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Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency
Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete ISG15 deficiency is a genetic variant of MSMD (see this term) characterized by Bacille Calmette-Guérin (BCG) infections.
ORPHA:319563Classification level: Disorder
- MSMD due to complete ISG15 deficiency
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Childhood
- ICD-10: D84.8
- OMIM: 616126
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
The prevalence is unknown. In 2012, three patients were reported from two unrelated kindreds from Turkey and Iran.
Patients are described to have BCG infections. Patients of 12 or 15 years of age were reported to have been infected in the past with many other viruses but with no unusually severe consequences reported.
MSMD due to complete ISG15 deficiency is caused by mutations in the ISG15 gene (1p36.33), which encodes an IFN-alpha/beta inducible, ubiquitin-like intracellular protein. These mutations impair ISG15 secretion by leukocytes, a molecule which plays an essential role as an IFN-gamma-inducing secreted molecule needed for optimal antimycobacterial immunity.
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. Similarly to patients with an IL12RB1 deficiency, patients with an ISG15 deficiency produce small amounts of IFN-gamma whereas they produce normal amounts of IL12p40 and IL12p70. Genetic testing reveals mutations in ISG15.
Other etiologies of MSMD, especially MSMD due to complete IL12RB1 deficiency (see this term), should be excluded.
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
MSMD due to complete ISG15 deficiency is inherited in an autosomal recessive manner and genetic counseling is possible.
Management and treatment
BCG vaccination should be avoided in those with a known ISG15 mutation. Treatment usually involves long term antimicrobial therapy combined with recombinant IFN-gamma.
With proper treatment the prognosis is presumed to be good.
- Summary information
- Polski (2013, pdf)