Summary about Disease
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a rare genetic primary immunodeficiency that primarily affects males. It is characterized by an extreme vulnerability to Epstein-Barr virus (EBV) infection. In susceptible individuals, EBV infection can lead to uncontrolled lymphoproliferation, hemophagocytic lymphohistiocytosis (HLH), B-cell lymphomas, and hypogammaglobulinemia. There are two types, XLP1 and XLP2, caused by mutations in different genes.
Symptoms
The symptoms of XLP are variable but are usually triggered by EBV infection. Common symptoms include:
Fulminant Infectious Mononucleosis (FIM): Severe and often fatal mononucleosis with liver failure, bone marrow suppression, and other complications.
Hemophagocytic Lymphohistiocytosis (HLH): A life-threatening hyperinflammatory syndrome with fever, hepatosplenomegaly, cytopenias, and neurological symptoms.
Lymphoma: Typically B-cell lymphomas.
Hypogammaglobulinemia: Low levels of antibodies, leading to recurrent infections.
Aplastic Anemia: Bone marrow failure.
Chronic or recurrent EBV infection: Persistent or repeated EBV-related symptoms.
Causes
XLP is caused by genetic mutations on the X chromosome. There are two forms:
XLP1: Caused by mutations in the SH2D1A gene (also known as *SAP* or *SIAF1*), which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP).
XLP2: Caused by mutations in the XIAP gene (also known as *BIRC4*), which encodes the X-linked inhibitor of apoptosis protein (XIAP). These genes are critical for proper immune cell function, particularly the regulation of T-cell and NK-cell responses to viral infections, especially EBV.
Medicine Used
Treatment for XLP primarily focuses on managing EBV infection and the resulting complications, as well as preventing future EBV-related issues. Common treatments include:
Antiviral Medications: Acyclovir, ganciclovir, or rituximab may be used to manage acute EBV infection.
Immunosuppressants: Corticosteroids, cyclosporine, or etoposide (VP-16) are used to treat HLH.
Intravenous Immunoglobulin (IVIG): Used to treat hypogammaglobulinemia and prevent recurrent infections.
Hematopoietic Stem Cell Transplantation (HSCT): HSCT is the only curative treatment for XLP. It replaces the patient's defective immune system with a healthy one from a donor.
Is Communicable
XLP itself is not communicable. It is a genetic disorder. However, the triggering EBV infection is communicable through saliva (e.g., kissing, sharing drinks). Individuals with XLP are just more susceptible to severe complications from EBV.
Precautions
For individuals with XLP:
Avoid Exposure to EBV: While difficult, minimizing contact with individuals who have active EBV infections (e.g., mononucleosis) is important.
Prompt Medical Attention: Any symptoms suggestive of EBV infection or HLH should be immediately evaluated by a physician.
Regular Monitoring: Regular monitoring of immune function, blood counts, and EBV viral load is necessary.
Genetic Counseling: Families with a history of XLP should undergo genetic counseling to understand the risk of recurrence and options for prenatal testing or preimplantation genetic diagnosis.
Prophylactic IVIG: In cases of hypogammaglobulinemia, prophylactic IVIG can help prevent infections.
How long does an outbreak last?
The duration of an "outbreak" (referring to the manifestations of EBV infection in XLP) varies considerably depending on the specific complication and the effectiveness of treatment.
Fulminant Infectious Mononucleosis (FIM): Can be rapidly fatal (within weeks) if not promptly treated.
Hemophagocytic Lymphohistiocytosis (HLH): Can persist for weeks to months and can be fatal if untreated. Treatment aims to control the hyperinflammation.
Lymphoma: The duration depends on the type of lymphoma and response to chemotherapy.
Hypogammaglobulinemia: Is a chronic condition requiring ongoing management.
Chronic EBV Infection: can continue for many years or life.
How is it diagnosed?
Diagnosis of XLP typically involves:
Clinical Evaluation: Assessment of symptoms, medical history, and family history.
Laboratory Tests:
Blood Counts: Complete blood count (CBC) to assess for cytopenias.
Immunoglobulin Levels: Measurement of IgG, IgA, and IgM levels.
EBV Serology: Detection of antibodies to EBV.
EBV Viral Load: Quantitative PCR to measure EBV DNA in the blood.
NK Cell Function: Assessment of NK cell cytotoxicity.
SAP/XIAP Protein Expression: Flow cytometry to assess SAP protein expression in lymphocytes (for XLP1) or XIAP expression in lymphocytes (for XLP2).
Genetic Testing: Sequencing of the SH2D1A gene (for XLP1) or the *XIAP* gene (for XLP2) to identify mutations.
Bone Marrow Aspirate and Biopsy: May be necessary to diagnose HLH or lymphoma.
Timeline of Symptoms
The timeline of symptoms in XLP can vary, but here's a general overview:
Early Childhood: Often asymptomatic until first exposure to EBV.
EBV Infection: After exposure to EBV, symptoms can develop rapidly, usually in childhood or adolescence. This could be as early as 2-3 years of age, although presentations into the teens or adulthood are also possible.
Acute Phase: Fulminant infectious mononucleosis or HLH can develop within days to weeks of EBV infection.
Long-Term Complications: Lymphoma or hypogammaglobulinemia may develop months to years after the initial EBV infection.
Without HSCT: Chronic or recurrent symptoms and complications can persist throughout life.
Important Considerations
Early Diagnosis: Early diagnosis is crucial for timely intervention and improved outcomes.
Genetic Counseling: Genetic counseling is recommended for families with XLP.
HSCT: HSCT is the only curative option and should be considered early in the disease course.
EBV Monitoring: Regular monitoring for EBV reactivation is important, even after initial treatment.
Multidisciplinary Care: Management of XLP requires a multidisciplinary team, including immunologists, hematologists, oncologists, and infectious disease specialists.
Family Screening: Screening of male relatives for XLP is essential to identify affected individuals before EBV exposure.