Mendelian Susceptibility To Mycobacterial Diseases Due To Complete Ifngammar2 Deficiency

Mendelian susceptibily to mycobacterial diseases (MSMD) due to complete interferon gamma receptor 2 (IFN-gammaR2) deficiency is a genetic variant of MSMD (see this term) characterized by a complete deficiency in IFN-gammaR2, leading to an undetectable response to IFN-gamma, and consequently, to severe and often fatal infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).

Epidemiology

The prevalence is unknown. Only ten children have been identified to date.

Clinical description

Severe and often fatal BCG and EM infections begin in early childhood (before the age of 3). The most common pathogens seen in patients include Mycobacterium fortuitum, Mycobacterium bovis BCG, Mycobacterium abscessus and Mycobacterium avium. Infections are disseminated and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Infections manifest with fever, weight loss, hepatosplenomegaly and lymphadenopathies and can be fatal.

Etiology

This disease is caused by mutations in IFNGR2 on chromosome 21q22.1-22.2 which encodes the IFN-gamma receptor signal transducing chain, essential for IFN-gamma mediated immunity. Two clinically indistinguishable forms have been reportedly defined by the presence or absence of protein expression on the cell surface.

Diagnostic methods

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. Leukocytes and fibroblasts from patients with this immunodeficiency do not respond to IFN-gamma in vitro. Genetic testing reveals mutations in IFNGR2.

Differential diagnosis

Differential diagnosis includes the other variants of MSMD, especially complete IFN-gammaR1 deficiency (see this term). Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency (see these terms) should also be excluded.

Antenatal diagnosis

As this disease is often fatal, antenatal diagnosis is offered to families with a known IFNGR2 mutation.

Genetic counseling

MSMD due to complete IFN-gammaR2 deficiency is inherited autosomal recessively and genetic counseling is recommended.

Management and treatment

The only curative option for MSMD due to complete IFN-gammaR2 deficiency is hematopoietic stem cell transplantation (HSCT). Due to a lack of specific receptors, IFN-gamma treatment is not indicated. BCG vaccination should be avoided in those with a known IFNGR2 mutation.

Prognosis

Prognosis is poor with most patients not living past 10 years of age.