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.
ALPS is a rare disorder; its prevalence is unknown.
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.
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.
Other Names for This Condition
- Canale-Smith syndrome
Additional Information & Resources
Genetic Testing Information
Genetic and Rare Diseases Information Center
Research Studies from ClinicalTrials.gov
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
- Bleesing JJH, Nagaraj CB, Zhang K. Autoimmune Lymphoproliferative Syndrome. 2006 Sep 14 [updated 2017 Aug 24]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1108/ Citation on PubMed
- 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. Citation on PubMed or Free article on PubMed Central
- 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. Citation on PubMed
- 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. Citation on PubMed or Free article on PubMed Central
- Madkaikar M, Mhatre S, Gupta M, Ghosh K. Advances in autoimmune lymphoproliferative syndromes. Eur J Haematol. 2011 Jul;87(1):1-9. doi: 10.1111/j.1600-0609.2011.01617.x. Review. Citation on PubMed
- Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L, Lanzarotti N, Stolzenberg MC, Bader-Meunier B, Aladjidi N, Chantrain C, Bertrand Y, Jeziorski E, Leverger G, Michel G, Suarez F, Oksenhendler E, Hermine O, Blanche S, Picard C, Fischer A, Rieux-Laucat F. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011 Nov 3;118(18):4798-807. doi: 10.1182/blood-2011-04-347641. Epub 2011 Sep 1. Citation on PubMed
- Oliveira JB, Bidère N, Niemela JE, Zheng L, Sakai K, Nix CP, Danner RL, Barb J, Munson PJ, Puck JM, Dale J, Straus SE, Fleisher TA, Lenardo MJ. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8953-8. Epub 2007 May 16. Citation on PubMed or Free article on PubMed Central
- 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. Citation on PubMed or Free article on PubMed Central
- Price S, Shaw PA, Seitz A, Joshi G, Davis J, Niemela JE, Perkins K, Hornung RL, Folio L, Rosenberg PS, Puck JM, Hsu AP, Lo B, Pittaluga S, Jaffe ES, Fleisher TA, Rao VK, Lenardo MJ. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014 Mar 27;123(13):1989-99. doi: 10.1182/blood-2013-10-535393. Epub 2014 Jan 7. Citation on PubMed or Free article on PubMed Central
- Rao VK. Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome. Front Pediatr. 2015 Jul 21;3:65. doi: 10.3389/fped.2015.00065. eCollection 2015. Review. Citation on PubMed or Free article on PubMed Central
- Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K, Muramatsu H, Doisaki S, Nagasawa M, Morio T, Kasahara Y, Koike K, Kojima S, Takao A, Mizutani S. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood. 2011 Mar 10;117(10):2887-90. doi: 10.1182/blood-2010-08-301515. Epub 2010 Nov 9. Citation on PubMed
- 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. Citation on PubMed or Free article on PubMed Central
- 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. Citation on PubMed
- 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. Citation on PubMed