(See also Overview of Immunodeficiency Disorders Overview of Immunodeficiency Disorders Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more and Approach to the Patient With an Immunodeficiency Disorder Approach to the Patient With Suspected Immunodeficiency Immunodeficiency typically manifests as recurrent infections. However, recurrent infections are more likely to have causes other than immunodeficiency (eg, inadequate treatment, resistant organisms... read more .)
X-linked lymphoproliferative syndrome (XLP) is a primary immunodeficiency disorder Primary Immunodeficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more that involves cellular immunity deficiencies Cellular immunity deficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more . It is caused by mutations in genes on the X chromosome. It is a recessive disorder and thus manifests only in males.
XLP type 1 is the most common type (about 60% of cases). It is caused by a mutation in the gene that encodes the signaling lymphocyte activation molecule (SLAM)–associated protein (SAP, also called the SH2 domain protein 1A [SH2D1A] or DSHP). Without SAP, lymphocytes proliferate unchecked in response to Epstein-Barr virus (EBV) infection Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more , and natural killer (NK) cells do not function.
XLP type 2 is clinically similar to type 1 and predisposes to hemophagocytic lymphohistiocytosis Hemophagocytic Lymphohistiocytosis (HLH) Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder causing immune dysfunction in infants and young children. Many patients have an underlying immune disorder, although in some... read more , an uncommon disorder that causes immunodeficiency in infants and young children. XLP2 is caused by mutations in a gene that encodes the X-linked inhibitor of apoptosis protein (XIAP).
Symptoms and Signs
X-linked lymphoproliferative syndrome is usually asymptomatic until EBV infection develops. Then, most patients develop fulminating or fatal infectious mononucleosis with liver failure (caused by cytotoxic T cells that react to EBV-infected B or other tissue cells). Survivors of initial infection develop B-cell lymphomas Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more , aplastic anemia Aplastic Anemia Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines ... read more , hypogammaglobulinemia (resembling that in common variable immunodeficiency Common Variable Immunodeficiency (CVID) Common variable immunodeficiency (acquired or adult-onset hypogammaglobulinemia) is characterized by low immunoglobulin (Ig) levels with phenotypically normal B cells that can proliferate but... read more ), splenomegaly, or a combination.
The diagnosis of X-linked lymphoproliferative syndrome should be considered in young males who have severe Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis, a suggestive family history, or other common manifestations.
Genetic testing is the gold standard test for confirming the diagnosis (before and after EBV infection and symptoms develop) as well as the carrier state. However, genetic testing can take weeks to complete, so other testing is done if the diagnosis must be made earlier (eg, flow cytometry to assess SH2D1A protein expression).
Suggestive findings include
Decreased antibody responses to antigens (particularly to EBV nuclear antigen)
Impaired T-cell proliferative responses to mitogens
Decreased NK-cell function
An inverted CD4:CD8 ratio
These findings are typical before and after Epstein-Barr virus infection. A bone marrow biopsy can help confirm hemophagocytic lymphohistiocytosis.
In survivors, laboratory and imaging tests are done yearly to check for lymphoma and anemia.
Genetic testing is done in relatives when a case or carrier is identified in a family. Prenatal screening is recommended for people if a mutation that causes XLP has been identified in their family.
Hematopoietic stem cell transplantation
Treatment of X-linked lymphoproliferative syndrome is hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more . About 75% of patients die by age 10, and all die by age 40 unless hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more is done. About 80% of patients who receive a transplant survive. Transplantation is curative if done before Epstein-Barr virus infection or other disorders become irreversible.
Rituximab can help prevent severe EBV infection before transplantation.