What are the other Names for this Condition? (Also known as/Synonyms)

• Idiopathic Infection caused by BCG or Atypical Mycobacteria
• Mendelian Susceptibility to Atypical Mycobacteria
• Mendelian Susceptibility to Mycobacterial Infections

What is Mendelian Susceptibility to Mycobacterial Diseases? (Definition/Background Information)

• Mendelian Susceptibility to Mycobacterial Diseases (MSMD) is a rare immunodeficiency syndrome, with susceptibility to mycobacteria, such as the vaccine against tuberculosis (bacillus Calmette-Guérin (BCG) and environmental mycobacteria. It is characterized by severe, recurrent infections, either systemic (widespread) or localized. It has many subtypes.
• The most serious types are the autosomal recessive complete interferongamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2) deficiencies. 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 are less severe subtypes. Only about half of patients with MSMD have an identified genetic cause
• Nine genes are known to be responsible for MSMD. Seven of them are inherited in an autosomal recessive or autosomal dominant pattern (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8 and ISG15genes) and 2 are X-linked (IKBKG and CYBB genes). BCG vaccination should be avoided in those with MSMD
• Treatment includes antibiotics and surgery for lymph node removal in some cases. Hematopoietic stem cell transplantation (HSCT) may be considered in specific cases.
• Prognosis depends on the specific mutation and the associated disorder

(Source: Mendelian Susceptibility to Mycobacterial Diseases; Genetic and Rare Disease Information Center (GARD) of National Center for Advancing Translational Science (NCATS), USA.)

Who gets Mendelian Susceptibility to Mycobacterial Diseases? (Age and Sex Distribution)

• Mendelian Susceptibility to Mycobacterial Diseases is a rare inherited disorder. Its exact prevalence is not known at the present time
• The condition can occur in individuals of all ages, and both genders
• Worldwide, all ethnicities and races may get affected by this disorder

What are the Risk Factors for Mendelian Susceptibility to Mycobacterial Diseases? (Predisposing Factors)

• A positive family history may be an important risk factor, since Mendelian Susceptibility to Mycobacterial Diseases can be inherited
• Currently, no other risk factors have been clearly identified for the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Mendelian Susceptibility to Mycobacterial Diseases? (Etiology)

• Mendelian Susceptibility to Mycobacterial Diseases may be caused my mutation(s) in at least 9 genes. These genes include IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8, ISG15, IIKBKG and CYBB
• The mutations in these genes are known to cause a defect in the IL-12 dependent interferon-gamma immunity
• Causative mutation(s) in the IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1 IRF8 and ISG15 genes are inherited in an autosomal manner, and can be either dominant or recessive 
• Mutation(s) in IIKBKG and CYBB genes are inherited in an X-linked manner

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

X-linked inheritance: The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What are the Signs and Symptoms of Mendelian Susceptibility to Mycobacterial Diseases?

The severity of signs and symptoms of Mendelian Susceptibility to Mycobacterial Diseases may be determined by the mutated gene and the inheritance pattern. The autosomal recessive gene mutation(s) lead to more severe symptoms.

The signs and symptoms of Mendelian Susceptibility to Mycobacterial Diseases may include:

• Disseminated infections with BCG vaccination (can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes)
• BCG or Bacille Calmette-Guerin is a vaccine against tuberculosis, and contains a live, non-virulent bacterium known as Mycobacterium bovis. Tuberculosis is caused by Mycobacterium tuberculosis
• Infections with Salmonella spp., Listeria monocytogenes and viruses
• Infection by Mycobacterium tuberculosis
• Severe non-typhoidal Salmonella infections (especially in those with IL-12R-beta1 or IL12B deficiencies)

How is Mendelian Susceptibility to Mycobacterial Diseases Diagnosed?

Mendelian Susceptibility to Mycobacterial Diseases is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests, including ELSIA to measure levels of IFN-gamma, IL-12p40 and IL-12p70 levels, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to specifically identify the causative gene mutation

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Mendelian Susceptibility to Mycobacterial Diseases?

The complications of Mendelian Susceptibility to Mycobacterial Diseases may include:

• Recurrent infections, causing scarring of tissues
• Tuberculosis

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Mendelian Susceptibility to Mycobacterial Diseases Treated?

There is no cure for Mendelian Susceptibility to Mycobacterial Diseases, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. The condition can be managed by the following:

• Antibiotic therapy (in those with IL-12B, IL-12R-beta1 or ISG15 deficiencies and partial IFN-gammaR, IRF8 and STAT1 deficiencies) 
• IFN-g therapy
• Abdominal lymph node resection 
• Hematopoietic stem cell transplantation (HSCT in individuals with complete IFN-gammaR1 and IFN-gammaR2 deficiencies)

How can Mendelian Susceptibility to Mycobacterial Diseases be Prevented?

Mendelian Susceptibility to Mycobacterial Diseases may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Avoiding BCG vaccination can help avoid disseminated infection following the vaccination
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Mendelian Susceptibility to Mycobacterial Diseases? (Outcomes/Resolutions)

• The prognosis of Mendelian Susceptibility to Mycobacterial Diseases is determined by the type of mutation an individual inherits, the severity of signs and symptoms, and associated complications, if any
• Complete deficiencies in interferon gamma receptors 1 and 2, caused by IFNGR1, IFNGR2 mutations, respectively, cause the most severe symptoms and can be fatal
• Less severe cases may be manageable by antibiotics or other therapies
• Typically, the prognosis may be made on a case-by-case basis

Additional and Relevant Useful Information for Mendelian Susceptibility to Mycobacterial Diseases:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/