Immunodeficiency 29

Alternative Names

  • IMD29
  • IL12B Deficiency
  • Mendelian Susceptibility to Mycobacterial Diseases due to Complete IL12B Deficiency

Associated Genes

Interleukin 12B
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Certain disorders involving the immune mechanism

OMIM Number

614890

Mode of Inheritance

Autosomal recessive

Gene Map Locus

5q33.3

Description

IL12B Deficiency is a rare condition involving the immune system characterized by an impairment of interferon-gamma mediated immunity.  This condition is typified by susceptibility to mycobacterial species, such as Mycobacterium tuberculosis, environmental non-tuberculous mycobacteria and the Bacillus Calmette-Guerin (BCG) vaccine.  Thus, patients present with BCG disease after routine vaccination in childhood.  In addition, affected patients may also be susceptible to Salmonella infections.  

The clinical severity of the immunodeficiencies involving interferon gamma varies widely, and depends on the degree of impairment of interferon-gamma mediated immunity.  In the most severe of cases, patients develop lepromatous-like lesions in early childhood, and ultimately succumb to mycobacterial infections.  In relatively milder cases, patients develop disseminated but curable infections with tuberculoid granulomas later on in their life.  Most cases of IMD29 are of the mild form, and prognosis is generally good.  Diagnosis is made on the basis of clinical features and by the absence of detection of IL12B secretion from leukocytes.  Extended periods of therapy with antimycobacterial drugs may be required for those patients who are infected, along with recombinant IFN gamma.  BCG immunization is contraindicated, and other live vaccines should also be avoided.

Molecular Genetics

Mutations in the IL12B gene are responsible for the development of IMD29.  The IL12B gene codes for the p40 subunit of the Interleukin 12 protein.  IL12 induces IFN gamma production, and is thus, a major component of IFN gamma mediated immunity.  Defects in IL12B, are thus, causally connected to IFN gamma related immunodeficiencies.  However, the clinical severity of the condition is much less in patients with IL12B deficiency than in patients with complete IFN gamma deficiencies. 

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Picard et al. (2002) described ten patients from four different Saudi kindreds affected with IMD29.  All patients were born to first-cousin consanguineous parents, originating from and living in Saudi Arabia.  Of the 10, nine developed either disseminated or local BCG infection following vaccination.  The tenth patient was not vaccinated and went on to develop disseminated M. chelonae infection.  Three of the patients also developed Salmonella infections, while one of them had a N. asteroides infection.  On the whole, the patients responded well to antimycobacterial therapy.  However, four of the patients succumbed to infections.  The affected patients in all four families had siblings who were vaccinated and showed no adverse effects.  Molecular analysis identified the same homozygous frameshift mutation in the IL12B gene in all the affected Saudi patients.  Prando et al. (2013) extended this study by incrporating 14 Saudi consanguineous kindreds with IL12B deficiency.  These included the four families described by Picard et al. (2002) and an additional 10 kindreds with 17 affected children.  Patients in all families were found to be homozygous for the same insertion mutation in the IL12B gene.

Tunisia

Elloumi-Zghal et al. (2002) described three Tunisian patients with IL12B Deficiency from two different families.  The first family had two affected siblings born to non-consanguineous parents, both of who presented with axillary lymphadenitis following neonatal BCG vaccination.  The older of the siblings had a severe course of disease progression, and later succumbed to a fulminant varicella infection.  His dizygotic twin brother was vaccinated without any adverse effects.  The younger affected sibling responded well to antimycobacterial therapy.  Their father and paternal grandfather were likely to have also been affected, although symptoms were much milder.  The third patient was born to second degree consanguineous parents, and developed fistulizing axillary adenitis and hepatosplenomegaly post BCG-vaccination.  She received multiple antimycobacterial drugs, and improved slightly.  However, she later died at the age of 2-years.  There was no family history of a similar condition.  Molecular analysis identified a deletion in the IL12B gene in all the three patients, suggesting a founder mutation. 

Prando et al. (2013) extended this study by incorporating six Tunisian kindreds with IL12B deficiency.  These included the two families described by Elloumi-Zghal et al. (2002) and an additional four kindreds with at least five affected children.  Patients in all families were found to be homozygous for the same insertion mutation in the IL12B gene.

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