What is X-linked lymphoproliferative disease?

A rare combined immunodeficiency disorder caused by gene mutations leading to defects in both T and B cells. It is an X-linked recessive genetic disease (XLP).

In 1975, American pathologist and immunologist Purtilo first discovered and reported this disease in the Duncan family, hence it is also called Purtilo syndrome or Duncan's disease.

Which department should be consulted for X-linked lymphoproliferative disease?

English name: X-linked Lymphoproliferative Disease, XLP, Purtilo syndrome, Duncan’s disease.

Aliases: X-linked lymphoproliferative syndrome, X-linked lymphoproliferative disease, Duncan's disease, Purtilo syndrome, X-linked familial hemophagocytic syndrome, X-linked lymphoproliferative disease, X-linked lymphoproliferation, Duncan's disease.

Departments: Pediatric Hematology, Pediatrics, Hematology.

What causes X-linked lymphoproliferative disease?

The exact mechanism of clinical manifestations is currently unclear. It may be related to uncontrolled immune surveillance or response to EB virus or other unknown antigens, or it may stem from failed interactions between T cells, natural killer cells, and B cells.

Although clinical manifestations of XLP are often triggered by EBV infection, most immune abnormalities in this disease do not originate from current or past EBV infections.

Based on different mutated genes, it can be divided into two types: XLP1 and XLP2.

• XLP1 is caused by SH2D1A gene mutations, leading to reduced or absent SAP protein (signaling lymphocytic activation molecule-associated protein) expression, which disrupts normal signal transduction between immune cells. This results in abnormal T/B cell interactions and defective NK cell-mediated cytotoxicity, ultimately causing immunodeficiency against EB virus.
• XLP2 is caused by mutations in the XIAP gene, leading to defective apoptosis inhibition factors.

Who is commonly affected by X-linked lymphoproliferative disease?

Male children and adolescents, with an incidence of approximately 1/1,000,000 to 3/1,000,000 (males).

What are the symptoms and manifestations of X-linked lymphoproliferative disease?

XLP1 most commonly presents as fulminant infectious mononucleosis after EBV infection, dysgammaglobulinemia, and B-cell lymphoma.

1. Fulminant infectious mononucleosis (FIM): Often caused by an inappropriate and excessive immune response to EB virus. It is the most common and severe manifestation of XLP1, presenting with fever, thrombocytopenia, anemia, liver necrosis, liver dysfunction, bone marrow failure, and meningoencephalitis, among other widespread tissue damage.

• Many patients may develop acute severe hepatitis and hemophagocytic syndrome, with extremely poor prognosis. Liver failure-induced hepatic encephalopathy or bleeding in the central nervous system, gastrointestinal tract, or lungs are the most common causes of death.

2. Dysgammaglobulinemia: Typically manifests as elevated IgA and IgM levels, with reduced IgG1 and IgG3.

3. Lymphoma: Mainly non-Hodgkin B-cell lymphoma.

4. Others: Lymphocytic vasculitis, aplastic anemia, and lymphomatoid granulomatosis.

XLP2 primarily manifests as hemophagocytic syndrome, such as persistent fever, hepatosplenomegaly, and pancytopenia. Some patients may also develop intestinal inflammation like Crohn's disease or colitis, but progression to lymphoma is rare.

How is X-linked lymphoproliferative disease diagnosed?

1. Clinical symptoms and family history: Persistent fever, hepatosplenomegaly, diarrhea, and other clinical symptoms. Family history may indicate male relatives on the maternal side with XLP-related manifestations.

2. Laboratory tests: Pancytopenia, decreased IgG, elevated IgM.

3. SAP or XIAP protein testing: Reduced or absent SAP in XLP1, reduced or absent XIAP in XLP2.

4. Imaging: Ultrasound may reveal superficial lymphadenopathy and hepatosplenomegaly; PET-CT may indicate widespread lymphadenopathy.

5. Pathological examination: Bone marrow aspiration may show hemophagocytosis; lymph node biopsy may indicate lymphoma.

6. Genetic testing: SH2D1A and XIAP gene sequencing confirms XLP1 and XLP2, respectively.

How is X-linked lymphoproliferative disease treated?

• Hematopoietic stem cell transplantation is the preferred treatment for XLP and currently the only curative method.
• During active EBV infection, antiviral therapy is administered.
• Immunoglobulin replacement therapy can prevent infections and mitigate acute reactions to EBV infection.
• Patients with low IgG may receive immunoglobulin infusions every 3–4 weeks.
• Inflammatory bowel disease requires immunosuppressive therapy.
• Standard chemotherapy regimens are implemented for patients with hemophagocytic syndrome or lymphoma.

What is the prognosis for X-linked lymphoproliferative disease?

The prognosis is extremely poor. Patients may develop fulminant hepatitis, liver necrosis, and bone marrow failure, with liver failure being the primary cause of death.

How can X-linked lymphoproliferative disease be prevented?

• If diagnosed, avoid EBV infection as much as possible.
• Pre-marital genetic counseling and prenatal diagnosis for better reproductive choices.