Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds

• Published in: Medicine (Baltimore) Vol. 92; no. 2; pp. 109 - 122
• Main Authors: Prando, Carolina, Samarina, Arina, Bustamante, Jacinta, Boisson-Dupuis, Stéphanie, Cobat, Aurelie, Picard, Capucine, AlSum, Zobaida, Al-Jumaah, Suliman, Al-Hajjar, Sami, Frayha, Husn, Al-Mousa, Hamoud, Ben-Mustapha, Imen, Adimi, Parisa, Feinberg, Jacqueline, de Suremain, Maylis, Jannière, Lucile, Filipe-Santos, Orchidée, Mansouri, Nahal, Stephan, Jean-Louis, Nallusamy, Revathy, Kumararatne, Dinakantha S, Bloorsaz, Mohamad Reza, Ben-Ali, Meriem, Elloumi-Zghal, Houda, Chemli, Jalel, Bouguila, Jihene, Bejaoui, Mohamed, Alaki, Emadia, AlFawaz, Tariq S, Al Idrissi, Eman, ElGhazali, Gehad, Pollard, Andrew J, Murugasu, Belinda, Wah Lee, Bee, Halwani, Rabih, Al-Zahrani, Mohammed, Al Shehri, Mohammed A, Al-Zahrani, Mofareh, Bin-Hussain, Ibrahim, Mahdaviani, Seyed Alireza, Parvaneh, Nima, Abel, Laurent, Mansouri, Davood, Barbouche, Ridha, Al-Muhsen, Saleh, Casanova, Jean-Laurent
• Format: Journal Article
• Language: English
• Published: United States Lippincott, Williams & Wilkins 01.03.2013; Wolters Kluwer Health
• Subjects: Adolescent; Adult; Age of Onset; Asia, Western; Asia, Western - epidemiology; Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; Endocrinology and metabolism; Female; Founder Effect; Genetic Predisposition to Disease; Genetics; Human health and pathology; Humans; Infant; Interleukin-12 Subunit p40; Interleukin-12 Subunit p40 - deficiency; Interleukin-12 Subunit p40 - genetics; Life Sciences; Male; Mycobacterium Infections, Nontuberculous; Mycobacterium Infections, Nontuberculous - genetics; Mycobacterium Infections, Nontuberculous - immunology; Mycobacterium Infections, Nontuberculous - mortality; Original Study; Penetrance; Salmonella Infections; Salmonella Infections - genetics; Survival Analysis; Tunisia; Tunisia - epidemiology; Young Adult; Tunisia; Asia, Western
• ISSN: 0025-7974; 1536-5964
• DOI: 10.1097/MD.0b013e31828a01f9

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.