X-linked lymphoproliferative syndrome

Title

Other Names:

XLP; X-linked lymphoproliferative disease; Lymphoproliferative disease, X-linked; XLP; X-linked lymphoproliferative disease; Lymphoproliferative disease, X-linked; XLPD; Duncan disease; Epstein Barr virus infection, familial fatal; EBV infection, severe, susceptibility to; EBVS; X-linked progressive combined variable immunodeficiency 5; Purtilo syndrome See More

Categories:

Congenital and Genetic Diseases; Immune System Diseases; Rare Cancers

This disease is grouped under:

T cell immunodeficiency primary

Summary 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]

XLP1 is mainly 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).
XLP2 is usually characterized by HLH (often associated with EBV), dysgammaglobulinemia, and inflammatory bowel disease (colitis). People with XLP2 have not been known to develop lymphoma.

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]

Last updated: 8/9/2018

Symptoms 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.

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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 antibody level in blood		0004313
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
Fever		0001945
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
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
Fulminant hepatitis		0004787
Hepatic encephalopathy		0002480
Hepatomegaly	Enlarged liver	0002240
Immunodeficiency	Decreased immune function	0002721
Increased circulating IgM level		0003496
Lymphocytosis	High lymphocyte count	0100827
Meningitis		0001287
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 respiratory infections	Frequent respiratory infections Multiple respiratory infections respiratory infections, recurrent Susceptibility to respiratory infections [ more ]	0002205
Recurrent skin infections	Skin infections Skin infections, recurrent [ more ]	0001581
Reduced natural killer cell activity		0012178
Thrombocytopenia	Low platelet count	0001873
X-linked inheritance		0001417
X-linked recessive inheritance		0001419

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Last updated: 8/1/2019

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Diagnosis 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 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 B-cells 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]

Last updated: 5/10/2018

Related Diseases Related Diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnoses include other hereditary forms of HLH (familial lymphohistiocytosis; see this term) and HLH acquired through infection with EBV. Visit the Orphanet disease page for more information.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

ClinicalTrials.gov lists trials that are related to X-linked lymphoproliferative syndrome. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.
Orphanet lists European clinical trials, research studies, and patient registries enrolling people with this condition.

Patient Registry

A registry supports research by collecting of information about patients that share something in common, such as being diagnosed with X-linked lymphoproliferative syndrome. The type of data collected can vary from registry to registry and is based on the goals and purpose of that registry. Some registries collect contact information while others collect more detailed medical information. Learn more about registries.

Registries for X-linked lymphoproliferative syndrome:
United States Immunodeficiency Network (USIDENT) Registry

Organizations 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

Immune Deficiencies Foundation Australia
PO Box 969
Penrith NSW 2751
Australia
Telephone: 800-100-198
E-mail: info@idfa.org.au
Website: http://www.idfa.org.au/
Immune Deficiency Foundation
110 West Road, Suite 300
Towson, MD 21204
Toll-free: 1-800-296-4433
Fax: +1-410-321-9165
E-mail: https://www.primaryimmune.org/services/ask-idf/
Website: https://www.primaryimmune.org/
Jeffrey Modell Foundation (JMF)
780 Third Ave
New York, NY 10017
Fax: 212-764-4180
E-mail: info@jmfworld.org
Website: http://www.info4pi.org/
JMF is a global patient organization devoted to early and precise diagnosis, meaningful treatments, and ultimately, cures - through clinical and basic research, physician education, patient support, advocacy, public awareness and newborn screening.
XLP Research Trust
60 Winchester Road
Romsey
Hampshire
SO51 8JA
United Kingdom
Telephone: +44 (0)1794 521077
E-mail: http://www.xlpresearchtrust.org/keepintouch.asp
Website: http://www.xlpresearchtrust.org/

Do you know of an organization? We want to hear from you.

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Financial Resources

The Social Security Administration has included this condition in their Compassionate Allowances Initiative. This initiative speeds up the processing of disability claims for applicants with certain medical conditions that cause severe disability. More information about Compassionate Allowances and applying for Social Security disability is available online.

Learn More 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

Genetics Home Reference (GHR) 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

Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective. Front Immunol. 2018; 9: 666.

News & Events News & Events

NCATS Co-Sponsored Conferences

The XLP Research Trust Symposium 2018 Monday, October 29, 2018
Location: London, England
Description: This 5th XLP symposium for researchers and clinicians will be held on the 29th October 2018 in Central London. Applications to present a paper at the event must be received by Friday June 22nd. Registration is £50.00 (plus a small booking fee). The symposium will be held at SAS office near Liverpool Street station, on the edge of the City of London and Shoreditch.

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