X-linked lymphoproliferative disease (XLP) is a rare, severe genetic disorder impacting the immune system. Inherited and X-linked, it primarily affects males. Individuals with XLP experience serious health problems due to their immune system’s inability to regulate responses to infections, particularly Epstein-Barr virus (EBV).
Understanding XLP and Its Cause
X-linked lymphoproliferative disease is an X-linked recessive disorder. Males, with one X chromosome, are typically affected if they inherit the mutated gene. Females, with two X chromosomes, usually remain carriers without symptoms.
Two primary XLP types exist. XLP1 results from mutations in the SH2D1A gene, producing the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). SAP regulates immune cell interactions. SAP absence or dysfunction impairs T and natural killer (NK) cells from eliminating infected B cells and controlling viral infections, particularly EBV.
XLP2 is caused by mutations in the XIAP gene (BIRC4). This gene makes X-linked inhibitor of apoptosis protein (XIAP), which suppresses programmed cell death (apoptosis) and regulates immune responses. Defective XIAP protein impairs immune cell function, leading to uncontrolled inflammation and poor viral clearance, including EBV.
How XLP Affects the Body
XLP’s dysfunctional immune response leads to diverse, severe manifestations. A hallmark is severe or fatal mononucleosis, developing when the immune system cannot control Epstein-Barr virus (EBV) infection. Instead of clearing the virus, immune cells proliferate uncontrollably, causing widespread tissue damage. This uncontrolled immune activity can also result in lymphoma, often aggressive B-cell non-Hodgkin lymphoma.
Another serious complication is aplastic anemia, where bone marrow fails to produce enough new blood cells. Hypogammaglobulinemia (low antibody levels) compromises the ability to fight infections. Recurrent infections (bacterial to fungal) are a challenge due to impaired antibody production. Less frequently, XLP can also cause vasculitis (blood vessel inflammation) or neurological issues.
Identifying XLP
Diagnosis for XLP begins with clinical suspicion, often from unusual or severe reactions to infections (particularly EBV) and a family history of immune problems. Genetic testing definitively confirms XLP.
Genetic testing analyzes DNA for SH2D1A (XLP1) or XIAP (XLP2) mutations. Immunological tests also aid diagnosis. They measure specific protein levels (SAP for XLP1, XIAP for XLP2), often deficient or absent. They also assess immune cell function, revealing characteristic impaired cellular responses.
Treating XLP
XLP treatment aims to manage severe complications and correct the underlying immune defect. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment. This procedure replaces the defective immune system with healthy blood-forming stem cells from a compatible donor, establishing a functional immune system to control infections and prevent disease. HSCT success depends on donor match and patient health before transplant.
Beyond HSCT, supportive care measures manage specific complications. Immunoglobulin replacement therapy provides necessary antibodies for recurrent infections in hypogammaglobulinemia. Antiviral medications manage active EBV infections and reduce viral load. For lymphoma, chemotherapy or immunotherapy target and eliminate cancerous cells. These supportive treatments improve quality of life and prevent severe outcomes.
Living with XLP
The long-term outlook for individuals with XLP is influenced by early diagnosis and timely interventions, particularly hematopoietic stem cell transplantation. Early diagnosis allows prompt symptom management and consideration of curative therapies before severe, irreversible complications arise. Successful HSCT can improve prognosis, often leading to restored immune function and reduced disease-related complications.
Even after successful transplant, individuals with XLP require lifelong monitoring for long-term complications and ongoing supportive care. This attention helps manage residual issues and new challenges. Living with XLP often involves navigating complex medical needs, requiring specialized care from immunology and hematology experts.
References
X-linked lymphoproliferative disease. National Institute of Allergy and Infectious Diseases. [https://www.niaid.nih.gov/diseases-conditions/x-linked-lymphoproliferative-disease](https://www.niaid.nih.gov/diseases-conditions/x-linked-lymphoproliferative-disease)
X-linked lymphoproliferative disease (XLP). Children’s Hospital of Philadelphia. [https://www.chop.edu/conditions-diseases/x-linked-lymphoproliferative-disease-xlp](https://www.chop.edu/conditions-diseases/x-linked-lymphoproliferative-disease-xlp)