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

Details

Serval ID
serval:BIB_9D8759A4A7D5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.
Journal
Medicine
Author(s)
Prando C., Samarina A., Bustamante J., Boisson-Dupuis S., Cobat A., Picard C., AlSum Z., Al-Jumaah S., Al-Hajjar S., Frayha H., Al-Mousa H., Ben-Mustapha I., Adimi P., Feinberg J., de Suremain M., Jannière L., Filipe-Santos O., Mansouri N., Stephan J.L., Nallusamy R., Kumararatne D.S., Bloorsaz M.R., Ben-Ali M., Elloumi-Zghal H., Chemli J., Bouguila J., Bejaoui M., Alaki E., AlFawaz T.S., Al Idrissi E., ElGhazali G., Pollard A.J., Murugasu B., Wah Lee B., Halwani R., Al-Zahrani M., Al Shehri M.A., Al-Zahrani M., Bin-Hussain I., Mahdaviani S.A., Parvaneh N., Abel L., Mansouri D., Barbouche R., Al-Muhsen S., Casanova J.L.
ISSN
1536-5964 (Electronic)
ISSN-L
0025-7974
Publication state
Published
Issued date
03/2013
Peer-reviewed
Oui
Volume
92
Number
2
Pages
109-122
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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-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.
Keywords
Adolescent, Adult, Age of Onset, Asia, Western/epidemiology, Child, Child, Preschool, Cohort Studies, DNA Mutational Analysis, Female, Founder Effect, Genetic Predisposition to Disease, Humans, Infant, Interleukin-12 Subunit p40/deficiency, Interleukin-12 Subunit p40/genetics, Male, Mycobacterium Infections, Nontuberculous/genetics, Mycobacterium Infections, Nontuberculous/immunology, Mycobacterium Infections, Nontuberculous/mortality, Penetrance, Salmonella Infections/genetics, Survival Analysis, Tunisia/epidemiology, Young Adult
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Web of science
Create date
04/02/2021 18:57
Last modification date
07/07/2021 5:37
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