidée Filipe-Santos (3, 9) , Nahal Mansouri (8) , Jean-Louis Stephan (10) , Revathy Nallusamy (11) , Dinakantha S. Kumararatne (12) , Mohamad Reza Bloorsaz (13) , Meriem Ben-Ali (7) , Houda Elloumi-Zghal (7) , Jalel Chemli (14) , Jihène Bouguila (15) , Mohamed Béjaoui (16) , Emadia Alaki (5) , Tariq S. Alfawaz (17) , Eman Al Idrissi (17) , Gehad Elghazali (17) , Andrew J. Pollard (18) , Belinda Murugasu (19) , Bee Wah Lee (19) , Rabih Halwani (5) , Mohammed Al-Zahrani (20) , Mohammed A. Al Shehri (21) , Mofareh Al-Zahrani (6, 21) , Ibrahim Bin-Hussain (6, 7) , Seyed Alireza Mahdaviani (8) , Nima Parvaneh (22) , Laurent Abel (1, 3) , Davood Mansouri (8) , Mohamed-Ridha Barbouche (7) , Saleh Al-Muhsen (6, 5) , Jean-Laurent Casanova (1, 3, 2, 5, 23)

1 Rockefeller University [New York]
2 CHU Necker - Enfants Malades [AP-HP]
3 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
4 Service d'immuno-hématologie pédiatrique [CHU Necker]
5 KSU - King Saud University [Riyadh]
6 King Faisal Specialist Hospital and Research Center
7 Institut Pasteur de Tunis
8 SBUMS - Shahid Beheshti University of Medical Sciences [Tehran]
9 INSERM - Institut National de la Santé et de la Recherche Médicale
10 Département de Pediatrie
11 Department of Pediatrics
12 Addenbrookes Hospital
13 Shahid Beheshti University
14 Sahloul Hospital
15 Farhat Hached Hospital
16 Department of Pediatrics
17 King Fahad Med City, Dept Pediat
18 Univ Oxford, NIHR Oxford Biomed Res Ctr, Childrens Hosp, Dept Paediat
19 NUS - National University of Singapore
20 Secur Forces Hosp, Dept Pediat
21 King Fahad Medical City
22 Univ Tehran Med Sci, Pediat Infect Dis Res Ctr
23 UPD5 Médecine - Université Paris Descartes - Faculté de Médecine

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)

Domains: Life Sciences [q-bio]; Endocrinology and metabolism; Genetics

Carolina Prando, Arina Samarina, Jacinta Bustamante, Stephanie Boisson-Dupuis, Aurélie Cobat, et al.. Inherited IL-12p40 Deficiency Genetic, Immunologic, and Clinical Features of 49 Patients From 30 Kindreds. Medicine, 2013, 92 (2), pp.109-122. ⟨10.1097/MD.0b013e31828a01f9⟩. ⟨pasteur-01375115⟩