X-linked lymphoproliferative disease

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at October 30, 2016
StartDiseasesX-linked lymphoproliferative disease

X-linked lymphoproliferative disease, sometimes referred to as XLP, is a genetic disorder that affects the immune system. Appearing almost exclusively in male patients, this disease is estimated to have a prevalence of less than 1 per million males. This rare condition was first identified in the 1970s by Dr. David Purtilo, leading to it occasionally being referred to as Purtilo syndrome

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Definition & Facts

X-linked lymphoproliferative disease is characterized by a mutation on genes located on the X chromosome. The result of this genetic mutation is a highly specific immunodeficiency which renders the body incapable of combatting the Epstein-Barr virus properly. The result can be either a depressed response or an exaggerated response, the latter often leading to the immune system attacking normal tissues.

This lack of normal immune response to Epstein-Barr and the inability to achieve adaptive immunity after initial infection can lead to severe complications from frequent infection, as Epstein-Barr virus is among the most common human viruses. This virus is responsible for mononucleosis, as well as a wide range of conditions affecting the lymphatic system and immune system.

XLP typically presents in childhood or adolescence, as most people will be exposed to the Epstein-Barr virus well before reaching adulthood. Because of this, XLP will usually result in death during the childhood or adolescent years of the patient if it is not diagnosed and treated. Under normal circumstances, children have a roughly 50 percent chance of being exposed to the virus by the age of five.

Symptoms & Complaints

Under normal immune conditions, cases of Epstein-Barr infection result in a basic immune response, eventually driving the virus into a state of dormancy for the remainder of the infected individual's lifetime. Patients with X-linked lymphoproliferative disease, however, often do not produce such an immune response, allowing the virus to run rampant.

Depending on the course the virus takes, this can result in one or more severe complications that would normally be prevented by normal immune response function. These complications include, but are not limited to, infectious mononucleosis, various forms of lymphoma, and hepatitis

Another complication caused by XLP combined with Epstein-Barr infection is a condition known as hemophagocytic lymphohistiocytosis, or HLH. This condition results from an uncontrolled excess production of white blood cells in cases of exaggerated response, which gradually attack tissues in the body. This complication can be fatal, as the attack of organ tissues can lead to multiple organ failures. A very similar condition known as macrophage-activation syndrome can also result, causing uncontrolled inflammation and eventual failure in multiple organ systems. 

Causes

X-linked lymphoproliferative disease is caused by a recessive mutation of genes on the X chromosome. The affected gene is usually the SH2D1A gene, which codes for activation of molecules critical for normal response to Epstein-Barr infections. Generally, XLP results in a complete deletion of this gene. However, other forms of the condition associated with genes other than SH2D1A are known to exist.

A secondary type of the disease, designated XLP2, is caused by a mutation of the XIAP gene. This gene also plays a crucial immune role, as it regulates parts of the cellular life cycle in cells that have been infected with a viral pathogen. Patients suffering from this form of the disease are especially prone to developing HLH. 

Also key to the mechanism by which XLP depresses immune response to Epstein-Barr is the fact that patients with this disease fail to produce B-cells for response to subsequent infections. B cells are cells which adapt to respond to certain pathogens after initial infection, resulting in acquired immunity. Those suffering from X-linked lymphoproliferative disease, however, produce very low numbers of such cells, resulting in an inability to acquire an immunity to the virus. 

Diagnosis & Tests

Owing to the rarity of the condition, X-linked lymphoproliferative disease is generally diagnosed when patients present with symptoms of Epstein-Barr viruses which are not being properly combatted by the immune system. The presentation of HLH is often a critical clue for medical professionals in identifying a case of XLP. Once the determination has been made that XLP is a likely cause of unchecked Epstein-Barr symptoms, genetic testing can be performed to confirm the diagnosis. 

In families known to include one or more members carrying an X-chromosome mutation associated with the disease, prenatal genetic screenings are generally recommended for parents who may carry the mutation as a recessive gene. These screenings can help to identify new cases of XLP in infants prior to birth. Given the very rare nature of the disease, however, such tests are usually not performed unless family members are known or suspected to carry a causative mutation. 

Treatment & Therapy

Treatment of patients with X-linked lymphoproliferative disease depends on the presentation of the Epstein-Barr symptoms. Less severe symptoms may be treated by introducing antibodies that the patient's body does not produce on its own because of the underlying genetic condition.

In cases that present with HLH, a more aggressive approach is required. Steroids and chemotherapy can be used to stop HLH by reducing the production of the white blood cells that cause it. 

Curing the genetic condition requires a hematopoietic stem cell transplantation from a matching donor without the X-chromosome mutation. These stem cells, which are usually derived from bone marrow, can then produce the B-cells and antibodies that are absent in the XLP patient. Such transplants are performed intravenously and can gradually restore normal immune response to Epstein-Barr. 

Prevention & Prophylaxis

Due to its genetic cause, there are no methods by which X-linked lymphoproliferative disease can be prevented. Family members of a patient known to possess one of the mutations that causes XLP may benefit from genetic counseling when planning to start a family.

Young relatives who may not yet have been exposed to the Epstein-Barr virus can also be tested for mutations, allowing a treatment plan to be developed before symptoms present.