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X-Linked Lymphoproliferative Disease

What is X-Linked Lymphoproliferative Disease?

X-linked lymphoproliferative (XLP) syndrome is a rare inherited disorder of the immune system which causes a dysregulation in the immune system and an overproduction of immune cells in response to certain infections. There are two types of XLP. Individuals affected by XLP type 1 (XLP1) are susceptible to an exaggerated immune reaction in response to an infection with the Epstein-Barr Virus (EBV), a common virus that causes a disease called mononucleosis. Symptoms include excessive immune cell production (hemophagocytic lymphohistiocytosis or HLH), dysgammaglobulinemia (reduction in the amount of gamma globulin antibodies involved in the immune response) and lymphomas, a group of cancers that affect the lymphatic system. XLP2 is often associated with an EBV infection, but that is not always the case. Symptoms include HLH, dysgammaglobulinemia, and inflammatory bowel disease. XLP1 and XLP2 are genetically distinct.

 

Synonyms

  • X-Linked Lymphoproliferative Disease
  • Duncan Disease
  • EBV Susceptibility
  • Epstein-Barr Virus-Induced Lymphoproliferative Disease in Males
  • Immunodeficiency-5
  • Purtilo Syndrome
  • X-Linked Progressive Combined Variable Immunodeficiency

X-linked lymphoproliferative (XLP) syndrome is a rare inherited disorder of the immune system which causes a dysregulation in the immune system and an overproduction of immune cells in response to certain infections. There are two types of XLP. Individuals affected by XLP type 1 (XLP1) are susceptible to an exaggerated immune reaction in response to an infection with the Epstein-Barr Virus (EBV), a common virus that causes a disease called mononucleosis. Symptoms include excessive immune cell production (hemophagocytic lymphohistiocytosis or HLH), dysgammaglobulinemia (reduction in the amount of gamma globulin antibodies involved in the immune response) and lymphomas, a group of cancers that affect the lymphatic system. XLP2 is often associated with an EBV infection, but that is not always the case. Symptoms include HLH, dysgammaglobulinemia, and inflammatory bowel disease. XLP1 and XLP2 are genetically distinct.

Acknowledgement of X-Linked Lymphoproliferative Disease has not been added yet.

XLP almost exclusively affects males. XLP1 is estimated to affect about one to two individuals per million, while the rarer subtype, XLP2, is estimated to affect about one individual per five million.

Name Abbreviation
X-Linked Lymphoproliferative Disease XLP
Duncan Disease Duncan Disease
EBV Susceptibility EBVS
Epstein-Barr Virus-Induced Lymphoproliferative Disease in Males Epstein-Barr Virus-Induced Lymphoproliferative Disease in Males
Immunodeficiency-5 IMD5
Purtilo Syndrome Purtilo Syndrome
X-Linked Progressive Combined Variable Immunodeficiency X-Linked Progressive Combined Variable Immunodeficiency

The immune system is a complex system of many different cells, proteins, and other substances. Due to its complexity, the regulation of the immune system and proper communication between different immune cells is essential to its proper function. Two important immune cells are B cells and T cells, which collectively are called lymphocytes. 

XLP symptoms are often triggered after exposure to EBV. EBV is a common virus that causes a disease called mononucleosis which often leads to no long-term effects in otherwise healthy individuals. EBV can infect B cells by entering these immune cells and transforming their function. However, a healthy immune system eventually can identify and control the EBV-transformed B cells.

The gene responsible for XLP1 is SH2D1A. The protein product of this gene is involved in regulating the communication between B cells and T cells, facilitating the killing EBV-transformed B cells by T cells, and the development of a certain subset of T cells (natural killer T Cells or NKT). If the gene is defective, the unregulated communication between B cells and T cells leads to an overproduction of B cells and T cells in response to EBV, and the reduction of natural killer T cells hinders the proper containment of the infection. XLP2 is caused by a defect in the XIAP gene. The protein product of this gene inhibits apoptosis or programmed cell death. However, whether this function has a role in the development of XLP symptoms is not clear. 

 XLP is inherited in an X-linked recessive manner. Chromosomes are structures in human cells that carry the genetic material. Each person inherits one copy of each chromosome from each parent, leading to 23 pairs. One pair of chromosomes determines the sex of the individual; these two chromosomes are known as sex chromosomes which are denoted as X and Y. Females have two X chromosomes and no Y chromosome, while men have an X chromosome and a Y chromosome. The Y chromosome is much smaller than the X chromosome and has fewer genes. XLP is an X-linked condition which means the associated genes are present on the X chromosome. It is also a recessive condition, meaning that having a functional copy of the gene can make up for the defective copy. In an X-linked recessive condition like XLP, women are far less frequently affected because if they inherit a defective copy, the second X chromosome can compensate for the defective copy. However, since men only have one X chromosome, if that copy is defective, there are no functional genes to compensate for it which leads to XLP.

 

XLP symptoms usually present between the ages of 6 months to about 10 years. When individuals affected by XLP1 are infected with EBV, symptoms include fever, inflammation and soreness of the throat, and swelling in the lymph nodes. HLH is a life-threatening complication of XLP and may lead to the enlargement and inflammation of the liver, and enlargement of the spleen. The over-production of B cells and T cells may damage the bone marrow. The bone marrow is the site of the production of red blood cells, immune cells, and platelets. Platelets are cellular fragments that are responsible for appropriate blood clotting. Damage to bone marrow leads to aplastic anemia which is a reduction in all types of blood cells as a result of decreased production. If aplastic anemia is present, individuals may experience easy bruising or excessive bleeding since platelets cannot sufficiently form blood clots. Other symptoms include fatigue, shortness of breath, pale skin, rapid or irregular heartbeat, and recurrent infections. Kidneys, heart, and other organs may also be affected. Individuals affected by XLP may also have low levels of certain antibodies (gamma globulins) in the blood, a condition known as dysgammaglobulinemia. Individuals with dysgammaglobulinemia are susceptible to recurrent infections. In addition, some affected individuals may develop certain types of lymphomas after EBV exposure. Lymphomas are a group of cancers that start from lymphocytes (B cells and T cells). XLP1 may lead to B-cell lymphoma, most commonly in the intestines. Symptoms of B-cell lymphoma are abdominal swelling and pain, malabsorption of nutrients, weight loss, nausea, and vomiting.

 

XLP2 symptoms are similar to XLP1; however, lymphomas have not been observed in individuals with XLP2. Some cases of inflammatory bowel disease (IBD) have been observed in XLP2. IBD describes a group of conditions involving long-term inflammation of and damage to the intestines. XLP2 has been reported without exposure to EBV.

The diagnosis of XLP relies on clinical evaluation, the presence of physical symptoms, characteristic immune system abnormalities, as well as family history. If present in the family, XLP almost exclusively only affects males. Laboratory tests and findings, as well as molecular genetic testing, can confirm the diagnosis. In addition, individuals diagnosed with B-cell lymphoma in the region where small and large intestines connect can indicate XLP1. 

 

The most definitive diagnostic test is molecular genetic testing; however, this is not yet widely available. Other tests such as flow cytometry or western blood analysis can be performed to measure the levels of proteins encoded by SH2D1A and XIAP. Flow cytometry is a technique that measures and determines the physical and chemical characteristics of cells. Western blot is a technique that detects and measures a specific protein in a sample. Flow cytometry can also be used to measure the number of natural killer T (NKT) cells in the blood which is expected to be reduced in XLP1. NKT numbers, however, are normal in XLP2, thus, this has no diagnostic value in XLP2.

 

The only cure for XLP1 is allogeneic hematopoietic stem cell transplantation. In this procedure, blood-cell producing cells are taken from the bone marrow, umbilical cord, or blood of a donor to replace the defective cells in the bone marrow or immune system of the affected individual. This procedure is recommended in individuals affected by both symptomatic or asymptomatic XLP1. 

Additionally, depending on clinical presentation, other treatments can benefit individuals. If individuals affected by XLP are identified before exposure to EBV, they may benefit from the administration of antibodies against EBV to prevent life-threatening EBV infections. This is known is IVIG replacement therapy. This might also be helpful after EBV exposure to prevent future infections as a result of the weakened immune system. If individuals develop lymphomas, surgery, radiation, and chemotherapy may be helpful. Furthermore, in the presence of HLH or the overproduction of B cells and T cells, drugs that suppress the immune system such as steroids may be administered.

Since XLP2 is rarer than XLP1, treatments are less established. It is unclear whether allogeneic hematopoietic stem cell transplantation is effective in XLP2. If inflammatory bowel disease is present immunosuppressive drugs may be used to reduce inflammation and the associated symptoms.

 

XLP is a life-threatening condition. Without treatment individuals typically do not live past childhood or adolescence. Individuals affected by XLP2 have a slightly higher life expectancy than those affected by XLP1. Death in individuals affected by XLP is often due to HLH or the overproduction of B cells and T cells that can damage many organs in the body. Since HLH typically occurs after exposure to EBV, identifying individuals affected by XLP before EBV exposure is essential. If individuals are identified before EBV exposure, preventative measures can prevent, postpone, or reduce life-threatening complications and improve the prognosis.

 

Tips or Suggestions of X-Linked Lymphoproliferative Disease has not been added yet.

Genetic and Rare Disease Information Center. X-linked lymphoproliferative syndrome. 2018. Available from https://rarediseases.info.nih.gov/diseases/10915/x-linked-lymphoproliferative-syndrome

Genetics Home Reference. X-linked lymphoproliferative disease.2020. Available from https://ghr.nlm.nih.gov/condition/x-linked-lymphoproliferative-disease#diagnosis

Filipovich AH, Zhang K, Snow AL, Marsh RA. X-linked lymphoproliferative syndromes: brothers or distant cousins?. Blood. 2010;116(18):3398–3408. doi:10.1182/blood-2010-03-275909

Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117(5):1522-1529.

Morra M, Howie D, Grande MS, et al. X-Linked Lymphoproliferative Disease: A Progressive Immunodeficiency. Annual Review of Immunology. 2001;19:1,657-682.

Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective. Front Immunol. 2018;9:666. Published 2018 Apr 4. doi:10.3389/fimmu.2018.00666

Nelson DL, Terhorst C. X-linked lymphoproliferative syndrome. Clin Exp Immunol. 2000;122(3):291–295. doi:10.1046/j.1365-2249.2000.01400.x

 

Community Details Update Created by RareshareTeam
Last updated 15 Apr 2020, 01:58 AM

Posted by RareshareTeam
15 Apr 2020, 01:58 AM

Hi everyone,

The X-linked lymphoproliferative syndrome community details have been updated. We added more information about the cause, prevalence, symptoms, diagnosis, and treatment. Hopefully, you find it helpful.

Info seek and share Created by adbianchi
Last updated 21 May 2013, 09:01 PM

Posted by adbianchi
21 May 2013, 09:01 PM

Hi all I am a family friend of 10 yo affected boy currently hospitized for severe diarrhea (continuos episodes up to 30 discharge per day) which seems unstoppable. Doctors are confused and situation critical. Nothing seems to work. Has anyone had any past experience of similar symptoms and , very very important, is there anyone able to indicate a medicine or procedure which worked well to stop diarrhea ?? Parents are desperate and doctors have tried various therapies but nothing seems to work. Confidently looking for some info.. thanks in advance for anything you may tell me. Dany

Community Resources
Title Description Date Link
XLP Research Trust

Founded in 2005, the XLP Research Trust exists to promote and fund research into the cause, management, symptoms and cure for XLP, provide a point of contact and support for those families affected by XLP, and raise the awareness of XLP amongst the medical profession and the general public.

03/20/2017

Clinical Trials


Cords registry

CoRDS, or the Coordination of Rare Diseases at Sanford, is based at Sanford Research in Sioux Falls, South Dakota. It provides researchers with a centralized, international patient registry for all rare diseases. This program allows patients and researchers to connect as easily as possible to help advance treatments and cures for rare diseases. The CoRDS team works with patient advocacy groups, individuals and researchers to help in the advancement of research in over 7,000 rare diseases. The registry is free for patients to enroll and researchers to access.

Enrolling is easy.

  1. Complete the screening form.
  2. Review the informed consent.
  3. Answer the permission and data sharing questions.

After these steps, the enrollment process is complete. All other questions are voluntary. However, these questions are important to patients and their families to create awareness as well as to researchers to study rare diseases. This is why we ask our participants to update their information annually or anytime changes to their information occur.

Researchers can contact CoRDS to determine if the registry contains participants with the rare disease they are researching. If the researcher determines there is a sufficient number of participants or data on the rare disease of interest within the registry, the researcher can apply for access. Upon approval from the CoRDS Scientific Advisory Board, CoRDS staff will reach out to participants on behalf of the researcher. It is then up to the participant to determine if they would like to join the study.

Visit sanfordresearch.org/CoRDS to enroll.

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Community User List

looking for other people suffering with this rare condition x-linked lymphoproliferative disease and how they have managed the care.
I am mother of 3 sons and a daughter. Our third son has diagnosed with xlp without one of the genes which are related with xlp. the problems started with the EBV virus. Since that moment our son...
My name is Denis and my wife's name is Yekaterina. We lost our eldest son in December of 2012 to XLP. After our son passed away from EBV doctors suspected that XLP caused this death. We are in...
Friend of affected children
I am the mother of 2 sons with XLP. My younger son, Brandon, lost his fight in 2002 at the age of 10. My older son Logan is 21 now and not doing well. He had a BMT in 2004 and never fully...
I am the mother of 2 boys Hunter age 7 and Parker age 3. For 5 years they have been lucky enough to be in a research study at the National Institute of Health hoping to receive a diagnosis for...
I am the last survivor of 6 in my family with XLP. My uncle was the oldest survivor @ 42 years. He passed in 03. My brother passed @ 27, and 3 uncles in the 1960s passed away @ 4, 8 and 18. I am...
I am 34 y/o only sister of 2 brothers who died of Duncan Disease. One died when he was 4y/o in 1974 a year before I was born. The other lived until he was 20y/o and died in 1991. We didn't know...
Leukemia, sarcoidosis, and many other autoimmune diseases. Chronic lymphoproliferative syndrome
I am a brother of a large familiy. Three of us have died when they were children, before we all know about this disease. Another brother has died some days after an narrow bond transplant, when he...
I am the Father of 4 boys with XLP and the Chairman of the XLP Research Trust -established to provide support for families affected by XLP any where in the world. We live in the UK and each of my...

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Community Details Update

Created by RareshareTeam | Last updated 15 Apr 2020, 01:58 AM

Info seek and share

Created by adbianchi | Last updated 21 May 2013, 09:01 PM


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