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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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Clinical phenotypes for IL-12p40-deficient index cases. Each patient is classified as a function of mycobacterial infection status (BCG, TB, EM) and Salmonella infection status, as labeled. [This figure can be viewed in color online at http://www.md-journal.com].
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F4-6: Clinical phenotypes for IL-12p40-deficient index cases. Each patient is classified as a function of mycobacterial infection status (BCG, TB, EM) and Salmonella infection status, as labeled. [This figure can be viewed in color online at http://www.md-journal.com].

Mentions: Figure 4 indicates the clinical features of the 30 IL-12p40-deficient index cases. The first clinical symptoms occurred in childhood (mean age, 1.1 yr; SD, 1.76 yr; range, 1 mo–7.6 yr). BCG was, by far, the most frequent infectious agent, causing the first clinical manifestation of MSMD (n = 27). Disseminated BCG disease (BCG-osis) was the most frequent presentation (19 of 27 cases), the other patients displaying regional BCG disease (BCG-itis; 8 of 27). Salmonella (2.II.3), EM (6.II.5) and M. tuberculosis (18.II.1) were responsible for the first clinical manifestation in 1 index case each. Patients 2.II.3 and 6.II.5 were not vaccinated with BCG. Patient 18.II.1 was vaccinated with BCG at the age of 3 years, with no adverse reaction. Twenty of 30 index cases (66.7%) presented with BCG disease as the only MSMD-related infection during their lifetime. After BCG disease, 5 patients developed salmonellosis, 1 patient developed tuberculosis (TB) (20.II.3), and another patient developed both salmonellosis and EM disease (12.II.1). Salmonellosis and TB were the only relevant infections observed during the lifetimes of patients 2.II.3 and 18.II.1, respectively. Patient 6.II.5 developed salmonellosis soon after EM infection.


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)

Clinical phenotypes for IL-12p40-deficient index cases. Each patient is classified as a function of mycobacterial infection status (BCG, TB, EM) and Salmonella infection status, as labeled. [This figure can be viewed in color online at http://www.md-journal.com].
© Copyright Policy
Related In: Results  -  Collection

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

F4-6: Clinical phenotypes for IL-12p40-deficient index cases. Each patient is classified as a function of mycobacterial infection status (BCG, TB, EM) and Salmonella infection status, as labeled. [This figure can be viewed in color online at http://www.md-journal.com].
Mentions: Figure 4 indicates the clinical features of the 30 IL-12p40-deficient index cases. The first clinical symptoms occurred in childhood (mean age, 1.1 yr; SD, 1.76 yr; range, 1 mo–7.6 yr). BCG was, by far, the most frequent infectious agent, causing the first clinical manifestation of MSMD (n = 27). Disseminated BCG disease (BCG-osis) was the most frequent presentation (19 of 27 cases), the other patients displaying regional BCG disease (BCG-itis; 8 of 27). Salmonella (2.II.3), EM (6.II.5) and M. tuberculosis (18.II.1) were responsible for the first clinical manifestation in 1 index case each. Patients 2.II.3 and 6.II.5 were not vaccinated with BCG. Patient 18.II.1 was vaccinated with BCG at the age of 3 years, with no adverse reaction. Twenty of 30 index cases (66.7%) presented with BCG disease as the only MSMD-related infection during their lifetime. After BCG disease, 5 patients developed salmonellosis, 1 patient developed tuberculosis (TB) (20.II.3), and another patient developed both salmonellosis and EM disease (12.II.1). Salmonellosis and TB were the only relevant infections observed during the lifetimes of patients 2.II.3 and 18.II.1, respectively. Patient 6.II.5 developed salmonellosis soon after EM infection.

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