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Autoimmune lymphoproliferative syndrome

(often shortened to ALPS)
Reviewed July 2014

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 cancers.

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), nerves (Guillain-Barre syndrome), or the connective tissues (systemic lupus erythematosus) that provide strength and flexibility to structures throughout the body.

Skin problems, usually rashes or hives (urticaria), can occur in ALPS. Occasionally, affected individuals develop hardened skin with painful lumps or patches (panniculitis). Other rare signs and symptoms of ALPS include joint inflammation (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 can also develop neurological damage (organic brain syndrome) with symptoms that may include headaches, seizures, or a decline in intellectual functions (dementia).

ALPS can have different patterns of signs and symptoms, which are sometimes considered separate forms of the disorder. In the most common form, lymphoproliferation generally 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 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 disorders and lymphoma develop at an early age. People with this pattern of signs and symptoms generally do not live beyond childhood. Another 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.

Some people have signs and symptoms that resemble those of ALPS, but the specific pattern of these signs and symptoms or the genetic cause may be different than in other forms. Researchers disagree whether individuals with these non-classic forms should be considered to have ALPS or a separate condition.

How common is ALPS?

ALPS is a rare disorder; its prevalence is unknown. More than 200 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 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 result in an abnormal protein that interferes with apoptosis. 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 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
  • CASP8
  • FAS
  • FASLG
  • KRAS
  • NRAS

How do people inherit ALPS?

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.

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 1a (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1866119)
  • Genetic Testing Registry: Autoimmune lymphoproliferative syndrome, type 1b (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1866120)
  • Genetic Testing Registry: Autoimmune lymphoproliferative syndrome, type 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1858968)
  • Genetic Testing Registry: Autoimmune lymphoproliferative syndrome type 1, autosomal recessive (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1866121)
  • Genetic Testing Registry: RAS-associated autoimmune leukoproliferative disorder (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2674723)
  • National Institute of Allergy and Infectious Diseases (NIAID): ALPS Treatment (http://www.niaid.nih.gov/topics/ALPS/Pages/treatment.aspx)

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

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

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 ; autosomal recessive ; cancer ; cell ; dementia ; embryonic ; enlarged spleen ; FAS ; gene ; hemolytic anemia ; hepatitis ; immune system ; infection ; inflammation ; inherited ; joint ; joint inflammation ; lupus ; lymph ; lymphoma ; mutation ; neurological ; neutropenia ; ovarian ; panniculitis ; platelets ; population ; prevalence ; protein ; recessive ; somatic mutation ; 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://ghr.nlm.nih.gov/glossary).

References

  • 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. 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)
  • 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. (http://www.ncbi.nlm.nih.gov/pubmed/21447005?dopt=Abstract)
  • 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. (http://www.ncbi.nlm.nih.gov/pubmed/21885602?dopt=Abstract)
  • 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. (http://www.ncbi.nlm.nih.gov/pubmed/17517660?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)
  • 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. (http://www.ncbi.nlm.nih.gov/pubmed/24398331?dopt=Abstract)
  • 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. (http://www.ncbi.nlm.nih.gov/pubmed/21063026?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)
  • 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.

 
Reviewed: July 2014
Published: March 23, 2015