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

• HIGM1 (Hyper-IgM Syndrome 1)
• Hyper-IgM Syndrome 1
• Immunodeficiency with Hyper-IgM, Type 1

What is X-Linked Hyper IgM Syndrome? (Definition/Background Information)

• X-linked Hyper IgM Syndrome is an infrequent genetic disorder that disrupts the immune system, weakening the body immunity. The body is, hence, susceptible to many infections and diseases
• X-linked Hyper IgM Syndrome is marked by reduced levels of antibodies, which is very important to a strong and robust immunity. Hence, the affected individuals remain immunocompromised and are unable to prevent or fight any infections that attack them
• This congenital disorder is inherited as an X-linked recessive trait and affects only males (almost all cases). Boys are frequently prone to ear infection (otitis), lung infection (pneumonia), sinusitis, and many other diseases
• Due to the chronicity of the infections, children are prone to severe malnutrition and longstanding gastrointestinal disorders. X-linked Hyper IgM Syndrome is a lethal condition if prompt and continuous medical support and treatment is not provided
• The management of X-linked Hyper IgM Syndrome may involve immunoglobulin therapy, bone marrow and stem cell transplants, administration of antimicrobial drugs, and dietary control
• Despite continuous support and therapy, the prognosis of X-linked Hyper IgM Syndrome is poor. A majority of individuals do not survive past early adulthood

Who gets X-Linked Hyper IgM Syndrome? (Age and Sex Distribution)

• X-linked Hyper IgM Syndrome is a rare, congenital condition that manifests at birth. This condition almost exclusively affects males
• The prevalence rate of the condition is 1 in 500,000 among the general population
• There is no particular racial or ethnic preference observed and the condition is seen worldwide

What are the Risk Factors for X-Linked Hyper IgM Syndrome? (Predisposing factors)

• A positive family history of X-linked Hyper IgM Syndrome is the only known risk factor 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 ones 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 X-Linked Hyper IgM Syndrome? (Etiology)

• X-linked Hyper IgM Syndrome is a genetic disorder that is inherited in an X-linked recessive manner
• In this disorder, there are genetic mutations in the CD40LG gene, which is responsible for the production of a protein (CD40 ligand)
• Due to the abnormal mutations, the protein production is affected or is deficient. By a complex set of processes, this results in poorly-functioning B cells and T cells that are vital to the immune system. Due to this, there are low levels of antibodies in the affected individuals
• The various signs and symptoms of X-linked Hyper IgM Syndrome are the result of a dysfunctional immune system. Moreover, since the condition is an X-linked one, only the male child is affected

X-linked recessive: X-linked recessive conditions are traits or disorders that occur when two copies of an abnormal gene are inherited on a sex chromosome (X or Y chromosome). All X-linked recessive traits are fully evident in males, because they have only one copy of the X chromosome. This means that there is no normal gene present to mask the effects of the mutant copy. All males who are affected will pass the mutated gene onto their female offspring, because they must inherit one copy of the X chromosome from each parent. This means that they will be unaffected carriers. Females are rarely affected by X-linked recessive disorders because they have two copies of the X chromosome. In the rare case that they inherit two mutated copies of the gene, they will inherit the condition.

What are the Signs and Symptoms of X-Linked Hyper IgM Syndrome?

X-linked Hyper IgM Syndrome is present at birth. Right from infancy, the affected children are unable to protect themselves against bacterial, viral, fungal, or other infections. Due to frequently being affected by infections, the growth and development of the child is hampered. In children, the following signs and symptoms may be observed:

• Loss of weight
• Chronic diarrhea
• Failure to thrive
• Onset of autoimmune disorders
• Infections affecting any part of the body or organ, such as the ear, liver, gastrointestinal tract, lungs, central nervous system, and other regions

How is X-Linked Hyper IgM Syndrome Diagnosed?

The diagnosis of X-linked Hyper IgM Syndrome may involve the following tests and exams:

• Complete physical examination with comprehensive evaluation of family medical history
• Blood and sputum tests
• Urine and stool analysis
• Genetic tests and analysis to detect abnormal mutations
• Liver function tests
• A tissue biopsy may be performed in case of liver infection
• Pulmonary function tests, bronchoscopy
• Prenatal exams include amniocentesis and chorionic villus sampling
• CT, MRI scans for lung and abdomen related conditions
• Lymph node biopsy

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 X-Linked Hyper IgM Syndrome?

Complications due to X-linked Hyper IgM Syndrome may include:

• Bronchiectasis, particularly in individuals with frequent pneumonia
• Liver enlargement due to hepatitis, cholangitis, and liver failure
• Chronic gastrointestinal disorders, formation of adenocarcinomas
• Longstanding diarrhea, malnutrition
• Progressive meningoencephalitis causing neurological abnormalities
• Higher susceptibility to cancers such as lymphoma
• Side effect of the medications administered for treatment

How is X-Linked Hyper IgM Syndrome Treated?

X-linked Hyper IgM Syndrome is a serious disorder that has no known cures. An individualized treatment (case-by-case) approach is planned and provided to improve the quality of life, based on the specific conditions/complications that develop. Also, appropriate treatment to prevent any infections (into the future) may be considered.

The treatment measures may include the following:

• Blood and bone marrow and stem cell transplants are best performed before organ damage and other fatal complications set in
• Intravenous immunoglobulin therapy to lower incidences of lung and other infection
• For stimulating white blood production, the use of granulocyte colony-stimulating factor
• Antibiotic, antimicrobial, antiviral drug administration for various infections
• Use of immunosuppressants to treat disorders related to autoimmunity
• Surgery for chronic sinusitis
• Self-care is of extreme importance: It is always recommended that the affected individuals drink clean, treated water and regularly exercise
• Diet control is strictly advised and a high-calorie diet intake is recommended in many cases

How can X-Linked Hyper IgM Syndrome be Prevented?

• Currently, there are no specific methods or guidelines to prevent X-linked Hyper IgM Syndrome, since it is a genetic condition
• 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
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as X-linked Hyper IgM Syndrome
• Regular medical screening at periodic intervals with tests, scans and physical examinations are mandatory
• Once prenatal diagnosis is confirmed, pneumocystis carinii pneumonia prophylaxis (treatment to prevent pneumonia) and intravenous immunoglobulin therapy helps significantly increase the survival rate
• It is advised to avoid any child vaccination that use live virus injections, such as polio, mumps-measles-rubella, and varicella vaccinations

What is the Prognosis of X-Linked Hyper IgM Syndrome? (Outcomes/Resolutions)

• X-linked Hyper IgM Syndrome is a fatal genetic disorder; the mortality rate into early adulthood (age 25 years) is around 80%
• Death usually occurs due to complications affecting the liver, lung (pneumonia), brain, and due to infectious diseases caused by microorganisms such as viruses, bacteria, and fungi
• Most children, who survive the initial few years, are severely affected by multiple congenital defects and developmental deformities. However, with constant care and support by families and medical aids, some affected individuals are able to manage their lives

Additional and Relevant Useful Information for X-Linked Hyper IgM Syndrome:

Early diagnosis and intensive treatment with allogeneic hematopoietic cell (cord blood) transplantation have reduced the mortality rates to 25-30%. This procedure is indicated as being curative for X-linked Hyper IgM Syndrome.