Autoimmune lymphoproliferative syndrome (ALPS)

After the body fights an infection, the extra lymphocytes (white blood cells that fight germs) normally switch themselves off and die. This planned cell death is called apoptosis. In ALPS, a protein that starts it, called FAS, does not work properly, so these cells build up. Lymph nodes, the spleen and sometimes the liver become enlarged.

Many of the extra cells are an unusual kind of T cell called double-negative T cells. They lack the CD4 and CD8 markers most T cells carry. Leftover immune cells can also turn on the body, most often by attacking blood cells. ALPS is not a cancer, but it raises the chance of lymphoma, a cancer of lymphocytes.

Doctors name each type of ALPS for the gene involved. ALPS-FAS is the most common. Other types involve the FASLG or CASP10 genes, or a FAS change found only in some blood cells (ALPS-sFAS). When no gene change is found, it is called ALPS-U. ALPS was once called Canale-Smith syndrome.

ALPS is caused by a change in a gene that controls lymphocyte cell death. MedlinePlus Genetics says changes in the FAS gene cause about 75% of cases. Some people have a FAS change only in certain blood cells, which happened during life rather than being inherited.

In most families, ALPS is autosomal dominant: one changed copy of the gene is enough. A person usually inherits it from an affected parent, but the change can also start new in a child. A small number of cases are autosomal recessive, with both copies of the gene changed.

Not everyone with a FAS change becomes ill. In a U.S. National Institutes of Health (NIH) study, 58% of people who carried a FAS change had symptoms, and the rest had none. Illness was more common in males who carried the change than in females.

Signs usually start in early childhood. In an NIH study of 150 people with ALPS-FAS, the median age when the illness began was 2.7 years. Almost everyone had swollen lymph nodes (97%) and an enlarged spleen (95%). Nodes in the neck, armpits and groin can be large enough to see. They are not lymphoma, although they can be mistaken for it.

The immune system often attacks blood cells. Too few red cells (anemia) cause tiredness and weakness. Too few platelets (thrombocytopenia) cause bruising and nosebleeds. Too few neutrophils (neutropenia), white blood cells that fight germs, raise the risk of infection. Less often, the immune attack targets the liver, kidneys or eyes.

People with ALPS have a much higher chance of lymphoma than other people. The U.S. National Institute of Allergy and Infectious Diseases (NIAID) estimates that about 1 in 5 develop lymphoma by age 40, although most people with ALPS never do. Symptoms are often worst in childhood, and many people improve as adults.

Doctors often suspect ALPS when a child’s lymph nodes or spleen stay swollen for more than 6 months. No infection or cancer explains the swelling. Low blood counts or a family history of similar problems add to the suspicion. ALPS can look like lymphoma, leukemia or a long-lasting viral infection such as mono, so those are ruled out.

A key blood test counts double-negative T cells. Under criteria set at a 2009 NIH workshop, ALPS requires two findings. One is the long-lasting swelling. The other is a double-negative T-cell level of at least 1.5% of all lymphocytes, with normal or high lymphocyte counts. High blood levels of vitamin B12, IL-10, IL-18 or soluble FAS ligand support the diagnosis. Together with raised double-negative T cells, these markers predict a FAS gene change 85% to 97% of the time.

A gene test looks for changes in FAS and related genes. A special lab test can check whether lymphocytes die normally, but few labs offer it. A lymph node biopsy may be done to rule out lymphoma. Under the microscope, the build-up of T cells in ALPS can look like lymphoma, and it has sometimes been mistaken for a T-cell lymphoma. So an experienced pathologist reviews the sample.

Treatment aims to control low blood counts and a very large spleen. Swollen lymph nodes on their own are usually not treated just to shrink them. Short courses of steroid medicine can raise blood counts quickly, but they are not meant for long-term use.

For people who need longer treatment, doctors often use sirolimus (also called rapamycin) or mycophenolate mofetil (MMF). Sirolimus can also shrink the spleen and lymph nodes; MMF does not. A U.S. trial treated children whose other medicines had not worked or had caused serious side effects. All 12 children with ALPS had a complete response to sirolimus, most within 3 months. People taking it have blood level checks and are watched for side effects such as mouth sores and high cholesterol.

Removing the spleen (splenectomy) was common until the early 2000s. It is now avoided when possible. In the NIH study, it did not stop low blood counts from coming back. It also led to serious, sometimes deadly blood infections, even many years later.

A donor stem cell transplant (allogeneic transplant) can replace the immune system. Most people with ALPS do well on medicines, and low blood counts often ease with age. So NIH experts wrote that transplant does not need to be considered for the vast majority. It has been used for a few people with very severe disease. Examples include lymphoma, severe inflammation of the blood vessels, and a form caused by two changed FAS copies with low blood counts that medicines could not control.

ALPS is usually a lifelong condition that is watched over time. Care often involves several specialists who know ALPS. Checkups follow blood counts and the size of the spleen and lymph nodes, and some people take a daily medicine for years.

A large spleen can tear (rupture) after a hard hit, although this is very rare. At the NIH, some children with large spleens wear a molded spleen guard so they can join school activities and sports with care. Care teams advise people whose spleen was removed to take daily antibiotics, wear a medical alert bracelet and get care right away for any fever.

Families learn which changes to report, such as fever, night sweats, weight loss or a lymph node that suddenly grows. These can be signs of lymphoma. Visible lymph nodes can cause worry or embarrassment, and attention to a young person’s feelings is part of good care.

Most people with ALPS will never need a stem cell donor. Medicines control the condition for most people, and symptoms often ease with age.

For the rare person who needs a transplant, the donor may be a relative or an unrelated volunteer. A brother or sister who carries the family’s gene change is not a suitable donor, even if they seem healthy. So a relative being considered as a donor is checked for that gene change.

Joining a registry is not the usual next step for someone with ALPS. But registries serve patients with many blood and immune diseases, and each new volunteer widens the choices for someone without a matched relative.

Most people with ALPS live well into adulthood, and many improve with age. In the largest NIH study, the main causes of serious illness and death were blood infections after spleen removal and lymphoma.

The NIH researchers concluded that avoiding spleen removal, and treating low blood counts with steroid-sparing medicines such as MMF or sirolimus, improves the outcome. Lifelong checks for lymphoma still matter. In the NIH study, lymphoma was found at ages 5 to 60.