Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care . No consensus clinical diagnostic criteria for X-linked lymphoproliferative disease (XLP) have been published. XLP has traditionally been separated into two recognizable subtypes: XLP1, due to pathogenic variants in SH2D1A, and XLP2, due to pathogenic variants in XIAP .

Suggestive Findings

XLP should be suspected in a proband (most typically a male but rarely a female) with any of the following clinical, supportive laboratory, or family history findings.

Clinical Findings

General clinical findings suggestive of either XLP1 or XLP2. Fever and/or hepatomegaly, splenomegaly, lymphadenopathy, and rash resembling hemophagocytic lymphohis...

Source: GeneReviews — "X-Linked Lymphoproliferative Disease"

Differential Diagnosis

The differential diagnosis of X-linked lymphoproliferative disease (XLP) includes the following hereditary and acquired disorders:

Source: GeneReviews — "X-Linked Lymphoproliferative Disease"

Management Guidelines

No clinical practice guidelines for X-linked lymphoproliferative disease (XLP) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with XLP, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

X-Linked Proliferative Disease: Recommended Evaluations Following Initial Diagnosis1

System/Concern | Evaluation | Comment

Gastroenterology

/Hepatology | Physical exam to assess for hepatosplenomegaly | • Consider liver imaging if there is hepatomegaly w/abnormal serum transaminases or bilirubin.

• Consider MR cholangiopancreatography if there is concern for cholangitis in those w/XLP2 (XIAP-related XLP) colitis.2

Serum transaminases, bilirubin, triglycerides, lactate dehydrogenase, prothrombin time, PTT, fibrinogen | To assess for liver dysfunction/failure coagulopathy

Serum triglyceride levels | To evaluate for HLH

Assess for signs symptoms of colitis cholangitis (rare)2 | In persons w/XLP2; consider referral to gastroenterologist.

Hematology/ Spleen/ Lymph nodes/ Oncology

| Physical exam to assess for hepatosplenomegaly lymphadenopathy | • Splenomegaly can be seen in setting of HLH or incomplete HLH (fever cytopenias only).

• Splenomegaly lymphadenopathy should prompt further investigation for lymphoma in those w/XLP1 (SH2D1A-related XLP).

• In persons w/XLP2, transient splenomegaly can be seen after vaccinations.

Source: GeneReviews — "X-Linked Lymphoproliferative Disease"

Clinical Guidance

Infections. Individuals with XLP who come into contact with Epstein-Barr virus (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.

Source: GeneReviews — "X-Linked Lymphoproliferative Disease"

Therapies Under Investigation

The following therapies are under investigation for XLP:

Source: GeneReviews — "X-Linked Lymphoproliferative Disease"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 8. X-Linked Proliferative Disease: Recommended Surveillance1

Source: GeneReviews — "X-Linked Lymphoproliferative Disease"