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

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 KF, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, Ben-Ali M, Elloumi-Zghal H, Chemli J, Bouguila J, Bejaoui M, Alaki E, AlFawaz TS, Al Idrissi E, ElGhazali G, Pollard AJ, Murugasu B, Wah Lee B, Halwani R, Al-Zahrani M, Al Shehri MA, Al-Zahrani M, Bin-Hussain I, Mahdaviani SA, Parvaneh N, Abel L, Mansouri D, Barbouche R, Al-Muhsen S, Casanova JL - Medicine (Baltimore) (2013)

Bottom Line: Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries.As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ).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.

View Article: PubMed Central - PubMed

Affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.

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.

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First onset of MSMD-related infections in IL-12p40-deficient patients (BCG, EM, Salmonella, and TB).
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F8-6: First onset of MSMD-related infections in IL-12p40-deficient patients (BCG, EM, Salmonella, and TB).

Mentions: Consistent information concerning the onset of clinical symptoms was available for 42 of the 44 symptomatic patients: 30 index cases and 12 sibs. First infection occurred early in childhood, at a mean age of 1 year (range, 1 mo–7.6 yr; SD, 1.59 yr) (Figure 8). BCG was the most frequent causal agent (n = 40) and disseminated disease occurred as the first clinical manifestation of MSMD in 25 patients. BCG disease occurred in children as young as 1 month, with a mean age at onset of 9 months (range, 1 mo–7.6 yr; SD, 1.39 yr). In 35 cases (83.3%), BCG disease occurred within 1 year of vaccination. The mean time from BCG vaccination to disease was 6.37 months (range, 1 mo-4.16 yr; SD, 7.95 mo). The onset of salmonellosis (n = 11) occurred over a larger range of ages, extending from 3 months to 33 years (mean, 5.39 yr; SD, 9.78 yr). EM infection was found in 2 patients, at the ages of 3 and 4 years, respectively. Mean age at the onset of TB was 2.8 years (range, 6 mo–5 yr; SD, 2.25 yr). We can conclude that BCG disease was not only the most frequent infection in IL-12p40-deficient patients, but also the infection with the earliest age at onset.


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

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 KF, Ben-Mustapha I, Adimi P, Feinberg J, de Suremain M, Jannière L, Filipe-Santos O, Mansouri N, Stephan JL, Nallusamy R, Kumararatne DS, Bloorsaz MR, Ben-Ali M, Elloumi-Zghal H, Chemli J, Bouguila J, Bejaoui M, Alaki E, AlFawaz TS, Al Idrissi E, ElGhazali G, Pollard AJ, Murugasu B, Wah Lee B, Halwani R, Al-Zahrani M, Al Shehri MA, Al-Zahrani M, Bin-Hussain I, Mahdaviani SA, Parvaneh N, Abel L, Mansouri D, Barbouche R, Al-Muhsen S, Casanova JL - Medicine (Baltimore) (2013)

First onset of MSMD-related infections in IL-12p40-deficient patients (BCG, EM, Salmonella, and TB).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822760&req=5

F8-6: First onset of MSMD-related infections in IL-12p40-deficient patients (BCG, EM, Salmonella, and TB).
Mentions: Consistent information concerning the onset of clinical symptoms was available for 42 of the 44 symptomatic patients: 30 index cases and 12 sibs. First infection occurred early in childhood, at a mean age of 1 year (range, 1 mo–7.6 yr; SD, 1.59 yr) (Figure 8). BCG was the most frequent causal agent (n = 40) and disseminated disease occurred as the first clinical manifestation of MSMD in 25 patients. BCG disease occurred in children as young as 1 month, with a mean age at onset of 9 months (range, 1 mo–7.6 yr; SD, 1.39 yr). In 35 cases (83.3%), BCG disease occurred within 1 year of vaccination. The mean time from BCG vaccination to disease was 6.37 months (range, 1 mo-4.16 yr; SD, 7.95 mo). The onset of salmonellosis (n = 11) occurred over a larger range of ages, extending from 3 months to 33 years (mean, 5.39 yr; SD, 9.78 yr). EM infection was found in 2 patients, at the ages of 3 and 4 years, respectively. Mean age at the onset of TB was 2.8 years (range, 6 mo–5 yr; SD, 2.25 yr). We can conclude that BCG disease was not only the most frequent infection in IL-12p40-deficient patients, but also the infection with the earliest age at onset.

Bottom Line: Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries.As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ).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.

View Article: PubMed Central - PubMed

Affiliation: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York 10065, USA.

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.

Show MeSH
Related in: MedlinePlus