Autoimmune lymphoproliferative syndrome

(often shortened to ALPS)

Reviewed January 2011

What is ALPS?

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).

People with ALPS have an increased risk of developing cancer of the immune system cells (lymphoma) and may also be at increased risk of developing other types of cancers.

Autoimmune disorders are also characteristic of ALPS. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Most of the autoimmune disorders associated with ALPS 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). Other autoimmune disorders that may occur in people with ALPS damage the kidneys (glomerulonephritis), liver (autoimmune hepatitis), eyes (uveitis), nerves (Guillain-Barre syndrome), or connective tissues, the material that provides strength and flexibility to structures throughout the body (systemic lupus erythematosus).

Individuals with ALPS may develop skin rashes or hardened skin with painful lumps or patches (panniculitis). Other signs and symptoms such as arthritis, inflammation of blood vessels (vasculitis), mouth sores (oral ulcers), or an early loss of ovarian function (premature ovarian failure) may also occur in this disorder. Affected individuals may also develop neurological damage (organic brain syndrome) with symptoms that may include headaches, seizures, or a loss of intellectual functions (dementia).

ALPS is categorized into several types based mainly on the genetic cause. In the most common form of the disorder, lymphoproliferation generally becomes apparent during childhood. Enlargement of the lymph nodes and spleen frequently occur in affected individuals. Autoimmune disorders typically develop later in life, most frequently as a combination of hemolytic anemia and thrombocytopenia called Evans syndrome. People with this form of ALPS have a greatly increased risk of developing lymphoma compared with the general population.

Other types of ALPS are very rare. In some affected individuals, severe lymphoproliferation begins around the time of birth, and autoimmune diseases and lymphoma develop at an early age. People with this pattern of signs and symptoms generally do not live beyond childhood. One form of ALPS involves lymphoproliferation and the tendency to develop systemic lupus erythematosus. Individuals with this form of the disorder do not have an enlarged spleen.

How common is ALPS?

ALPS is a rare disorder; its prevalence is unknown. More than 100 affected individuals have been identified worldwide.

What genes are related to ALPS?

Mutations in the FAS gene cause ALPS in approximately 75 percent of affected individuals. 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 activated to fight an infection, large numbers of lymphocytes are produced. Normally, these lymphocytes are destroyed by apoptosis when they are no longer required, so that they do not attack the body's own tissues. FAS gene mutations result in an abnormal protein that interferes with the initiation of apoptosis. Excess lymphocytes accumulate in the body's tissues and organs, causing the signs and symptoms of ALPS. Interference with apoptosis allows cells to multiply out of control, leading to the lymphomas and other cancers that occur in people with this disorder.

ALPS may also be caused by mutations in additional genes, some of which have not been identified.

Related Gene(s)

Changes in these genes are associated with autoimmune lymphoproliferative syndrome.

CASP10
FAS
FASLG

How do people inherit ALPS?

This condition is generally inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. People with the most severe form of the disorder inherit two altered copies of the gene, one from each parent.

Where can I find information about diagnosis or management of ALPS?

These resources address the diagnosis or management of ALPS and may include treatment providers.

Gene Review: Autoimmune Lymphoproliferative Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1108/)
Genetic Testing Registry: Autoimmune lymphoproliferative syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1328840)
Genetic Testing Registry: Autoimmune lymphoproliferative syndrome, type 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1858968)
Genetic Testing Registry: AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL RECESSIVE (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1866121)
National Institute of Allergy and Infectious Diseases (NIAID): Ways to Manage ALPS (http://www.niaid.nih.gov/topics/ALPS/understanding/Pages/manageALPS.aspx)

You might also find information on the diagnosis or management of ALPS in Educational resources (http://www.ghr.nlm.nih.gov/condition/autoimmune-lymphoproliferative-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/autoimmune-lymphoproliferative-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about ALPS?

You may find the following resources about ALPS helpful. These materials are written for the general public.

MedlinePlus - Health information
- Health Topic: Autoimmune Diseases (http://www.nlm.nih.gov/medlineplus/autoimmunediseases.html)
- Health Topic: Immune System and Disorders (http://www.nlm.nih.gov/medlineplus/immunesystemanddisorders.html)
- Health Topic: Lymphatic Diseases (http://www.nlm.nih.gov/medlineplus/lymphaticdiseases.html)
Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases (http://rarediseases.info.nih.gov/gard/8686/resources/resources/1)
Additional NIH Resources - National Institutes of Health
- National Institute of Allergy and Infectious Diseases (NIAID): Autoimmune Lymphoproliferative Syndrome (ALPS) (http://www.niaid.nih.gov/topics/alps/pages/default.aspx)
- National Institute of Allergy and Infectious Diseases (NIAID): Ways to Manage ALPS (http://www.niaid.nih.gov/topics/ALPS/understanding/Pages/manageALPS.aspx)
Educational resources - Information pages
- Madisons Foundation (http://www.madisonsfoundation.org/index.php?option=com_mpower&task=disease&diseaseID=71)
- Swedish Information Centre for Rare Diseases (http://www.socialstyrelsen.se/rarediseases/autoimmunelymphoproliferatives)
Patient support - For patients and families
American Autoimmune Related Diseases Association (https://www.aarda.org/)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary (http://www.ncbi.nlm.nih.gov/books/NBK1108/)
Genetic Testing Registry - Repository of genetic test information
- Genetic Testing Registry: Autoimmune lymphoproliferative syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1328840)
- Genetic Testing Registry: Autoimmune lymphoproliferative syndrome, type 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1858968)
- Genetic Testing Registry: AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL RECESSIVE (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1866121)
ClinicalTrials.gov - Linking patients to medical research (http://clinicaltrials.gov/ct2/results?cond=%22autoimmune%20lymphoproliferative%20syndrome%22%20OR%20%22Autoimmune%20Lymphoproliferative%20Syndrome%22)
PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=(autoimmune%20lymphoproliferative%20syndrome%5BTIAB%5D)%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%20720%20days%22%5Bdp%5D)
OMIM - Genetic disorder catalog
- AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (http://omim.org/entry/601859)
- AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIA (http://omim.org/entry/603909)
- NEUROBLASTOMA RAS VIRAL ONCOGENE HOMOLOG (http://omim.org/entry/164790)

What other names do people use for ALPS?

Canale-Smith syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about ALPS?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding ALPS?

anemia ; apoptosis ; arthritis ; autoimmune ; autosomal ; autosomal dominant ; cancer ; cell ; dementia ; enlarged spleen ; FAS ; gene ; hemolytic anemia ; hepatitis ; immune system ; infection ; inflammation ; lupus ; lymph ; lymphoma ; neurological ; neutropenia ; ovarian ; panniculitis ; platelets ; population ; prevalence ; protein ; splenomegaly ; syndrome ; systemic lupus ; systemic lupus erythematosus ; thrombocytopenia ; uveitis ; white blood cells

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

Bleesing JJ. Autoimmune lymphoproliferative syndrome (ALPS). Curr Pharm Des. 2003;9(3):265-78. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12570831?dopt=Abstract)
Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB, Puck JM, Jaffe ES, Pittaluga S, Cohen JI, Fleisher TA, Rao VK. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood. 2010 Jun 24;115(25):5164-9. doi: 10.1182/blood-2010-01-263145. Epub 2010 Apr 1. (http://www.ncbi.nlm.nih.gov/pubmed/20360470?dopt=Abstract)
Fleisher TA, Straus SE, Bleesing JJ. A genetic disorder of lymphocyte apoptosis involving the fas pathway: the autoimmune lymphoproliferative syndrome. Curr Allergy Asthma Rep. 2001 Nov;1(6):534-40. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11895618?dopt=Abstract)
Fleisher TA. The autoimmune lymphoproliferative syndrome: an experiment of nature involving lymphocyte apoptosis. Immunol Res. 2008;40(1):87-92. doi: 10.1007/s12026-007-8001-1. (http://www.ncbi.nlm.nih.gov/pubmed/18193364?dopt=Abstract)
Gene Review: Autoimmune Lymphoproliferative Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1108/)
Lenardo MJ, Oliveira JB, Zheng L, Rao VK. ALPS-ten lessons from an international workshop on a genetic disease of apoptosis. Immunity. 2010 Mar 26;32(3):291-5. doi: 10.1016/j.immuni.2010.03.013. (http://www.ncbi.nlm.nih.gov/pubmed/20346767?dopt=Abstract)
Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, Rieux-Laucat F, Siegel RM, Su HC, Teachey DT, Rao VK. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010 Oct 7;116(14):e35-40. doi: 10.1182/blood-2010-04-280347. Epub 2010 Jun 10. (http://www.ncbi.nlm.nih.gov/pubmed/20538792?dopt=Abstract)
Poppema S, Maggio E, van den Berg A. Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations. Leuk Lymphoma. 2004 Mar;45(3):423-31. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15160902?dopt=Abstract)
Rieux-Laucat F. Inherited and acquired death receptor defects in human Autoimmune Lymphoproliferative Syndrome. Curr Dir Autoimmun. 2006;9:18-36. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16394653?dopt=Abstract)
Teachey DT, Seif AE, Grupp SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol. 2010 Jan;148(2):205-16. doi: 10.1111/j.1365-2141.2009.07991.x. Epub 2009 Nov 23. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19930184?dopt=Abstract)
Turbyville JC, Rao VK. The autoimmune lymphoproliferative syndrome: A rare disorder providing clues about normal tolerance. Autoimmun Rev. 2010 May;9(7):488-93. doi: 10.1016/j.autrev.2010.02.007. Epub 2010 Feb 17. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20170754?dopt=Abstract)
van der Burg M, de Groot R, Comans-Bitter WM, den Hollander JC, Hooijkaas H, Neijens HJ, Berger RM, Oranje AP, Langerak AW, van Dongen JJ. Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease? Pediatr Res. 2000 Mar;47(3):336-43. (http://www.ncbi.nlm.nih.gov/pubmed/10709732?dopt=Abstract)
Worth A, Thrasher AJ, Gaspar HB. Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol. 2006 Apr;133(2):124-40. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16611303?dopt=Abstract)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.



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