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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 individuals with two pathogenic alleles, either homozygotes (two copies of the same 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
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
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, KRAS, 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 the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. 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; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. 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. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs 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, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published. [from GeneReviews]
Authors:
Jack JH Bleesing  |  Chinmayee B Nagaraj  |  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).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.  https://ghr.nlm.nih.gov/condition/autoimmune-lymphoproliferative-syndrome

Clinical features

Vasculitis
MedGen UID:
12054
Concept ID:
C0042384
Disease or Syndrome
An inflammatory process involving the wall of the vessels (large, medium, or small-sized vessels). The inflammatory process may cause necrosis or formation of granulomas in the vascular wall. It may be the result of an autoimmune disorder, infection, or malignancy. Representative examples include polyarteritis nodosa, temporal arteritis, Wegener granulomatosis, Kawasaki disease, Takayasu arteritis, and Henoch-Schonlein purpura.
Urticaria
MedGen UID:
776575
Concept ID:
C2186740
Finding
Raised, well-circumscribed areas of erythema and edema involving the dermis and epidermis. Urticaria is intensely pruritic, and blanches completely with pressure.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement of the spleen.
Autoimmune hemolytic anemia
MedGen UID:
1918
Concept ID:
C0002880
Disease or Syndrome
Acquired hemolytic anemia due to the presence of AUTOANTIBODIES which agglutinate or lyse the patient's own RED BLOOD CELLS.
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Abnormal increase of EOSINOPHILS in the blood, tissues or organs.
Iron deficiency anemia
MedGen UID:
57668
Concept ID:
C0162316
Disease or Syndrome
Anemia caused by low iron intake, inefficient iron absorption in the gastrointestinal tract, or chronic blood loss.
Increased IgA level
MedGen UID:
66800
Concept ID:
C0239984
Finding
An abnormally increased level of immunoglobulin A in blood.
Autoimmune neutropenia
MedGen UID:
137947
Concept ID:
C0340971
Disease or Syndrome
Autoimmune-induced neutropenia.
Autoimmune thrombocytopenia
MedGen UID:
584986
Concept ID:
C0398650
Disease or Syndrome
Immune thrombocytopenia is a disorder characterized by a blood abnormality called thrombocytopenia, which is a shortage of blood cell fragments called platelets that are needed for normal blood clotting.Affected individuals can develop red or purple spots on the skin caused by bleeding just under the skin's surface. Small spots of bleeding under the skin are called purpura and larger spots are called ecchymoses. People with immune thrombocytopenia can have significant bleeding episodes, such as nose bleeds (epistaxis) or bleeding in the moist lining (mucosae) of the mouth. In severe cases, individuals may have gastrointestinal bleeding or blood in the urine or stool, or heavy and prolonged menstrual bleeding (menorrhagia). In very rare instances, bleeding inside the skull (intracranial hemorrhage) can occur, which can be life-threatening. A greater reduction in platelet numbers is often associated with more frequent bleeding episodes and an increased risk of severe bleeding.While immune thrombocytopenia can be diagnosed at any age, there are two periods when the condition is most likely to develop: early childhood and late adulthood. In children, the reduction in platelets is often sudden, but platelet levels usually return to normal levels within weeks to months. Immune thrombocytopenia in children is often preceded by a minor infection, such as an upper respiratory infection, but the relationship between the infection and immune thrombocytopenia is not clear. In adults, the development of immune thrombocytopenia is usually gradual and the condition tends to persist throughout life.
Coombs-positive hemolytic anemia
MedGen UID:
105458
Concept ID:
C0520736
Disease or Syndrome
A type of hemolytic anemia in which the Coombs test is positive.
Increased IgM level
MedGen UID:
333454
Concept ID:
C1839972
Finding
An abnormally increased level of immunoglobulin M in blood.
Elevated proportion of CD4-negative, CD8-negative, alpha-beta regulatory T cells
MedGen UID:
395145
Concept ID:
C1858973
Finding
An abnormally increased proportion of CD4-negative, CD8-negative (double negative or DN) alpha-beta regulatory T cells (Tregs) as compared to total number of T cells.
Increased proportion of HLA DR+ and CD57+ T cells
MedGen UID:
349068
Concept ID:
C1858974
Finding
An elevated proportion of T cells that express human leukocyte antigen (HLA)-DR. HLA-DR is an MHC class II cell surface receptor that presents antigens (peptides of at least 9 amino acids), thereby constituting a ligand for the T-cell receptor. HLA-DR can be upregulated in response to immune stimulation.
Increased IgG level
MedGen UID:
347032
Concept ID:
C1858977
Finding
An abnormally increased level of immunoglobulin G in blood.
Autoimmune hemolytic anemia
MedGen UID:
1918
Concept ID:
C0002880
Disease or Syndrome
Acquired hemolytic anemia due to the presence of AUTOANTIBODIES which agglutinate or lyse the patient's own RED BLOOD CELLS.
Eosinophilia
MedGen UID:
41824
Concept ID:
C0014457
Disease or Syndrome
Abnormal increase of EOSINOPHILS in the blood, tissues or organs.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal enlargement of the spleen.
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
Indicates that antibodies directed against nuclear antigens have been detected.
Increased IgA level
MedGen UID:
66800
Concept ID:
C0239984
Finding
An abnormally increased level of immunoglobulin A in blood.
Smooth muscle antibody positivity
MedGen UID:
116117
Concept ID:
C0241185
Laboratory or Test Result
The presence in serum of antibodies against smooth muscle.
Autoimmune neutropenia
MedGen UID:
137947
Concept ID:
C0340971
Disease or Syndrome
Autoimmune-induced neutropenia.
Autoimmune thrombocytopenia
MedGen UID:
584986
Concept ID:
C0398650
Disease or Syndrome
Immune thrombocytopenia is a disorder characterized by a blood abnormality called thrombocytopenia, which is a shortage of blood cell fragments called platelets that are needed for normal blood clotting.Affected individuals can develop red or purple spots on the skin caused by bleeding just under the skin's surface. Small spots of bleeding under the skin are called purpura and larger spots are called ecchymoses. People with immune thrombocytopenia can have significant bleeding episodes, such as nose bleeds (epistaxis) or bleeding in the moist lining (mucosae) of the mouth. In severe cases, individuals may have gastrointestinal bleeding or blood in the urine or stool, or heavy and prolonged menstrual bleeding (menorrhagia). In very rare instances, bleeding inside the skull (intracranial hemorrhage) can occur, which can be life-threatening. A greater reduction in platelet numbers is often associated with more frequent bleeding episodes and an increased risk of severe bleeding.While immune thrombocytopenia can be diagnosed at any age, there are two periods when the condition is most likely to develop: early childhood and late adulthood. In children, the reduction in platelets is often sudden, but platelet levels usually return to normal levels within weeks to months. Immune thrombocytopenia in children is often preceded by a minor infection, such as an upper respiratory infection, but the relationship between the infection and immune thrombocytopenia is not clear. In adults, the development of immune thrombocytopenia is usually gradual and the condition tends to persist throughout life.
Increased IgM level
MedGen UID:
333454
Concept ID:
C1839972
Finding
An abnormally increased level of immunoglobulin M in blood.
Reduced delayed hypersensitivity
MedGen UID:
334744
Concept ID:
C1843386
Finding
Decreased ability to react to a delayed hypersensitivity skin test.
Decreased lymphocyte apoptosis
MedGen UID:
349066
Concept ID:
C1858969
Finding
A reduction in the rate of apoptosis in lymphocytes.
Chronic noninfectious lymphadenopathy
MedGen UID:
395144
Concept ID:
C1858970
Finding
A chronic form of lymphadenopathy that is not related to infection.
Elevated proportion of CD4-negative, CD8-negative, alpha-beta regulatory T cells
MedGen UID:
395145
Concept ID:
C1858973
Finding
An abnormally increased proportion of CD4-negative, CD8-negative (double negative or DN) alpha-beta regulatory T cells (Tregs) as compared to total number of T cells.
Increased proportion of HLA DR+ and CD57+ T cells
MedGen UID:
349068
Concept ID:
C1858974
Finding
An elevated proportion of T cells that express human leukocyte antigen (HLA)-DR. HLA-DR is an MHC class II cell surface receptor that presents antigens (peptides of at least 9 amino acids), thereby constituting a ligand for the T-cell receptor. HLA-DR can be upregulated in response to immune stimulation.
Increased IgG level
MedGen UID:
347032
Concept ID:
C1858977
Finding
An abnormally increased level of immunoglobulin G in blood.
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.
Increased IgA level
MedGen UID:
66800
Concept ID:
C0239984
Finding
An abnormally increased level of immunoglobulin A in blood.
Increased IgM level
MedGen UID:
333454
Concept ID:
C1839972
Finding
An abnormally increased level of immunoglobulin M in blood.
Reduced delayed hypersensitivity
MedGen UID:
334744
Concept ID:
C1843386
Finding
Decreased ability to react to a delayed hypersensitivity skin test.
Increased IgG level
MedGen UID:
347032
Concept ID:
C1858977
Finding
An abnormally increased level of immunoglobulin G in blood.
Urticaria
MedGen UID:
776575
Concept ID:
C2186740
Finding
Raised, well-circumscribed areas of erythema and edema involving the dermis and epidermis. Urticaria is intensely pruritic, and blanches completely with pressure.

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

Gu H, Ma J, Chen Z, Wang J, Zhang R, Wu R
Gene 2018 Sep 25;672:45-49. Epub 2018 Jun 1 doi: 10.1016/j.gene.2018.05.097. PMID: 29864493
Xie Y, Pittaluga S, Price S, Raffeld M, Hahn J, Jaffe ES, Rao VK, Maric I
Haematologica 2017 Feb;102(2):364-372. Epub 2016 Oct 20 doi: 10.3324/haematol.2015.138081. PMID: 27846610Free PMC Article
Ucar D, Kim JS, Bishop RJ, Nussenblatt RB, Rao VK, Sen HN
Ocul Immunol Inflamm 2017 Oct;25(5):703-709. Epub 2016 May 26 doi: 10.1080/09273948.2016.1175637. PMID: 27229379Free PMC Article
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
Shah S, Wu E, Rao VK, Tarrant TK
Curr Allergy Asthma Rep 2014 Sep;14(9):462. doi: 10.1007/s11882-014-0462-4. PMID: 25086580Free PMC Article

Diagnosis

Gu H, Ma J, Chen Z, Wang J, Zhang R, Wu R
Gene 2018 Sep 25;672:45-49. Epub 2018 Jun 1 doi: 10.1016/j.gene.2018.05.097. PMID: 29864493
Bartels AK, Banks TA, Bay JL
Allergy Asthma Proc 2017 Jul 1;38(4):317-321. doi: 10.2500/aap.2017.38.4062. PMID: 28668112
Xie Y, Pittaluga S, Price S, Raffeld M, Hahn J, Jaffe ES, Rao VK, Maric I
Haematologica 2017 Feb;102(2):364-372. Epub 2016 Oct 20 doi: 10.3324/haematol.2015.138081. PMID: 27846610Free PMC Article
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
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

Therapy

Nocerino A, Valencic E, Loganes C, Pelos G, Tommasini A
Pediatr Int 2018 Mar;60(3):315-317. Epub 2018 Feb 26 doi: 10.1111/ped.13494. PMID: 29480551
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
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
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
Curr Allergy Asthma Rep 2014 Sep;14(9):462. doi: 10.1007/s11882-014-0462-4. PMID: 25086580Free PMC Article

Prognosis

Bartels AK, Banks TA, Bay JL
Allergy Asthma Proc 2017 Jul 1;38(4):317-321. doi: 10.2500/aap.2017.38.4062. PMID: 28668112
Xie Y, Pittaluga S, Price S, Raffeld M, Hahn J, Jaffe ES, Rao VK, Maric I
Haematologica 2017 Feb;102(2):364-372. Epub 2016 Oct 20 doi: 10.3324/haematol.2015.138081. PMID: 27846610Free PMC Article
Aberdein D, Munday JS, Gandolfi B, Dittmer KE, Malik R, Garrick DJ, Lyons LA; 99 Lives Consortium.
Mamm Genome 2017 Feb;28(1-2):47-55. Epub 2016 Oct 21 doi: 10.1007/s00335-016-9668-1. PMID: 27770190
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
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

Clinical prediction guides

Bartels AK, Banks TA, Bay JL
Allergy Asthma Proc 2017 Jul 1;38(4):317-321. doi: 10.2500/aap.2017.38.4062. PMID: 28668112
Aberdein D, Munday JS, Gandolfi B, Dittmer KE, Malik R, Garrick DJ, Lyons LA; 99 Lives Consortium.
Mamm Genome 2017 Feb;28(1-2):47-55. Epub 2016 Oct 21 doi: 10.1007/s00335-016-9668-1. PMID: 27770190
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
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
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

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

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