Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.
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, Sau...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2013
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| _version_ | 1826260960393822208 |
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| author | 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, K Ben-Mustapha, I Adimi, P Feinberg, J de Suremain, M Jannière, L Filipe-Santos, O Mansouri, N Stephan, J Nallusamy, R Kumararatne, D Bloorsaz, MR Ben-Ali, M |
| author_facet | 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, K Ben-Mustapha, I Adimi, P Feinberg, J de Suremain, M Jannière, L Filipe-Santos, O Mansouri, N Stephan, J Nallusamy, R Kumararatne, D Bloorsaz, MR Ben-Ali, M |
| author_sort | Prando, C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T19:14:01Z |
| format | Journal article |
| id | oxford-uuid:17bb0f8e-9d26-411e-9027-6feb9607a6b2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:14:01Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:17bb0f8e-9d26-411e-9027-6feb9607a6b22022-03-26T10:39:13ZInherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:17bb0f8e-9d26-411e-9027-6feb9607a6b2EnglishSymplectic Elements at Oxford2013Prando, CSamarina, ABustamante, JBoisson-Dupuis, SCobat, APicard, CAlSum, ZAl-Jumaah, SAl-Hajjar, SFrayha, HAlangari, AAl-Mousa, HMobaireek, KBen-Mustapha, IAdimi, PFeinberg, Jde Suremain, MJannière, LFilipe-Santos, OMansouri, NStephan, JNallusamy, RKumararatne, DBloorsaz, MRBen-Ali, MAutosomal 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. |
| spellingShingle | 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, K Ben-Mustapha, I Adimi, P Feinberg, J de Suremain, M Jannière, L Filipe-Santos, O Mansouri, N Stephan, J Nallusamy, R Kumararatne, D Bloorsaz, MR Ben-Ali, M Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. |
| title | Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. |
| title_full | Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. |
| title_fullStr | Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. |
| title_full_unstemmed | Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. |
| title_short | Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. |
| title_sort | inherited il 12p40 deficiency genetic immunologic and clinical features of 49 patients from 30 kindreds |
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