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Autoimmune lymphoproliferative syndrome type 1(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
SNOMED CT: Autoimmune lymphoproliferative syndrome (702444009); Canale-Smith syndrome (702444009)
 
Genes (locations): FAS (10q23.31); FASLG (1q24.3)
 
Monarch Initiative: MONDO:0011158
OMIM®: 601859

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 MedlinePlus Genetics
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://medlineplus.gov/genetics/condition/autoimmune-lymphoproliferative-syndrome

Clinical features

From HPO
Vasculitis
MedGen UID:
12054
Concept ID:
C0042384
Disease or Syndrome
Inflammation of blood vessel.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
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.
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.
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.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size 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
The presence of autoantibodies in the serum that react against nuclei or nuclear components.
Increased circulating IgA level
MedGen UID:
66800
Concept ID:
C0239984
Finding
An abnormally increased level of immunoglobulin A in blood.
Anti-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.
Neutropenia in presence of anti-neutropil antibodies
MedGen UID:
137947
Concept ID:
C0340971
Disease or Syndrome
A type of neutropenia that is observed in the presence of granulocyte-specific antibodies.
Increased circulating 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 circulating 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 proportion of HLA DR+ T cells
MedGen UID:
1642955
Concept ID:
C4703376
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.
Urticaria
MedGen UID:
22587
Concept ID:
C0042109
Disease or Syndrome
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

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Recent clinical studies

Etiology

Chasset F, Richez C, Martin T, Belot A, Korganow AS, Arnaud L
Joint Bone Spine 2019 Mar;86(2):165-171. Epub 2018 Oct 26 doi: 10.1016/j.jbspin.2018.10.007. PMID: 30837156
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Diagnosis

Chasset F, Richez C, Martin T, Belot A, Korganow AS, Arnaud L
Joint Bone Spine 2019 Mar;86(2):165-171. Epub 2018 Oct 26 doi: 10.1016/j.jbspin.2018.10.007. PMID: 30837156
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Therapy

Hyser E
J Med Case Rep 2022 Sep 5;16(1):336. doi: 10.1186/s13256-022-03526-0. PMID: 36059007Free PMC Article
Gu H, Chen Z, Ma J, Wang J, Zhang R, Wu R, Wang T
Int J Immunopathol Pharmacol 2021 Jan-Dec;35:20587384211025934. doi: 10.1177/20587384211025934. PMID: 34187243Free PMC Article
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Prognosis

Chasset F, Richez C, Martin T, Belot A, Korganow AS, Arnaud L
Joint Bone Spine 2019 Mar;86(2):165-171. Epub 2018 Oct 26 doi: 10.1016/j.jbspin.2018.10.007. PMID: 30837156
Novotný I, Díte P, Lata J, Nechutová H, Kianicka B
Dig Dis 2010;28(2):334-8. Epub 2010 Sep 1 doi: 10.1159/000319410. PMID: 20814208
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Orphanet J Rare Dis 2008 Sep 16;3:25. doi: 10.1186/1750-1172-3-25. PMID: 18796155Free PMC Article
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Clinical prediction guides

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Recent systematic reviews

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