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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, * 
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-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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Submitted on : Wednesday, September 6, 2017 - 12:47:41 PM
Last modification on : Tuesday, December 7, 2021 - 3:32:24 PM

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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, Lippincott, Williams & Wilkins, 2013, 92 (2), pp.109-122. ⟨10.1097/MD.0b013e31828a01f9⟩. ⟨pasteur-01375115⟩



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