Mendelian susceptibility to mycobacterial diseases (ORPHA:748)
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare immunodeficiency syndrome, characterized by a narrow vulnerability to poorly virulent mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM), and defined by severe, recurrent infections, either disseminated or localized.
Epidemiology
The prevalence is unknown.
Clinical description
MSMD due to autosomal recessive (AR) complete interferon gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2) deficiencies (see these terms), the most serious variants, develop in early childhood with first infections generally occurring around the age of 3. Serious, disseminated infections with BCG and EM are observed and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Other infections with Salmonella spp., Listeria monocytogenes and viruses have been reported. MSMD due to partial IFN-gammaR1, partial IFN-gammaR2, complete IL-12R-beta1, complete IL12B, complete ISG15, partial STAT1 and partial IRF8 deficiencies and MSMD due to partial X-linked recessive (XR) mutations (see these terms) are usually less severe. They have minor symptoms and some occur after the age of 3 to adulthood. Patients are vulnerable to Mycobacterium tuberculosis. Severe diseases caused by non-typhoidal Salmonella species have been reported in half of patients, especially in those with IL-12R-beta1 or IL12B deficiencies.
Etiology
Only about half of patients with MSMD have an identified genetic etiology. Nine genes are known to be responsible for MSMD. Seven of them are inherited autosomally (IFNGR1, IFNGR2, STAT1, IL12B , IL12RB1 and more recently IRF8 and ISG15) and 2 are X-linked (IKBKG  and CYBB). MSMD is heterogeneous and thought to be mendelian based on the large number of consanguineous and/or multiplex kindred identified and/or X-linked heritance. The genetic defects impair IL-12 dependent IFN-gamma immunity. The high allelic heterogeneity results in 17 genetic disorders according to the mode of transmission, impact on function, association of a lack of protein expression or expression of an abnormal protein, and the specific function affected. Molecular and cellular mechanisms remain largely unknown.
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. Mutational analysis is necessary to identify the exact causative genes involved.
Differential diagnosis
Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency should be excluded as well as complete defects in IRF8 or STAT1 and TyK2 (see these terms).
Antenatal diagnosis
Antenatal diagnosis can be offered to those families with the often fatal complete IFNGR deficiencies.
Genetic counseling
MSMD can be inherited in an AD, AR or X-linked manner. Genetic counseling is possible when a specific mutation is identified within a family.
Management and treatment
BCG vaccination should be avoided in those with MSMD. Patients with IL-12B, IL-12R-beta1 or ISG15 deficiencies and partial IFN-gammaR, IRF8 and STAT1 deficiencies respond well to antibiotic therapy and can also be treated with IFN-g therapy. Abdominal lymph node resection may be needed in some cases. Hematopoietic stem cell transplantation (HSCT) should be considered in those with complete IFN-gammaR1 and IFN-gammaR2 deficiencies but rates of rejection are high, probably due to high levels of IFN-gamma detected in the serum of these patients.
Prognosis
Prognosis depends on the specific mutation involved and the corresponding associated disorder. Some cases are fatal while others resolve with antibiotic therapy.

                            Last update: 
                            February 2013


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