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Autoimmune lymphoproliferative syndrome(ALPS)

MedGen UID:
231300
Concept ID:
C1328840
Disease or Syndrome
Synonyms: ALPS; Autoimmune lymphoproliferative syndrome type 1, autosomal dominant; AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL DOMINANT; FAS-Related Autoimmune Lymphoproliferative Syndrome
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Autoimmune lymphoproliferative syndrome (702444009); Canale-Smith syndrome (702444009)
 
Genes (locations): FAS (10q23.31); FASLG (1q24.3)
Related genes: NRAS, CASP10, CASP8
OMIM®: 601859
Orphanet: ORPHA3261

Disease characteristics

Excerpted from the GeneReview: Autoimmune Lymphoproliferative Syndrome
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age; Autoimmune disease, mostly directed toward blood cells; and Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases in many affected individuals. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS is characterized by severe lymphoproliferation before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (α/β-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, keeping in mind that those with somatic pathogenic variants need to be better characterized, particularly with regard to the risk for lymphoma. [from GeneReviews]
Authors:
Jack JH Bleesing  |  Judith Johnson  |  Kejian Zhang   view full author information

Additional descriptions

From OMIM
Autoimmune lymphoproliferative syndrome is a heritable disorder of apoptosis, resulting in the accumulation of autoreactive lymphocytes. It manifests in early childhood as nonmalignant lymphadenopathy with hepatosplenomegaly and autoimmune cytopenias (summary by Dowdell et al., 2010). For a review of the autoimmune lymphoproliferative syndromes, see Teachey et al. (2009). Genetic Heterogeneity of Autoimmune Lymphoproliferative Syndrome Type IIA ALPS (ALPS2A; 603909) is caused by mutation in the caspase-10 gene (CASP10; 601762). Puck and Straus (2004) designated caspase-8 deficiency (607271), caused by mutations in the CASP8 gene (601763), as type IIB ALPS. ALPS3 (615559) is caused by mutation in the PRKCD gene (176977). RAS-associated ALPS (RALD, or ALPS4; 614470) is caused by mutation in the NRAS gene (164790). ALPS5 (616100) is caused by mutation in the CTLA4 gene (123890).  http://www.omim.org/entry/601859
From GHR
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.  https://ghr.nlm.nih.gov/condition/autoimmune-lymphoproliferative-syndrome

Clinical features

Vasculitis
MedGen UID:
12054
Concept ID:
C0042384
Disease or Syndrome
Vasculitis is an inflammation of the blood vessels. It happens when the body's immune system attacks the blood vessel by mistake. It can happen because of an infection, a medicine, or another disease. The cause is often unknown. Vasculitis can affect arteries, veins and capillaries. Arteries are vessels that carry blood from the heart to the body's organs. Veins are the vessels that carry blood back to the heart. Capillaries are tiny blood vessels that connect the small arteries and veins. . When a blood vessel becomes inflamed, it can. - Narrow, making it more difficult for blood to get through . - Close off completely so that blood can't get through . - Stretch and weaken so much that it bulges. The bulge is called an aneurysm. If it bursts, it can cause dangerous bleeding inside the body. Symptoms of vasculitis can vary, but usually include fever, swelling and a general sense of feeling ill. The main goal of treatment is to stop the inflammation. Steroids and other medicines to stop inflammation are often helpful. NIH: National Heart, Lung, and Blood Institute.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Sign or Symptom
Enlargement of the liver.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
Autoimmune hemolytic anemia
MedGen UID:
1918
Concept ID:
C0002880
Disease or Syndrome
An autoimmune form of hemolytic anemia.
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Increased count of eosinophils in the blood.
Rheumatoid factor positive
MedGen UID:
56226
Concept ID:
C0151379
Laboratory or Test Result
The presence in the serum of an autoantibody directed against the Fc portion of IgG.
Antinuclear antibody positivity
MedGen UID:
101792
Concept ID:
C0151480
Laboratory or Test Result
Antibodies directed against nuclear antigens; almost invariably found in systemic lupus erythematosus and are frequently found in rheumatoid arthritis, scleroderma, Sjogren's Syndrome and mixed connective tissue disease.
Smooth muscle antibody positivity
MedGen UID:
116117
Concept ID:
C0241185
Laboratory or Test Result
The presence in serum of antibodies against smooth muscle.
Autoimmune thrombocytopenia
MedGen UID:
116621
Concept ID:
C0242584
Disease or Syndrome
The presence of thrombocytopenia in combination with detection of antiplatelet antibodies.
Autoimmune neutropenia
MedGen UID:
137947
Concept ID:
C0340971
Disease or Syndrome
Autoimmune-induced neutropenia.
Reduced delayed hypersensitivity
MedGen UID:
334744
Concept ID:
C1843386
Finding
Decreased ability to react to a delayed hypersensitivity skin test.
Chronic noninfectious lymphadenopathy
MedGen UID:
395144
Concept ID:
C1858970
Finding
A chronic form of lymphadenopathy that is not related to infection.
Increased number of peripheral CD3+ T cells
MedGen UID:
347767
Concept ID:
C1858971
Finding
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell receptors
MedGen UID:
395145
Concept ID:
C1858973
Finding
Platelet antibody positive
MedGen UID:
349070
Concept ID:
C1858980
Laboratory or Test Result
The presence in the serum of autoantibodies directed against thrombocytes.
Antineutrophil antibody positivity
MedGen UID:
395147
Concept ID:
C1858981
Laboratory or Test Result
The presence of autoantibodies in the serum that react against neutrophils.
Follicular hyperplasia
MedGen UID:
863170
Concept ID:
C4014733
Finding
Lymphadenopathy (enlargement of lymph nodes) owing to hyperplasia of follicular (germinal) centers.
Antiphospholipid antibody positivity
MedGen UID:
866404
Concept ID:
C4019436
Finding
The presence of circulating autoantibodies to phospholipids.
Reduced delayed hypersensitivity
MedGen UID:
334744
Concept ID:
C1843386
Finding
Decreased ability to react to a delayed hypersensitivity skin test.

Professional guidelines

PubMed

Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, Rieux-Laucat F, Siegel RM, Su HC, Teachey DT, Rao VK
Blood 2010 Oct 7;116(14):e35-40. Epub 2010 Jun 10 doi: 10.1182/blood-2010-04-280347. PMID: 20538792Free PMC Article

Recent clinical studies

Etiology

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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
Blood 2014 Mar 27;123(13):1989-99. Epub 2014 Jan 7 doi: 10.1182/blood-2013-10-535393. PMID: 24398331Free PMC Article
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
Blood 2011 Nov 3;118(18):4798-807. Epub 2011 Sep 1 doi: 10.1182/blood-2011-04-347641. PMID: 21885602
Rao VK, Oliveira JB
Blood 2011 Nov 24;118(22):5741-51. Epub 2011 Sep 1 doi: 10.1182/blood-2011-07-325217. PMID: 21885601Free PMC Article

Diagnosis

Li P, Huang P, Yang Y, Hao M, Peng H, Li F
Clin Rev Allergy Immunol 2016 Feb;50(1):55-63. doi: 10.1007/s12016-015-8466-y. PMID: 25663566
Ruiz-García R, Mora S, Lozano-Sánchez G, Martínez-Lostao L, Paz-Artal E, Ruiz-Contreras J, Anel A, González-Granado LI, Moreno-Pérez D, Allende LM
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Meena KR, Bisht S, Tamaria KC
Indian J Pediatr 2015 Dec;82(12):1172-4. Epub 2015 May 15 doi: 10.1007/s12098-015-1779-2. PMID: 25972287
Nabhani S, Hönscheid A, Oommen PT, Fleckenstein B, Schaper J, Kuhlen M, Laws HJ, Borkhardt A, Fischer U
Clin Immunol 2014 Dec;155(2):231-7. Epub 2014 Oct 24 doi: 10.1016/j.clim.2014.10.006. PMID: 25451160
Hsu AP, Dowdell KC, Davis J, Niemela JE, Anderson SM, Shaw PA, Rao VK, Puck JM
Genet Med 2012 Jan;14(1):81-9. Epub 2011 Oct 7 doi: 10.1038/gim.0b013e3182310b7d. PMID: 22237435

Therapy

George LA, Teachey DT
Paediatr Drugs 2016 Aug;18(4):261-72. doi: 10.1007/s40272-016-0175-3. PMID: 27139496
Nabhani S, Ginzel S, Miskin H, Revel-Vilk S, Harlev D, Fleckenstein B, Hönscheid A, Oommen PT, Kuhlen M, Thiele R, Laws HJ, Borkhardt A, Stepensky P, Fischer U
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Indian J Pediatr 2015 Dec;82(12):1172-4. Epub 2015 May 15 doi: 10.1007/s12098-015-1779-2. PMID: 25972287
Berio A, Mangiante G, Piazzi A
Pediatr Med Chir 2014 Dec 30;36(5-6):100. doi: 10.4081/pmc.2014.100. PMID: 25669891
Shah S, Wu E, Rao VK, Tarrant TK
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Prognosis

Yokoyama S, Perera PY, Terawaki S, Watanabe N, Kaminuma O, Waldmann TA, Hiroi T, Perera LP
J Clin Immunol 2015 Oct;35(7):661-7. Epub 2015 Oct 9 doi: 10.1007/s10875-015-0203-z. PMID: 26453583
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Blood 2014 Mar 27;123(13):1989-99. Epub 2014 Jan 7 doi: 10.1182/blood-2013-10-535393. PMID: 24398331Free PMC Article
Lambotte O, Neven B, Galicier L, Magerus-Chatinet A, Schleinitz N, Hermine O, Meyts I, Picard C, Godeau B, Fischer A, Rieux-Laucat F
Haematologica 2013 Mar;98(3):389-92. Epub 2012 Sep 14 doi: 10.3324/haematol.2012.067488. PMID: 22983577Free PMC Article
Venkataraman G, McClain KL, Pittaluga S, Rao VK, Jaffe ES
Am J Surg Pathol 2010 Apr;34(4):589-94. doi: 10.1097/PAS.0b013e3181d5ddf8. PMID: 20216376Free PMC Article

Clinical prediction guides

Li P, Huang P, Yang Y, Hao M, Peng H, Li F
Clin Rev Allergy Immunol 2016 Feb;50(1):55-63. doi: 10.1007/s12016-015-8466-y. PMID: 25663566
Yokoyama S, Perera PY, Terawaki S, Watanabe N, Kaminuma O, Waldmann TA, Hiroi T, Perera LP
J Clin Immunol 2015 Oct;35(7):661-7. Epub 2015 Oct 9 doi: 10.1007/s10875-015-0203-z. PMID: 26453583
Nabhani S, Ginzel S, Miskin H, Revel-Vilk S, Harlev D, Fleckenstein B, Hönscheid A, Oommen PT, Kuhlen M, Thiele R, Laws HJ, Borkhardt A, Stepensky P, Fischer U
Haematologica 2015 Sep;100(9):1189-98. Epub 2015 Jun 25 doi: 10.3324/haematol.2014.114967. PMID: 26113417Free PMC Article
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
Blood 2014 Mar 27;123(13):1989-99. Epub 2014 Jan 7 doi: 10.1182/blood-2013-10-535393. PMID: 24398331Free PMC Article
Lambotte O, Neven B, Galicier L, Magerus-Chatinet A, Schleinitz N, Hermine O, Meyts I, Picard C, Godeau B, Fischer A, Rieux-Laucat F
Haematologica 2013 Mar;98(3):389-92. Epub 2012 Sep 14 doi: 10.3324/haematol.2012.067488. PMID: 22983577Free PMC Article

Recent systematic reviews

Miano M, Ramenghi U, Russo G, Rubert L, Barone A, Tucci F, Farruggia P, Petrone A, Mondino A, Lo Valvo L, Crescenzio N, Bellia F, Olivieri I, Palmisani E, Caviglia I, Dufour C, Fioredda F
Br J Haematol 2016 Nov;175(3):490-495. Epub 2016 Jul 22 doi: 10.1111/bjh.14261. PMID: 27447678
Liang Y, Zhang L, Gao J, Hu D, Ai Y
PLoS One 2012;7(5):e36698. Epub 2012 May 30 doi: 10.1371/journal.pone.0036698. PMID: 22666325Free PMC Article
Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, Rieux-Laucat F, Siegel RM, Su HC, Teachey DT, Rao VK
Blood 2010 Oct 7;116(14):e35-40. Epub 2010 Jun 10 doi: 10.1182/blood-2010-04-280347. PMID: 20538792Free PMC Article
Randhawa SR, Chahine BG, Lowery-Nordberg M, Cotelingam JD, Casillas AM
Ann Allergy Asthma Immunol 2010 Apr;104(4):286-92. doi: 10.1016/j.anai.2010.01.021. PMID: 20408337
Straus SE, Sneller M, Lenardo MJ, Puck JM, Strober W
Ann Intern Med 1999 Apr 6;130(7):591-601. PMID: 10189330

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