Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency (ORPHA:99898)
Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interferon gamma receptor 1 (IFN-gammaR1) deficiency is a genetic variant of MSMD (see this term) characterized by a complete deficiency in IFN-gammaR1, leading to impaired IFN-gamma immunity and, consequently, to severe and often fatal infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).
Epidemiology
The prevalence is unknown.
Clinical description
Severe and often fatal BCG and EM infections begin in early childhood (before the age of 3) as a complete deficiency displays complete clinical penetrance in childhood. The most common pathogens include Mycobacterium fortuitum,  Mycobacterium chelonae, Mycobacterium smegmatis and Mycobacterium peregrinum. Infection is disseminated and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Manifestations include fever, weight loss, hepatosplenomegaly, lymphadenopathies and lepromatous-like lesions. Salmonellosis has been reported in 5% of patients. Other infections caused by cytomegalovirus, Listeria monocytogenes and human herpes virus 8 have been reported in a single case.
Etiology
MSMD due to complete IFN-gammaR1 deficiency is caused by mutations in the  IFNGR1 gene on chromosome 6q23-q24. This gene encodes the IFN-gamma receptor ligand binding chain and a mutation leads to the halt of IFN-gammaR1 at the cell surface. More than 21 causal mutations have been identified to date, with most of them being homozygous. Two forms of clinically indistinguishable complete IFN-gammaR1 deficiency have been identified: with or without the expression of cell surface receptors.
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. High plasma concentrations of IFN-gamma suggest a complete IFN-gammaR deficiency. Leukocytes and fibroblasts from patients with this immunodeficiency do not respond to IFN-gamma in vitro. Histology of lymph nodes shows ill defined and poorly differentiated lepromatous-like multibacillary granulomas with few giant cells. Genetic testing reveals mutations in IFNGR1.
Differential diagnosis
Differential diagnoses include other genetic etiologies of MSMD, especially complete IFN-gammaR2 deficiency (see these terms). Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency (see these terms) should also be excluded.
Antenatal diagnosis
As this variant is often fatal, antenatal diagnosis is offered to families with a known IFNGR1 mutation.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.
Management and treatment
The only curative option for MSMD due to AR complete IFN-gammaR1 deficiency is hematopoietic stem cell transplantation (HSCT). As there is a high risk for rejection with this procedure, treatment with IFN-gamma-depleted antibodies to lower pre-transplantation IFN-gamma levels will favor a more positive outcome. Due to a lack of specific receptors, IFN-gamma treatment is not indicated. BCG vaccination should be avoided in those with a known IFNGR1 mutation.
Prognosis
Prognosis is poor with most patients not living past 10 years of age.

                            Last update: 
                            February 2013


                            - Expert reviewer(s): 
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA