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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 319552
Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interleukin-12 receptor subunit beta-1 (IL12RB1) deficiency is a genetic variant of MSMD (see this term) characterized by mild bacillus Calmette-Guérin (BCG) infections and recurrent Salmonella infections.
The prevalence is unknown. Over 140 cases have been reported in the world.
Disease onset usually occurs in patients before the age of 12 with the appearance of BCG disease, usually after receiving the vaccination. Over half of patients with this variant experience an additional infection with non- typhoidal Salmonella. Severe tuberculosis caused by Mycobacterium tuberculosis has been reported in several unrelated patients, providing the first documented evidence of a mendelian predisposition to tuberculosis. Other infections with Paracoccidiodes brasiliensis , Leishmania and Klebsiella have been reported in a single patient. Some patients also suffer from Candida infections. Most genetically affected siblings of index cases are asymptomatic, indicating low penetrance for case definition phenotypes.
MSMD due to complete IL12RB1 deficiency is caused by mutations in the IL12RB1 gene (19p13.1) subunit that encodes for the IL-12R-beta1 chain. These mutations impair the IL-12/IL-23 pathway essential for production of IFN-beta and the resulting immunity against Salmonella and BCG infections. Two clinically indistinguishable forms have been reported defined by the presence or absence of protein expression on the cell surface.
Diagnosis is made by laboratory analysis. In general, there is no expression of IL12RB1 at the surface of activated T-lymphocytes and NK cells. For the moment, only one mutation of IL12 RB1 leads to residual expression of the receptor on the cell surface. Low IFN-gamma levels are measured by ELISA after whole blood activation by BCG and BCG+IL-12. Genetic testing reveals mutations in IL12RB1. Impaired development of the Th17 cells is demonstrated in patients with this immunodeficiency.
Other genetic etiologies of MSMD should be excluded.
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
MSMD due to complete IL12RB1 deficiency is inherited in an autosomal recessive manner so genetic counseling is possible.
Management and treatment
BCG vaccination should be avoided in those with a known mutation in the IL12RB1 gene. Treatment is usually attained from long term antimicrobial therapy combined with recombinant IFN-gamma. For those who have localized splenic/mesenteric lesions with poor drug penetration, surgical removal is indicated.
With proper treatment the prognosis is usually good with most patients reaching adulthood.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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