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Disease Profile

X-linked lymphoproliferative syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

D82.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

XLP; X-linked lymphoproliferative disease; Lymphoproliferative disease, X-linked;

Categories

Congenital and Genetic Diseases; Immune System Diseases; Rare Cancers

Summary

X-linked lymphoproliferative syndrome (XLP) is an immune system disorder that occurs almost exclusively in males. People with XLP have an increased risk of infection because their body cannot properly regulate the number of immune system cells (lymphocytes) and blood cells. The symptoms associated with XLP vary from person to person, and even among family members. In most cases, symptoms begin anywhere from 6 months of age to 10 years of age.[1] XLP generally has two subtypes, which are caused by mutations in different genes:[2][3]

Signs and symptoms of HLH include fever, enlarged lymph nodes and spleen, skin rashes, and problems with the lungs, digestive system, liver, and nervous system.[3][4] The heart, kidneys, or other organs may also be affected.[3] Mononucleosis may cause fatigue; fever; an inflamed and sore throat; enlarged lymph nodes, liver, and spleen; and symptoms of anemia.[1][5] Dysgammaglobulinemia causes an increased risk of recurrent infections.[3]

XLP1 is caused by mutations in the SH2D1A gene, and XLP2 is caused by mutations in the XIAP gene. Inheritance is X-linked recessive. However, in rare cases, females with a mutation on one copy of the responsible gene develop symptoms of XLP.[3] A diagnosis of either type of XLP can be confirmed with genetic testing.[2] Of note, there have been males with mutations known to cause XLP that have not developed symptoms.[2]

The only cure for XLP is allogeneic hematopoietic cell transplantation, which should be considered as early as possible. Treatment of XLP-related HLH may include immunosuppressive agents (such as steroids and etoposide or anti-thymocyte globulin), and rituximab when HLH is associated with EBV infection. Hypogammaglobulinemia is treated with IVIG replacement therapy, and lymphoma is treated with standard chemotherapy. Inflammatory bowel disease is treated with immunosuppression.[2]

Without treatment, many people with XLP do not survive beyond childhood, usually due to HLH.[3] The average age of death for males has been reported as 11 years (with a range of 2-69 years) for XLP1, and 16 years (with a range of 1-52 years) for XLP2.[2]

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Cellular immunodeficiency
0005374
30%-79% of people have these symptoms
Decreased circulating antibody level
0004313
Hepatomegaly
Enlarged liver
0002240
Lymphadenopathy
Swollen lymph nodes
0002716
Lymphoma
Cancer of lymphatic system
0002665
Splenomegaly
Increased spleen size
0001744
5%-29% of people have these symptoms
Anemia
Low number of red blood cells or hemoglobin
0001903
1%-4% of people have these symptoms
Aplastic anemia
0001915
Burkitt lymphoma
0030080
Dysgammaglobulinemia
0002961
Fever
0001945
Fulminant hepatitis
0004787
Hemophagocytosis
0012156
Hepatitis
Liver inflammation
0012115
Hypertriglyceridemia
Increased plasma triglycerides
Increased serum triglycerides
Increased triglycerides

[ more ]

0002155
Hypofibrinogenemia
0011900
Increased serum ferritin
Elevated serum ferritin
High ferritin level
Increased ferritin
Increased serum ferritin level

[ more ]

0003281
Meningitis
0001287
Neutropenia
Low blood neutrophil count
Low neutrophil count

[ more ]

0001875
Recurrent respiratory infections
Frequent respiratory infections
Multiple respiratory infections
respiratory infections, recurrent
Susceptibility to respiratory infections

[ more ]

0002205
Severe Epstein Barr virus infection
0031693
Vasculitis
Inflammation of blood vessel
0002633
Percent of people who have these symptoms is not available through HPO
Acne
0001061
Colitis
0002583
Decreased circulating IgG level
0004315
Encephalitis
Brain inflammation
0002383
Erythema nodosum
0012219
Folliculitis
0025084
Hepatic encephalopathy
0002480
Immunodeficiency
Decreased immune function
0002721
Increased circulating IgM level
0003496
Lymphocytosis
High lymphocyte count
0100827
Pancytopenia
Low blood cell count
0001876
Recurrent fever
Episodic fever
Increased body temperature, episodic
Intermittent fever

[ more ]

0001954
Recurrent pharyngitis
Recurrent sore throat
0100776
Recurrent skin infections
Skin infections, recurrent
0001581
Reduced natural killer cell activity
0012178
Thrombocytopenia
Low platelet count
0001873
X-linked inheritance
0001417
X-linked recessive inheritance
0001419

Diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • Orphanet lists international laboratories offering diagnostic testing for this condition.

    Treatment

    X-linked lymphoproliferative syndrome treatment requires the coordinated effort of a team of specialists, such as a pediatrician or internist, immunologist, hematologist, and oncologist.[1] Because XLP can cause life-threatening conditions, it is important to identify males with XLP as soon as possible. Close monitoring (such as of EBV viral loads, IgG levels, blood counts, liver tests, inflammatory marker, coagulation studies as needed) is a very important aspect of care.  Treatment will vary depending on a variety of factors, including the severity of a person’s symptoms. [1][6]

    If a person is identified before EBV exposure, regular infusions with immunoglobulins (IgG replacement therapy) may be recommended to help prevent life-threatening infectious mononucleosis and the onset of other symptoms and findings potentially associated with XLP.[1]

    If a person with XLP is diagnosed after EBV exposure, treatment may include therapies to help prevent opportunistic infections associated with XLP, such as antibiotic medications, intravenous gammaglobulin therapy, and rituximab (to deplete Bcells harboring EBV).[6][1]

    People with XLP are at risk for hemophagocytic lymphohistiocytosis (HLH). HLH is
    a condition in which the body makes too many activated immune cells (macrophages and lymphocytes). Treatment of HLH may include a combination of strong immune suppressing medications followed by a stem cell transplant.[1][2][6] Studies on new treatments for HLH have been completed in recent years (e.g., anti-thymocyte globulin), and others are underway (Toculizumab, Novimmune NI-0501, and Ruxolitinib).[2] It is hoped that new medications will improve success rates and long term outlook for people with HLH who undergo stem cell transplant.  

    Bone marrow or stem cell transplant is currently the only definitive treatment for XLP1. A tailored discussion regarding the risks and benefits of transplant for each individual patient is critical.

    Some people with XLP have developed B-cell lymphoma. The lymphoma may be treated with surgery, radiation, and/or chemotherapy. Genetic counseling should be offered to people with XLP and their families. Other treatment is symptomatic and supportive.

    Studies investigating novel treatments, such as SLAM family inhibitors, gene editing, and gene therapy, have been underway.[6] Improvements in gene therapy techniques have resulted in better outcomes and less risk for adverse reactions. Gene therapy clinical trials may soon prove this approach to be a viable alternative to stem cell transplant.[6]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • MedlinePlus Genetics contains information on X-linked lymphoproliferative syndrome. This website is maintained by the National Library of Medicine.
        • The Merck Manuals Online Medical Library provides information on this condition for patients and caregivers.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
            OMIM: X-linked lymphoproliferative syndrome 1
            OMIM: X-linked lymphoproliferative syndrome 2
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss X-linked lymphoproliferative syndrome. Click on the link to view a sample search on this topic.

            Selected Full-Text Journal Articles

              References

              1. X linked Lymphoproliferative Syndrome. National Organization for Rare Disorders. 2007; https://rarediseases.org/rare-diseases/x-linked-lymphoproliferative-syndrome/.
              2. Zhang K, Wakefield E, Marsh R. Lymphoproliferative disease, X-linked. GeneReviews. June 30, 2016; https://www.ncbi.nlm.nih.gov/books/NBK1406/.
              3. X-linked lymphoproliferative disease. Genetics Home Reference (GHR). November, 2014; https://ghr.nlm.nih.gov/condition/x-linked-lymphoproliferative-disease.
              4. Hemophagocytic Lymphohistiocystosis. Johns Hopkins Medicine Health Library. https://www.hopkinsmedicine.org/healthlibrary/conditions/hematology_and_blood_disorders/hemophagocytic_lymphohistiocystosis_134,212. Accessed 8/9/2018.
              5. Mononucleosis. Mayo Clinic. January 3, 2018; https://www.mayoclinic.org/diseases-conditions/mononucleosis/symptoms-causes/syc-20350328.
              6. Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective. Front Immunol. Apr 4 2018; 9:666:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893764/.

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