X-linked lymphoproliferative disease

Overview

X-linked lymphoproliferative disease (XLP) is a rare, inherited immunodeficiency disorder that primarily affects males. It is characterized by an abnormal and often fatal immune response to the Epstein–Barr virus (EBV), a common virus that typically causes only mild illness in healthy individuals. In patients with XLP, infection with EBV can trigger uncontrolled immune activation, leading to severe and life-threatening complications such as fulminant infectious mononucleosis, lymphoma, or hemophagocytic lymphohistiocytosis (HLH). XLP is classified into two types: XLP1 and XLP2, each associated with different gene mutations and clinical features.

Causes

XLP is caused by mutations in genes involved in regulating the immune system:

• XLP1: Caused by mutations in the SH2D1A gene, which encodes the SAP protein (SLAM-associated protein). This protein plays a critical role in signaling pathways in immune cells such as T cells and natural killer (NK) cells.

• XLP2: Caused by mutations in the BIRC4 gene, which encodes the XIAP protein (X-linked inhibitor of apoptosis protein). This protein helps prevent programmed cell death and regulates immune responses.

Both forms of the disease follow an X-linked recessive inheritance pattern, meaning that the faulty gene is located on the X chromosome. Because males have only one X chromosome, a single defective copy of the gene results in the disease. Female carriers usually do not show symptoms but can pass the mutation to their children.

Symptoms

The clinical presentation of XLP can vary widely. The most common and severe manifestations typically appear in early childhood and include:

• Fulminant infectious mononucleosis: A severe, often fatal reaction to EBV infection, characterized by high fever, liver failure, and multi-organ damage

• Hemophagocytic lymphohistiocytosis (HLH): A life-threatening condition with uncontrolled immune activation, leading to fever, enlarged liver/spleen, low blood cell counts, and organ failure

• Hypogammaglobulinemia: Low levels of immunoglobulins (antibodies), resulting in recurrent bacterial infections

• Lymphoma: An increased risk of developing B-cell lymphomas, often in the gastrointestinal tract or central nervous system

Other symptoms may include fatigue, lymphadenopathy, hepatosplenomegaly, and failure to thrive. Symptoms tend to be more severe in XLP1 compared to XLP2.

Diagnosis

Diagnosis of XLP is based on clinical suspicion in patients (especially males) with severe EBV-related illness, recurrent infections, or HLH. Diagnostic steps include:

• Family history: Investigation of early male deaths or known XLP cases in the family

• Laboratory tests: Blood tests showing abnormal immune cell function, low immunoglobulin levels, or signs of HLH

• Viral testing: EBV PCR to detect active infection

• Genetic testing: Confirmation through identification of mutations in the SH2D1A (for XLP1) or BIRC4 (for XLP2) genes

• Flow cytometry: May be used to evaluate SAP or XIAP protein expression in immune cells

Early diagnosis is critical for timely intervention, particularly before EBV exposure or the development of HLH.

Treatment

Treatment of XLP depends on the type and severity of clinical presentation. Common approaches include:

• Supportive care: Management of infections, liver function, and organ support during acute episodes

• Immunoglobulin replacement therapy: For patients with hypogammaglobulinemia to reduce infections

• Antiviral therapy and immunosuppression: Used in cases of EBV infection or HLH

• Chemotherapy: For patients with lymphoma or severe HLH

• Hematopoietic stem cell transplantation (HSCT): The only curative option for XLP1 and many XLP2 cases. Ideally performed before severe complications occur

Genetic counseling is recommended for families with a history of XLP to identify carriers and inform future reproductive decisions.

Prognosis

Without treatment, XLP has a high mortality rate, particularly in patients who experience fulminant EBV infection or HLH. The prognosis significantly improves with early diagnosis and timely hematopoietic stem cell transplantation. Long-term outcomes depend on the subtype, the age at diagnosis, and the presence of complications. Advances in genetic screening and transplant medicine continue to improve survival and quality of life for patients with XLP.