Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder in which the body cannot properly regulate the number of immune system cells (lymphocytes). ALPS is characterized by the production of an abnormally large number of lymphocytes (lymphoproliferation). Accumulation of excess lymphocytes results in enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly), and the spleen (splenomegaly).

Autoimmune disorders are also common in ALPS. Autoimmune disorders occur when the immune system malfunctions and attacks the body's own tissues and organs. Most of the autoimmune disorders associated with ALPS target and damage blood cells. For example, the immune system may attack red blood cells (autoimmune hemolytic anemia), white blood cells (autoimmune neutropenia), or platelets (autoimmune thrombocytopenia). Less commonly, autoimmune disorders that affect other organs and tissues occur in people with ALPS. These disorders can damage the kidneys (glomerulonephritis), liver (autoimmune hepatitis), eyes (uveitis), or nerves (Guillain-Barre syndrome). Skin problems, usually rashes or hives (urticaria), can also occur in ALPS.

ALPS can have varying patterns of signs and symptoms. Most commonly, lymphoproliferation becomes apparent during childhood. Enlargement of the lymph nodes and spleen frequently occur in affected individuals. Autoimmune disorders typically develop several years later, most frequently as a combination of hemolytic anemia and thrombocytopenia, also called Evans syndrome. People with this classic form of ALPS generally have a near-normal lifespan, but have a greatly increased risk of developing cancer of the immune system cells (lymphoma) compared with the general population.

Some people have signs and symptoms that resemble those of ALPS, including lymphoproliferation, lymphadenopathy, splenomegaly, and low blood counts, but the specific pattern of these signs and symptoms or the genetic cause may be different. Researchers disagree whether individuals with these non-classic forms should be considered to have ALPS or a separate condition.

Mutations in the FAS gene cause ALPS in approximately 75 percent of affected individuals; these mutations are associated with the classic form of the disorder. The FAS gene provides instructions for making a protein involved in cell signaling that results in the self-destruction of cells (apoptosis).

When the immune system is turned on (activated) to fight an infection, large numbers of lymphocytes are produced. Normally, these lymphocytes undergo apoptosis when they are no longer required. FAS gene mutations lead to an abnormal protein that interferes with apoptosis. As a result, excess lymphocytes accumulate in the body's tissues and organs and often begin attacking them, leading to autoimmune disorders. Interference with apoptosis allows cells to multiply without control, leading to the lymphomas that often occur in people with this disorder.

Non-classic forms of ALPS may be caused by mutations in additional genes, some of which have not been identified.

Normal Function

The FAS gene provides instructions for making a protein that is involved in cell signaling. Three FAS proteins group together to form a structure called a trimer, which then interacts with other molecules to perform its signaling function. This signaling initiates a process called a caspase cascade. The caspase cascade is a series of steps that results in the self-destruction of cells (apoptosis) when they are not needed.

Health Conditions Related to Genetic Changes

Autoimmune lymphoproliferative syndrome

At least 115 mutations in the FAS gene have been identified in people with a disorder of the immune system called autoimmune lymphoproliferative syndrome (ALPS). ALPS is characterized by the production of an abnormally large number of immune system cells (lymphocytes), resulting in enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly), and the spleen (splenomegaly). Autoimmune disorders, in which the immune system malfunctions and attacks the body's own tissues and organs, are also common in ALPS. People with ALPS have an increased risk of developing cancer of the immune system cells (lymphoma).

When the immune system is activated to fight an infection, large numbers of lymphocytes are produced. Normally, these lymphocytes undergo apoptosis when they are no longer required. FAS gene mutations lead to an abnormal trimer that interferes with the initiation of apoptosis. As a result, excess lymphocytes accumulate in the body's tissues and organs and often begin attacking them, leading to autoimmune disorders. Interference with apoptosis allows cells to multiply without control, leading to the lymphomas that occur in people with this disorder.

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Cancers

Studies have associated certain FAS gene variations with increased risk of developing cancer, including cancers of the lung, breast, and esophagus. Researchers believe that these variations may affect the signaling that initiates apoptosis, increasing the risk that cells will multiply out of control and result in cancer.

Other Names for This Gene

• APO-1
• apo-1 antigen
• APO-1 cell surface antigen
• apoptosis antigen 1
• apoptosis-mediating surface antigen FAS
• APT1
• CD95
• CD95 antigen
• Fas (TNF receptor superfamily, member 6)
• Fas AMA
• Fas antigen
• FAS1
• FASLG receptor
• TNFRSF6
• TNR6_HUMAN
• tumor necrosis factor receptor superfamily member 6

Genomic Location

In most people with ALPS, including the majority of those with FAS gene mutations, this condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In these cases, an affected person usually inherits the mutation from one affected parent. Other cases with an autosomal dominant pattern result from new (de novo) gene mutations that occur early in embryonic development in people with no history of the disorder in their family.

In a small number of cases, including some cases caused by FAS gene mutations, ALPS is inherited in an autosomal recessive pattern, which means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

ALPS can also arise from a mutation in lymphocytes that is not inherited but instead occurs during an individual's lifetime. This alteration is called a somatic mutation.

The major clinical symptoms of ALPS result from lymphoproliferation, or the excessive production of a type of white blood cell called a lymphocyte, and autoimmune destruction of blood cells. Many people with ALPS experience a lessening or complete resolution of their autoimmune and lymphoproliferative symptoms in adulthood.

Lymphoproliferation

The main lymphoproliferative symptoms in ALPS are enlarged lymph nodes and spleen. While the spleen can be massive in some children, the National Institutes of Health team is aware of only one case of splenic rupture. The swollen lymph nodes in the neck, armpit, and groin are usually most noticeable. Sometimes, these enlarged lymph nodes are confused with cancer of the lymph gland, or lymphoma. Large, visible lymph nodes are normal for many people with ALPS. It also is normal for lymph nodes to change somewhat in size, shape, or feel over time. Such changes are usually not a lymphoma.

Autoimmunity

The main autoimmune issues in ALPS are related to reactions against components of blood.

• Anemia occurs when the body destroys its own red blood cells. This causes a feeling of weakness and fatigue.
• Thrombocytopenia occurs when the body attacks and destroys blood components called platelets. When platelet levels are low, the blood does not clot well, and bleeding cannot be stopped following minor injuries. Thrombocytopenia can lead to nosebleeds, gum bleeds, and bruises.
• Neutropenia occurs when the body destroys infection-fighting cells called neutrophils. A decrease in neutrophils increases the risk of infection, which can lead to symptoms such as mouth ulcers and slow wound healing.

ALPS-related autoimmunity sometimes targets organs, leading to conditions such as

• Hepatitis (inflammation of the liver)
• Glomerulonephritis (inflammation of the kidneys)
• Uveitis (inflammation of the iris in the eye).

Lymphoma

People with ALPS have an increased risk of developing lymphoma. Up to age 40, people with ALPS have an approximately 20 percent risk of developing lymphoma. In other words, about 1 in 5 patients will develop ALPS lymphoma by the time they are 40. The risk continues past age 40, although the data on older age groups are limited. Thus, doctors should monitor patients with ALPS for symptoms of lymphoma, such as night sweats, fever, fatigue, weight loss, loss of appetite, and sudden lymph-node enlargement in one area. Although the lymphoma risk for people with ALPS is much higher than that for the general population, most people with ALPS never develop lymphoma.

The diagnosis of ALPS is based on clinical findings, laboratory findings, and identification of mutations in genes, such as FAS, that affect the programmed destruction of cells (apoptosis). Clinical findings that suggest ALPS include:

• Non-cancerous swelling of the lymph nodes (lymphadenopathy) that lasts for more than six months
• Autoimmune disease, especially against blood cells
• Cancer of the lymph nodes (lymphoma)
• Family history of ALPS or ALPS-like features

Laboratory Findings

Prominent findings suggesting an ALPS diagnosis include elevated levels of CD4- and CD8-negative T lymphocytes, called double-negative T cells. Lab tests also can confirm defects in apoptosis of lymphocytes, which is highly suggestive of ALPS. Additionally, an increase in serum vitamin B12 can indicate lymphoproliferation in the form of ALPS caused by mutations in the FAS gene (ALPS-FAS). NIAID scientists also found that people with ALPS-FAS tend to have much higher B12 levels than do healthy people without this condition.

Doctors may perform additional blood tests to help diagnose ALPS. Other markers that may be elevated in ALPS include plasma interleukin-10; plasma interleukin-18; immunoglobulin subtypes IgG, IgA, and IgM; absolute monocyte count; absolute eosinophil count; anticardiolipin antibody; and antinuclear antibody. In contrast, people with ALPS often have abnormally low levels of HDL (high density lipoprotein) and total cholesterol.

There currently is no standard cure for ALPS. The disorder can be managed by treating low blood-cell counts (cytopenias) and other autoimmune diseases that occur in people with ALPS. The disease also can be managed by monitoring for and treating the excessive production of a type of white blood cell called a lymphocyte (lymphoproliferation), an enlarged spleen, and cancer of the lymph nodes (lymphoma).

Doctors closely observe lymphoproliferation in people with ALPS. They may conduct routine imaging tests to observe the lymph nodes. If lymphoma is suspected, the doctor may perform a biopsy—the removal of a small piece of tissue. Lymphomas in people with ALPS can be successfully treated with standard cancer-treatment protocols. The defective apoptosis underlying ALPS does not seem to hinder response to cancer treatment.

When lymphoproliferation causes complications such as airway obstruction, doctors may prescribe corticosteroids and other immunosuppressive medications. ALPS-related autoimmunity also can be treated by suppressing the immune system with medication. The corticosteroid prednisone is often given for this purpose. However, low blood-cell counts frequently recur after a short course of treatment with prednisone, requiring repeated doses of corticosteroids or the use of different types of immune-suppressing medications. Chronic low blood-cell counts often can be managed successfully with steroid-sparing approaches, including medications such as mycophenolate mofetil and sirolimus. In most cases, rare autoimmune complications of ALPS, such as hepatitis, glomerulonephritis, and uveitis, can be treated effectively with immune-suppressing medications.

Spleen removal, or splenectomy, may be necessary in rare cases of difficult-to-control cytopenias. Unfortunately, many patients still struggle with low blood-cell counts after splenectomy. Additionally, lack of a spleen increases the risk of sepsis, a potentially fatal response to severe infection with common bacteria called pneumococcus. NIAID scientists found in 2014 that sepsis is a major cause of severe illness and death among people with ALPS-FAS, the most common form of ALPS.