Since XLP is an X-linked disorder, what does this mean for inheritance and family planning?

X-linked means the gene mutation is on the X chromosome. Males have one X and one Y chromosome, so if they inherit the affected X, they develop the disorder. Females have two X chromosomes; if they inherit one affected X, they are typically carriers and usually do not show symptoms, but they can pass the mutation to their children. Genetic counseling is highly recommended for families to understand inheritance patterns and discuss options for future pregnancies and testing of other family members.

Given that EBV is so common, how is XLP typically diagnosed, and what tests are involved?

Diagnosis of XLP often begins with a strong suspicion in a male child who experiences severe or unusual reactions to Epstein-Barr virus (EBV) infection, such as prolonged fever, enlarged liver or spleen, or low blood counts. Genetic testing for mutations in the SH2D1A (for XLP1) or XIAP (for XLP2) genes is the definitive way to confirm the diagnosis. Blood tests to check immune cell function and antibody levels are also part of the diagnostic workup.

What are the critical warning signs of hemophagocytic lymphohistiocytosis (HLH) in someone with XLP, and when is it an emergency?

Key warning signs of HLH in XLP include persistent high fever, significant fatigue, unexplained bruising or bleeding, yellowing of the skin or eyes (jaundice), and a rapidly enlarging abdomen due to an enlarged liver or spleen. If these symptoms appear, especially after an EBV infection, it is a medical emergency requiring immediate hospital evaluation, as HLH can rapidly become life-threatening.

What are the main treatment approaches for XLP to prevent or manage its severe complications?

The primary treatment for XLP is hematopoietic stem cell transplantation (HSCT), also known as a bone marrow transplant, which can cure the immune defect. Other treatments focus on managing symptoms and complications: immunosuppressive therapies are used to control HLH episodes, and immunoglobulin replacement therapy may be given to individuals with dysgammaglobulinemia to prevent recurrent infections. Regular monitoring for lymphoma is also crucial.

X-linked lymphoproliferative disease

A rare X‑linked immune disorder that causes an exaggerated response to Epstein‑Barr virus and often leads to life‑threatening hemophagocytic lymphohistiocytosis in childhood.

Overview

X-linked lymphoproliferative disease (XLP) is a disorder of the immune system that is found almost exclusively in males. More than half of individuals with this disorder experience an exaggerated immune response to the Epstein‑Barr virus (EBV). EBV is a very common virus that eventually infects most humans. In some people it causes infectious mononucleosis (commonly known as “mono”). Normally, after initial infection, EBV remains in certain immune system cells (lymphocytes) called B cells. However, the virus is generally inactive (latent) because it is controlled by other lymphocytes called T cells that specifically target EBV‑infected B cells.

People with XLP may respond to EBV infection by producing abnormally large numbers of T cells, B cells, and other lymphocytes called macrophages. This proliferation of immune cells often causes a life‑threatening reaction called hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis causes fever, destroys blood‑producing cells in the bone marrow, and damages the liver. The spleen, heart, kidneys, and other organs and tissues may also be affected. In some individuals with XLP, hemophagocytic lymphohistiocytosis or related symptoms may occur without EBV infection.

About one‑third of people with XLP experience dysgammaglobulinemia, which means they have abnormal levels of some types of antibodies (also known as immunoglobulins). Individuals with dysgammaglobulinemia are prone to recurrent infections.

Cancers of immune system cells (lymphoma) occur in about one‑third of people with XLP.

Without treatment, most people with XLP survive only into childhood. Death usually results from hemophagocytic lymphohistiocytosis.

Frequency

XLP1 is estimated to occur in about 1 per million males worldwide. XLP2 is less common, occurring in about 1 per 5 million males.

Causes & Risk Factors

Mutations in the SH2D1A and XIAP genes cause XLP. SH2D1A gene mutations cause XLP1, and XIAP gene mutations cause XLP2.

The SH2D1A gene provides instructions for making a protein called signaling lymphocyte activation molecule (SLAM) associated protein (SAP). This protein is involved in the functioning of cytotoxic lymphocytes and is necessary for the development of natural killer T cells. The SAP protein also helps control immune reactions by triggering self‑destruction (apoptosis) of cytotoxic lymphocytes when they are no longer needed.

Some SH2D1A gene mutations impair SAP function. Others result in an abnormally short protein that is unstable or nonfunctional, or prevent any SAP from being produced. The loss of functional SAP disrupts proper signaling in the immune system and may prevent the body from controlling the immune reaction to EBV infection. In addition, hemophagocytic lymphohistiocytosis may develop when defective lymphocytes are not properly destroyed by apoptosis.

The XIAP gene provides instructions for making a protein that helps protect cells from undergoing apoptosis in response to certain signals. XIAP gene mutations can lead to an absence of XIAP protein or decrease the amount of XIAP protein that is produced. It is unknown how a lack of XIAP protein results in the signs and symptoms of XLP, or why features of this disorder differ somewhat between people with XIAP and SH2D1A gene mutations.

Learn more about the genes associated with X-linked lymphoproliferative disease

SH2D1A
XIAP

Inheritance

This condition is generally inherited in an X‑linked recessive pattern. The genes associated with this condition are located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of an associated gene in each cell is sufficient to cause the condition. A characteristic of X‑linked inheritance is that fathers cannot pass X‑linked traits to their sons.

In females (who have two X chromosomes), a mutation usually has to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of an associated gene, males are affected by X‑linked recessive disorders much more frequently than females. However, in rare cases a female carrying one altered copy of the SH2D1A or XIAP gene in each cell may develop signs and symptoms of this condition.

Types

XLP can be divided into two types based on its genetic cause and pattern of signs and symptoms:

XLP1 (classic XLP) – caused by SH2D1A mutations.
XLP2 – caused by XIAP mutations. People with XLP2 have not been known to develop lymphoma, are more likely to develop hemophagocytic lymphohistiocytosis without EBV infection, usually have an enlarged spleen (splenomegaly), and may also have inflammation of the large intestine (colitis). Some researchers believe that these individuals should actually be considered to have a similar but separate disorder rather than a type of XLP.

Other Names for This Condition

Duncan disease
Epstein‑Barr virus‑induced lymphoproliferative disease in males
Familial fatal Epstein‑Barr infection
Purtilo syndrome
Severe susceptibility to EBV infection
Severe susceptibility to infectious mononucleosis
X‑linked lymphoproliferative syndrome
XLP

Additional Information & Resources

Genetic Testing Information

Genetic Testing Registry: X‑linked lymphoproliferative disease due to SH2D1A deficiency
Genetic Testing Registry: X‑linked lymphoproliferative disease due to XIAP deficiency
Genetic Testing Registry: X‑linked lymphoproliferative syndrome

Genetic and Rare Diseases Information Center

X‑linked lymphoproliferative disease

Patient Support and Advocacy Resources

National Organization for Rare Disorders (NORD)

Clinical Trials

ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

LYMPHOPROLIFERATIVE SYNDROME, X‑LINKED, 1; XLP1
LYMPHOPROLIFERATIVE SYNDROME, X‑LINKED, 2; XLP2

Scientific Articles on PubMed

PubMed

References

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