X-linked mendelian susceptibility to mycobacterial diseases (ORPHA:319605)
X-linked (XR) Mendelian susceptibility to mycobacterial diseases (MSMD; see this term) describes a rare group of immunodeficiencies due to specific mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG) or the cytochrome b-245, beta polypeptide (CYBB) genes. They are characterized by mycobacterial infections, occuring in males.
Epidemiology
The prevalence is unknown. Six male patients have been reported with XR-MSMD deficiency due to IKBKG mutations and seven male patients have been reported with XR-MSMD deficiency due to CYBB mutations.
Clinical description
XR-MSMD due to IKBKG deficiency affects otherwise healthy male patients. The most common infections seen are Mycobacterium avium, Mycobacterium bovis  BCG and Mycobacterium tuberculosis. An invasive Haemophilus influenza type b infection was reported in one patient. In two cases, mild signs of anhidrotic ectodermal dysplasia (AED; see this term), limited to conical deciduous incisors, were observed. Patients with XR-MSMD due to CYBB deficiency present with disseminated tuberculosis mycobacterial disease (such as BCG or M. tuberculosis). They do not suffer from any other infectious diseases.
Etiology
XR-MSMD is due to hemizygous mutations in the IKBKG or CYBB genes. IKBKG (Xq28) encodes the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma. This mutation causes defects in T-cell dependant IL-12 production and consequently IFN-gamma production. The mutations disturb the plasticity of the leucine zipper domain (LDZ) helix of IKBKG interfering selectively with the CD40-NEMO-NFkB signaling pathway. These hypomorphic mutations are associated with impaired NF-kB activation of c-Rel containing proteins in response to CD40. The CYBB gene (Xp21.1) encodes the gp91-phox subunit of the phagocyte NADPH oxydase. These mutations do not impair the respiratory burst in granulocytes and monocytes, but they impair macrophages and B-cell lines selectively.
Diagnostic methods
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA. Low levels of IFN-gamma and IL-12 production by the patients' mononuclear cells upon phytohemagglutinin (PHA) are detected in those with an IKBKG mutation. In addition, an impaired IL-12 production by monocytes upon PHA stimulation by activated T cells is shown. Impaired NADPH activity is demonstrated in vitro in macrophages and B-cell lines in those with a CYBB mutation. A mutational analysis is necessary to identify the exact causative genes involved allowing for the implementation of a specific treatment plan.
Differential diagnosis
Differential diagnoses include other diseases caused by IKBKG mutations such as EDA with immunodeficiency (see this term). It is important to exclude the diagnosis of chronic granulomatous disease (CGD; see this term) caused by CYBB mutations. Other genetic forms of MSMD should also be excluded.
Antenatal diagnosis
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Genetic counseling
The occurrence of mycobacterial diseases in maternally-related males suggests an X-linked recessive form of MSMD. Genetic counseling is possible when a known mutation is present in the family.
Management and treatment
BCG vaccination should be avoided in those with a known XR-MSMD mutation. Treatment usually involves IFN-gamma therapy in addition to antibiotics.
Prognosis
The prognosis is good.

                            Last update: 
                            February 2013


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