Clinical characteristics: X-linked lymphoproliferative disease (XLP) in general is characterized by an inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis, dysgammaglobulinemia, and lymphoproliferative disease (malignant lymphoma). The condition primarily affects males. XLP has two recognizable subtypes, XLP1 (due to pathogenic variants in SH2D1A) and XLP2 (due to pathogenic variants in XIAP). HLH / fulminant infectious mononucleosis is the most common presentation regardless of subtype. HLH is characterized as an acute illness with prolonged and high fever, bi- or trilineage cytopenias, and hepatosplenomegaly, which is often severe or fatal. Death is generally secondary to liver failure or multisystem organ dysfunction. In those with XLP1, dys- or hypogammaglobulinemia can lead to varying degrees of humoral immune dysfunction associated with bronchiectasis and recurrent respiratory infections that, if untreated, may result in death. Lymphoproliferative disease (malignant lymphoma) and other lymphoproliferative diseases are specific to XLP1 and often develop in childhood, usually following EBV exposure. Rarer findings in those with XLP1 can include aplastic anemia, vasculitis, and lymphoid granulomatosis. Males with XLP2 are more likely to have HLH without EBV infection, recurrent episodes of HLH (which is not typically seen in those with XLP1), splenomegaly, and gastrointestinal disease, including enterocolitis and perirectal abscesses or fistulae. Rarely, individuals with XLP2 and inflammatory bowel disease have been reported to develop inflammatory liver disease, which can progress to fatal liver failure. Transient hypogammaglobulinemia has been rarely observed in those with XLP2. To date, neither lymphoproliferative disease nor common variable immunodeficiency has been reported in males with XLP2.

Heterozygous females rarely have symptoms. There are, however, increasing numbers of reports of affected females with unfavorable (skewed) X-chromosome inactivation favoring the X chromosome with the pathogenic variant who develop HLH, inflammatory bowel disease, and erythema nodosum.

Diagnosis/testing: The diagnosis of XLP1 or XLP2 can be established in a male proband who has a hemizygous germline pathogenic variant in SH2D1A (XLP1) or XIAP (XLP2) identified on molecular genetic testing. These males typically have low or absent SAP or XIAP protein expression, respectively, by flow cytometry. Female probands with a heterozygous pathogenic variant in SH2D1A or XIAP identified on molecular genetic testing and skewed X-chromosome inactivation toward expression of the chromosome with the pathogenic SH2DA1 or XIAP variant have been reported; such individuals may be symptomatic.

Management: Targeted therapy: The only known curative therapy for XLP1 is allogeneic hematopoietic stem cell transplant (HSCT), which should be strongly considered in all males as early in life as is feasible, particularly in those who have not developed symptoms; HSCT is not recommended for asymptomatic heterozygous females. For individuals with XLP2, many manifestations of disease can be improved with HSCT; however, there are more complications in these individuals.

Supportive care: Standard treatment for liver dysfunction/failure, hypogammaglobulinemia (IVIG or IgG), fulminant EBV infection / HLH (including etoposide and steroids and consideration of rituximab), lymphoma, colitis, aplastic anemia, and vasculitis.

Surveillance: At each visit, obtain history of any neurologic changes; physical exam for evidence of hepatosplenomegaly, lymphadenopathy, and neurologic changes; monitor for signs and symptoms of colitis and cholangitis in those with XLP2. Based on clinical status / evaluation for early evidence of HLH, monitor for liver dysfunction with hepatic profiles and coagulation; measurement of complete blood count; measurement of serum inflammatory markers (ferritin, soluble IL2R). As needed, measurement of serum IgG levels based on phenotype or in those with recurrent respiratory infections; EBV-PCR in blood for evidence of EBV infection if a person has symptoms of infection or HLH develops.

Agents/circumstances to avoid: Individuals with XLP who come into contact with EBV are at risk of developing HLH and/or lymphoproliferation. Individuals are also at risk of developing HLH or inflammatory problems secondary to other infections.

Evaluation of relatives at risk: Evaluation of apparently asymptomatic older and younger at-risk sibs and other maternal male relatives of an affected individual in order to identify as early as possible those who would benefit from medical management and consideration of presymptomatic bone marrow transplantation in males.

Genetic counseling: XLP is inherited in an X-linked manner. The risk to the sibs of a male proband depends on the genetic status of the mother: if the mother is heterozygous for an SH2D1A or XIAP pathogenic variant, the chance of transmitting the SH2D1A or XIAP pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be heterozygotes and will typically not be affected (in rare cases, heterozygous females may be symptomatic due to skewed X-chromosome inactivation). Genetic testing of at-risk female relatives is most informative if the pathogenic variant has been identified in the proband. Prenatal testing is possible for a pregnancy at increased risk if the familial pathogenic variant is known.