Linked Lymphoproliferative Syndrome

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X-linked lymphoproliferative syndrome (XLP) is an X-linked recessive disorder. The pathogenesis is a defect in the regulation of T-cell-mediated immune response, which is induced by EBV. It is unknown why this occurs with EBV and not other viruses in this condition.

Recently, clinical manifestations of XLP such as dysgammaglobulinemia, aplastic anemia, and LPD have been described in the absence of EBV infection.


Familial XLP results from mutations in the SH2D1A (also known as SAP) gene, which makes SAP protein (SLAM-associated protein), which is also known as SH2D1A protein. Normally, in activated T cells and NK cells, SAP levels increase. SAP interacts with SLAM (signaling lymphocyte activation molecule family), a molecule expressed on T-cell surface, B-cell surface, and dendritic cell surface. In T cells,

Table 13-6. Treatment of Post-Transplantation Lymphoproliferative Disorder with Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP)a

Cyclophosphamide 750 mg/m2 intravenous on day 1 of each cycle

Doxorubicin 50 mg/m2 intravenous on day 1 of each cycle

Vincristine 1.4 mg/m2 intravenous (with maximum dose 2 mg) on day 1 of each cycle

Prednisone 100 mg/m2/day orally (with maximum dose 100 mg) per day on days 1 through 5

Treatment cycles are repeated every 21 days or following hematopoietic recovery. Patients who experience complete remission after four cycles are treated with two additional cycles of chemotherapy. Patients are maintained on reduced cyclosporine level indefinitely.

"This same regime (CHOP) can also be utilized for treatment of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-type lymphoma.

SAP regulates T-cell receptor (TCR)-induced interferon y (IFN-y). In NK cells, SAP binds to 2B4 and NTB-A (which also belong to SLAM family receptors) and activates NK-cell-induced cytotoxicity.

In XLP, various types of SAP (SH2D1A) gene mutations have been described including deletion, nonsense, missense, and splice site mutations. As a result of this, SAP protein may be absent or truncated or may contain altered amino acid residue at highly conserved sites.

No correlation has been found between genotypes and phenotypes or in the outcomes of these patients. It has been postulated that the mutation of SAP protein in XLP causes defective helper and cytotoxic T cell function. In contrast to familial XLP, no mutations of SAP occur in sporadic XLP.

Clinical Manifestations

Fulminant infectious mononucleosis (frequency 58%; survival 4%). It is characterized by infiltration of various organs with polyclonal B and T cells, production of inflammatory cytokines, and necrosis of liver, bone marrow, lymph nodes, and spleen caused by the invading cytotoxic T-cell and uncontrolled killer cell activity. Death is generally attributable to liver failure with hepatic encephalopathy or bone marrow failure with fatal hemorrhage in the lungs, brain, or gastrointestinal tract and occurs within 1 month of onset of symptoms. Secondary dysgammaglobulinemia (frequency 30%; survival 55%). B-cell lymphoproliferative disease including malignant lymphoma (extranodal non-

Hodgkin lymphoma) (frequency 25%; survival 35%). Aplastic anemia

Virus-associated hemophagocytic syndrome. Patients usually die within 1 month of onset of symptoms. Vasculitis and pulmonary lymphomatoid granulomatosis.

In the same patient, several sequential phenotypes of the disease may manifest over time. This phenotypic variation most often includes dysgammaglobulinemia, malignant lymphoma, and marrow aplasia.

Patients with the XLP syndrome reveal many humoral and cellular immunologic defects, which include the following:

• Selective impaired immunity to EBV but normal immune responses to other herpes viruses

• Uncontrolled TH1 responses (with high levels of IFN-y in some patients)

• Inverted CD4/CD8 ratio (due to increase in CD8+ cells)

• Dysgammaglobulinemia: low IgG, high IgM, and high IgA

• Defective NK-cell activity

• Decreased T-cell regression assay

• Failure to switch from IgM to IgG class response after secondary challenge with OX174 and diminished mitogen-induced transformation of lymphocytes

• Unchanged lymphocyte-mediated antibody-dependent cellular cytotoxicity.

Table 13-7 lists the diagnostic criteria for XLP. Treatment

1. Prevention of EBV infection: Prophylactic use of intravenous immunoglobulin (IVIG) has been used without much success. High-dose IVIG 600 mg/kg per month, however, has been effective in some patients.

2. Treatment of acute EBV infection in XLP patients: High-dose IVIG and/or acy-clovir are ineffective.

Table 13-7. Diagnostic Criteria for X-Linked Lymphoproliferative Syndrome

Definitive Diagnosis of XLP

Male patient with lymphoma or Hodgkin disease, fatal EBV infection, immunodeficiency, aplastic anemia, or lymphohistiocytic disorder and at least one of the following: (1) mutations in SH2D1A, (2) absent SH2D1A RNA on Northern blot analysis of lymphocytes, and (3) absent SH2D1A protein in lymphocytes.

Probable Diagnosis of XLP

Male patient experiencing death, lymphoma or Hodgkin disease, immunodeficiency, aplastic anemia, or lymphohistiocytic disorder following acute EBV infection and maternal cousins, uncles, or nephews with a history of similar diagnoses following acute EBV infection.

XLP Phenotype

Male patient experiencing death, lymphoma or Hodgkin disease, immunodeficiency disorder, aplastic anemia or lymphohistiocytic disorder following acute EBV infection and who have normal expression of SH2D1A.

Abbreviation: EBV, Epstein-Barr virus.

From: Ochs HD, Nelson DL, Stiehm ER. Other well-defined immunodeficiency syndromes (Contributor: Sullivan, JL). In: Immunologic Disorders in Infants and Children. 5th ed. Philadelphia, WB Saunders, 2004, with permission.

3. Treatment of virus-associated hemophagocytosis: Etoposide and cyclosporine A are effective. Etoposide decreases macrophage activity and cyclosporine A decreases T cell activity. HLH (2004) protocol may be used (see Chapter 22, Histiocytosis Syndromes, page 622).

4. Treatment of aplastic anemia: Etoposide and cyclosporine A are effective.

5. Treatment of lymphoma: Standard therapy for lymphoma is used, that is, chemotherapy and radiation therapy where indicated.

Allogeneic HSCT is the only curative therapy for XLP syndrome. Prognosis: 70% of patients with XLP die before 10 years of age.

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