Autoimmune Lymphoproliferative Syndrome

Mendelian MONDO:0017979 Pathograph 3 Show in embeddings browser Primary Immunodeficiency Autoimmune Disorder Lymphoproliferative Disorder

Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity in which lymphocytes fail to undergo Fas-mediated apoptosis. Because the FAS death receptor pathway is what normally removes activated and autoreactive lymphocytes once an immune response has resolved, a defect in it produces the syndrome's defining triad: chronic non-malignant lymphoproliferation (lymphadenopathy and splenomegaly), autoimmunity directed mainly at blood cells, and an expanded population of alpha-beta double-negative (CD3+ CD4- CD8-) T cells that has no normal clearance route. Lymphoma risk is raised lifelong. ALPS is classified by genotype rather than by organ or clinical course. Germline heterozygous FAS variants account for most cases (ALPS-FAS); somatic FAS variants confined to the double-negative T-cell compartment (ALPS-sFAS) explain a substantial further share and are the reason the disease long looked non-Mendelian; FASLG and CASP10 defects are rare; and a residual group with the phenotype but no identified lesion is designated ALPS-U. This root entry carries only what holds for ALPS as a whole — the genotype-based classification axis, the shared apoptosis-defect mechanism, and the shared consequences. The FAS-specific detail, including diagnostics and management, is not re-derived here: see `FAS-related_Autoimmune_Lymphoproliferative_Syndrome.yaml`. `CTLA4_Haploinsufficiency.yaml` and `CD27-related_lymphoproliferative_and_immune_disorder.yaml` cover ALPS-like disorders that reach a similar phenotype by other routes.

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1
Inheritance
3
Pathophys.
4
Phenotypes
1
Gaps
3
Pathograph
5
Subtypes
🏷

Classifications

IUIS Category
immune dysregulation
👪

Inheritance

1
Autosomal dominant (germline FAS, incomplete penetrance) HP:0000006
Most ALPS is caused by a heterozygous germline FAS variant acting through a dominant-negative mechanism on the trimeric death receptor. Penetrance is markedly incomplete: healthy relatives frequently carry the same variant, which is why a second, somatic hit in the double-negative T-cell compartment is thought to be required for overt disease in many families.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29911256 SUPPORT Human Clinical
"The ALPS-FAS was the first description of a monogenic cause of autoimmunity, but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients."
States the non-Mendelian behaviour of ALPS-FAS explicitly and attributes its resolution to the recognition of combined somatic and germline variants.
◆

Subtypes

5
ALPS-FAS (germline FAS defect) MONDO:1060194
FAS hgnc:11920 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FAS (hgnc:11920). hgnc:11920 is a gene from the HUGO Gene Nomenclature Committee.
The commonest form, caused by germline FAS variants impairing Fas-mediated apoptosis. Historically ALPS type Ia. Fully curated in `FAS-related_Autoimmune_Lymphoproliferative_Syndrome.yaml`.
ALPS-sFAS (somatic FAS defect)
FAS hgnc:11920 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FAS (hgnc:11920). hgnc:11920 is a gene from the HUGO Gene Nomenclature Committee.
Caused by somatic FAS variants restricted to the double-negative T-cell compartment rather than present in the germline. Clinically indistinguishable from ALPS-FAS but not transmitted, and missed by germline-only sequencing of unsorted blood. No separate MONDO term is bound here: MONDO does not currently carve the somatic form out from FAS-related ALPS.
ALPS-FASLG (FAS ligand defect)
FASLG hgnc:11936 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in FASLG (hgnc:11936). hgnc:11936 is a gene from the HUGO Gene Nomenclature Committee.
Rare, and usually biallelic. Homozygous FASLG variants abolish FasL cytotoxicity and produce early-onset severe ALPS; heterozygous variants impair FasL function biochemically but generally do not produce the ALPS biomarker profile, so heterozygous loss of function is better tolerated for FASLG than for FAS.
Show evidence (2 references)
PMID:36621650 SUPPORT Human Clinical
"Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised vitamin B12, and usually no soluble FasL."
Establishes the zygosity asymmetry that defines this subtype: homozygous FASLG abrogates cytotoxicity and causes severe early-onset ALPS.
PMID:36621650 SUPPORT Human Clinical
"Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG."
The authors' own conclusion explaining why ALPS-FASLG is rare, and a caution against calling heterozygous FASLG variants causal.
ALPS-CASP10 (caspase-10 defect) MONDO:0011383
Rare autosomal dominant form with incomplete penetrance caused by CASP10 variants acting downstream of the Fas receptor, historically ALPS type IIa. Presents with the same double-negative T-cell expansion, autoimmune cytopenias and chronic lymphadenopathy as ALPS-FAS.
ALPS-U (undetermined genetic defect)
Patients meeting the diagnostic criteria for ALPS, including the required double-negative T-cell expansion and defective in-vitro apoptosis, in whom no causative lesion in the Fas pathway has been identified. Retained as an explicit category by the revised classification rather than treated as undiagnosed disease.
?

Discussions and Knowledge Gaps

1
Which ALPS-like disorders belong inside the ALPS concept, and which are separate diseases that merely share its phenotype?
KNOWLEDGE GAP alps_scope_after_2009_reclassification
Attached to
pathophysiology#Defective Fas-Mediated Lymphocyte Apoptosis
The 2009 NIH revision narrowed ALPS to defects of the Fas apoptosis pathway and moved several conditions that had carried ALPS type numbers out of the syndrome — caspase-8 deficiency (historically ALPS type IIb) and RAS-associated autoimmune leukoproliferative disease (historically ALPS type IV) are the clearest cases, PRKCD-related type 3 disease is a third, and CTLA4 haploinsufficiency and CD27 deficiency reach an ALPS-like phenotype without a Fas-pathway lesion at all. MONDO still carries several of these as descendants of `MONDO:0017979`, so the ontology and the clinical classification disagree. This entry follows the narrow Fas-pathway definition and binds only Fas-pathway subtypes, but the boundary is a curation decision rather than a settled fact, and it determines whether the KB's ALPS-like entries should be members here or siblings.
Show evidence (1 reference)
PMID:29911256 SUPPORT Human Clinical
"The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic defects of this apoptosis pathway, such as FADD and CASPASE 8 deficiencies."
Explicitly distinguishes ALPS-FAS from other monogenic defects of the same apoptosis pathway, which is the distinction the scope question turns on.
⚙

Pathophysiology

3
Defective Fas-Mediated Lymphocyte Apoptosis
The initiating lesion in every genetically defined form of ALPS is loss of function somewhere in the FAS death receptor pathway — the receptor itself (FAS), its ligand (FASLG), or the downstream initiator caspase (CASP10). Engagement of Fas by FasL normally assembles a death-inducing signalling complex and triggers extrinsic apoptosis; in ALPS that signal fails. Most germline FAS variants act in a dominant-negative fashion, which is why heterozygosity suffices for FAS while FASLG generally requires biallelic loss.
FAS hgnc:11920 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FAS (hgnc:11920), qualified as loss of function. hgnc:11920 is a gene from the HUGO Gene Nomenclature Committee. ⇓ LOSS OF FUNCTION FASLG hgnc:11936 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FASLG (hgnc:11936), qualified as loss of function. hgnc:11936 is a gene from the HUGO Gene Nomenclature Committee. ⇓ LOSS OF FUNCTION
extrinsic apoptotic signaling pathway via death domain receptors GO:0008625 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625). GO:0008625 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Lymphocyte Homeostasis and Accumulation of Autoreactive Cells Fas-mediated apoptosis is the mechanism that contracts an activated lymphocyte pool once antigen is cleared and deletes autoreactive clones in the periphery. Losing it leaves both populations in place.
Show evidence (2 references)
PMID:36621650 SUPPORT Human Clinical
"Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers."
States the causal lesion (loss of function in FAS or FASLG) and names the resulting cellular hallmark in the same sentence.
PMID:29911256 SUPPORT Human Clinical
"The genetic etiology of the ALPS was described in 1995 by the discovery of the FAS gene mutations."
Anchors FAS as the founding genetic aetiology of the syndrome.
Failure of Lymphocyte Homeostasis and Accumulation of Autoreactive Cells
Lymphocytes that should have been deleted persist. Two consequences follow and together define the syndrome. First, the surviving pool includes autoreactive clones, producing autoimmunity that is directed predominantly at blood cells rather than at solid organs. Second, a normally rare population of alpha-beta T cells that have lost both CD4 and CD8 expands markedly, because Fas-mediated deletion is precisely the route by which these cells are normally removed. That expansion is the diagnostic hallmark of ALPS rather than an incidental finding.
lymphocyte homeostasis GO:0002260 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves lymphocyte homeostasis (GO:0002260), qualified as loss of function. GO:0002260 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION activation-induced cell death of T cells GO:0006924 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased activation-induced cell death of T cells (GO:0006924). GO:0006924 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Chronic Lymphoproliferation, Autoimmune Cytopenias and Lymphoma Risk The accumulated lymphocyte mass presents clinically as chronic lymphadenopathy and splenomegaly, the autoreactive fraction as multilineage cytopenias, and the undeleted long-lived B-cell pool as a lifelong excess risk of lymphoma.
Show evidence (2 references)
PMID:29911256 SUPPORT Human Clinical
"The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia."
Characterises ALPS as uncontrolled, non-malignant, non-infectious lymphocyte proliferation accompanied by autoimmune cytopenia — the two arms of this node.
PMID:36621650 SUPPORT Human Clinical
"Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers."
Names expanded double-negative T cells as the characteristic cellular consequence.
Chronic Lymphoproliferation, Autoimmune Cytopenias and Lymphoma Risk
The clinical syndrome. Lymphadenopathy and splenomegaly are chronic, non-malignant and non-infectious, which is what distinguishes ALPS from the lymphoma and infection it mimics; the cytopenias are immune-mediated and multilineage; and the lymphoma risk persists for life, so resolution of childhood lymphoproliferation does not end surveillance.
Show evidence (1 reference)
PMID:20538792 SUPPORT Human Clinical
"Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosis resulting in an accumulation of lymphocytes and childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, and an increased risk of B-cell lymphoma."
The definitional statement of the clinical phenotype from the criteria paper.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autoimmune Lymphoproliferative Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Blood 2
Autoimmune Hemolytic Anemia HP:0001890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hemolytic anemia (HP:0001890). HP:0001890 is a phenotype from the Human Phenotype Ontology.
Autoimmune Thrombocytopenia HP:0001973 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune thrombocytopenia (HP:0001973). HP:0001973 is a phenotype from the Human Phenotype Ontology.
Cardiovascular 2
Chronic Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716), qualified as temporality chronic. HP:0002716 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744), qualified as temporality chronic. HP:0001744 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
🔬

Diagnosis

1
Alpha-Beta Double-Negative T Cell Quantification
Flow-cytometric measurement of circulating CD3+ TCR-alpha/beta+ CD4- CD8- T cells. An expanded double-negative T-cell population in the presence of chronic non-malignant lymphoproliferation is the required cellular criterion for ALPS, and the same compartment is where somatic FAS variants are found — so sorting it before sequencing is what makes ALPS-sFAS detectable.
Show evidence (1 reference)
PMID:36621650 SUPPORT Human Clinical
"Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers."
Names expanded double-negative T cells and elevated serum biomarkers as the characteristic diagnostic profile of ALPS.
{ }

Source YAML

click to show 
name: Autoimmune Lymphoproliferative Syndrome
creation_date: '2026-08-19T12:00:00Z'
category: Mendelian
description: >
  Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity in
  which lymphocytes fail to undergo Fas-mediated apoptosis. Because the FAS death
  receptor pathway is what normally removes activated and autoreactive lymphocytes
  once an immune response has resolved, a defect in it produces the syndrome's
  defining triad: chronic non-malignant lymphoproliferation (lymphadenopathy and
  splenomegaly), autoimmunity directed mainly at blood cells, and an expanded
  population of alpha-beta double-negative (CD3+ CD4- CD8-) T cells that has no normal
  clearance route. Lymphoma risk is raised lifelong.

  ALPS is classified by genotype rather than by organ or clinical course. Germline
  heterozygous FAS variants account for most cases (ALPS-FAS); somatic FAS variants
  confined to the double-negative T-cell compartment (ALPS-sFAS) explain a substantial
  further share and are the reason the disease long looked non-Mendelian; FASLG and
  CASP10 defects are rare; and a residual group with the phenotype but no identified
  lesion is designated ALPS-U.

  This root entry carries only what holds for ALPS as a whole — the genotype-based
  classification axis, the shared apoptosis-defect mechanism, and the shared
  consequences. The FAS-specific detail, including diagnostics and management, is not
  re-derived here: see `FAS-related_Autoimmune_Lymphoproliferative_Syndrome.yaml`.
  `CTLA4_Haploinsufficiency.yaml` and `CD27-related_lymphoproliferative_and_immune_disorder.yaml`
  cover ALPS-like disorders that reach a similar phenotype by other routes.
disease_term:
  preferred_term: autoimmune lymphoproliferative syndrome
  term:
    id: MONDO:0017979
    label: autoimmune lymphoproliferative syndrome
synonyms:
- ALPS
- Canale-Smith syndrome
categories:
- Inborn Error of Immunity
- Immune Dysregulation
- Lymphoproliferative Disorder
parents:
- Primary Immunodeficiency
- Autoimmune Disorder
- Lymphoproliferative Disorder

classifications:
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      IUIS phenotypic classification, diseases of immune dysregulation (Table 4)
      — the group that contains ALPS and the ALPS-like disorders. Matches the
      classification already recorded on
      `FAS-related_Autoimmune_Lymphoproliferative_Syndrome.yaml`. ALPS presents
      as lymphoproliferation and autoimmunity from failed apoptotic control of
      the adaptive response, not as susceptibility to infection, which is what
      separates Table 4 from the deficiency tables.
    evidence:
    - reference: PMID:29911256
      reference_title: >-
        The Autoimmune Lymphoproliferative Syndrome with Defective FAS or
        FAS-Ligand Functions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant
        and non-infectious uncontrolled proliferation of lymphocytes accompanied
        by autoimmune cytopenia.
      explanation: >-
        Characterizes ALPS as uncontrolled lymphoproliferation with
        autoimmunity, and explicitly as non-infectious — the immune-dysregulation
        phenotype that defines IUIS Table 4.
inheritance:
- name: Autosomal dominant (germline FAS, incomplete penetrance)
  description: >-
    Most ALPS is caused by a heterozygous germline FAS variant acting through a
    dominant-negative mechanism on the trimeric death receptor. Penetrance is markedly
    incomplete: healthy relatives frequently carry the same variant, which is why a
    second, somatic hit in the double-negative T-cell compartment is thought to be
    required for overt disease in many families.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29911256
    reference_title: >-
      The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand
      Functions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ALPS-FAS was the first description of a monogenic cause of autoimmunity, but its non-Mendelian expression remained elusive until the description of somatic and germline mutations in ALPS patients."
    explanation: >-
      States the non-Mendelian behaviour of ALPS-FAS explicitly and attributes its
      resolution to the recognition of combined somatic and germline variants.

has_subtypes:
- name: ALPS-FAS
  display_name: ALPS-FAS (germline FAS defect)
  classification: genetic
  description: >-
    The commonest form, caused by germline FAS variants impairing Fas-mediated
    apoptosis. Historically ALPS type Ia. Fully curated in
    `FAS-related_Autoimmune_Lymphoproliferative_Syndrome.yaml`.
  subtype_term:
    preferred_term: FAS-related autoimmune lymphoproliferative immune disorder
    term:
      id: MONDO:1060194
      label: FAS-related autoimmune lymphoproliferative immune disorder
  genes:
  - preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
- name: ALPS-sFAS
  display_name: ALPS-sFAS (somatic FAS defect)
  classification: genetic
  description: >-
    Caused by somatic FAS variants restricted to the double-negative T-cell
    compartment rather than present in the germline. Clinically indistinguishable from
    ALPS-FAS but not transmitted, and missed by germline-only sequencing of unsorted
    blood. No separate MONDO term is bound here: MONDO does not currently carve the
    somatic form out from FAS-related ALPS.
  genes:
  - preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
- name: ALPS-FASLG
  display_name: ALPS-FASLG (FAS ligand defect)
  classification: genetic
  description: >-
    Rare, and usually biallelic. Homozygous FASLG variants abolish FasL cytotoxicity
    and produce early-onset severe ALPS; heterozygous variants impair FasL function
    biochemically but generally do not produce the ALPS biomarker profile, so
    heterozygous loss of function is better tolerated for FASLG than for FAS.
  genes:
  - preferred_term: FASLG
    term:
      id: hgnc:11936
      label: FASLG
  evidence:
  - reference: PMID:36621650
    reference_title: >-
      Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous FASLG variants abrogated cytotoxicity and resulted in early-onset severe ALPS with elevated DNT, raised vitamin B12, and usually no soluble FasL."
    explanation: >-
      Establishes the zygosity asymmetry that defines this subtype: homozygous FASLG
      abrogates cytotoxicity and causes severe early-onset ALPS.
  - reference: PMID:36621650
    reference_title: >-
      Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous loss-of-function mutations are better tolerated for FASLG than for FAS, which may explain the low frequency of ALPS-FASLG."
    explanation: >-
      The authors' own conclusion explaining why ALPS-FASLG is rare, and a caution
      against calling heterozygous FASLG variants causal.
- name: ALPS-CASP10
  display_name: ALPS-CASP10 (caspase-10 defect)
  classification: genetic
  description: >-
    Rare autosomal dominant form with incomplete penetrance caused by CASP10 variants
    acting downstream of the Fas receptor, historically ALPS type IIa. Presents with
    the same double-negative T-cell expansion, autoimmune cytopenias and chronic
    lymphadenopathy as ALPS-FAS.
  subtype_term:
    preferred_term: autoimmune lymphoproliferative syndrome type 2A
    term:
      id: MONDO:0011383
      label: autoimmune lymphoproliferative syndrome type 2A
- name: ALPS-U
  display_name: ALPS-U (undetermined genetic defect)
  classification: genetic
  description: >-
    Patients meeting the diagnostic criteria for ALPS, including the required
    double-negative T-cell expansion and defective in-vitro apoptosis, in whom no
    causative lesion in the Fas pathway has been identified. Retained as an explicit
    category by the revised classification rather than treated as undiagnosed disease.

pathophysiology:
- name: Defective Fas-Mediated Lymphocyte Apoptosis
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The initiating lesion in every genetically defined form of ALPS is loss of function
    somewhere in the FAS death receptor pathway — the receptor itself (FAS), its ligand
    (FASLG), or the downstream initiator caspase (CASP10). Engagement of Fas by FasL
    normally assembles a death-inducing signalling complex and triggers extrinsic
    apoptosis; in ALPS that signal fails. Most germline FAS variants act in a
    dominant-negative fashion, which is why heterozygosity suffices for FAS while
    FASLG generally requires biallelic loss.
  genes:
  - preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
    modifier: LOSS_OF_FUNCTION
  - preferred_term: FASLG
    term:
      id: hgnc:11936
      label: FASLG
    modifier: LOSS_OF_FUNCTION
  biological_processes:
  - preferred_term: extrinsic apoptotic signaling pathway via death domain receptors
    term:
      id: GO:0008625
      label: extrinsic apoptotic signaling pathway via death domain receptors
    modifier: DECREASED
  evidence:
  - reference: PMID:36621650
    reference_title: >-
      Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers."
    explanation: >-
      States the causal lesion (loss of function in FAS or FASLG) and names the
      resulting cellular hallmark in the same sentence.
  - reference: PMID:29911256
    reference_title: >-
      The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand
      Functions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The genetic etiology of the ALPS was described in 1995 by the discovery of the FAS gene mutations."
    explanation: >-
      Anchors FAS as the founding genetic aetiology of the syndrome.
  downstream:
  - target: Failure of Lymphocyte Homeostasis and Accumulation of Autoreactive Cells
    causal_link_type: DIRECT
    description: >-
      Fas-mediated apoptosis is the mechanism that contracts an activated lymphocyte
      pool once antigen is cleared and deletes autoreactive clones in the periphery.
      Losing it leaves both populations in place.
    evidence:
    - reference: PMID:29911256
      reference_title: >-
        The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand
        Functions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic defects of this apoptosis pathway, such as FADD and CASPASE 8 deficiencies."
      explanation: >-
        Directly attributes the accumulation of autoreactive lymphocytes to the
        apoptosis defect.

- name: Failure of Lymphocyte Homeostasis and Accumulation of Autoreactive Cells
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Lymphocytes that should have been deleted persist. Two consequences follow and
    together define the syndrome. First, the surviving pool includes autoreactive
    clones, producing autoimmunity that is directed predominantly at blood cells rather
    than at solid organs. Second, a normally rare population of alpha-beta T cells that
    have lost both CD4 and CD8 expands markedly, because Fas-mediated deletion is
    precisely the route by which these cells are normally removed. That expansion is
    the diagnostic hallmark of ALPS rather than an incidental finding.
  biological_processes:
  - preferred_term: lymphocyte homeostasis
    term:
      id: GO:0002260
      label: lymphocyte homeostasis
    modifier: LOSS_OF_FUNCTION
  - preferred_term: activation-induced cell death of T cells
    term:
      id: GO:0006924
      label: activation-induced cell death of T cells
    modifier: DECREASED
  evidence:
  - reference: PMID:29911256
    reference_title: >-
      The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand
      Functions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant and non-infectious uncontrolled proliferation of lymphocytes accompanied by autoimmune cytopenia."
    explanation: >-
      Characterises ALPS as uncontrolled, non-malignant, non-infectious lymphocyte
      proliferation accompanied by autoimmune cytopenia — the two arms of this node.
  - reference: PMID:36621650
    reference_title: >-
      Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers."
    explanation: >-
      Names expanded double-negative T cells as the characteristic cellular consequence.
  downstream:
  - target: Chronic Lymphoproliferation, Autoimmune Cytopenias and Lymphoma Risk
    causal_link_type: DIRECT
    description: >-
      The accumulated lymphocyte mass presents clinically as chronic lymphadenopathy and
      splenomegaly, the autoreactive fraction as multilineage cytopenias, and the
      undeleted long-lived B-cell pool as a lifelong excess risk of lymphoma.
    evidence:
    - reference: PMID:20538792
      reference_title: >-
        Revised diagnostic criteria and classification for the autoimmune
        lymphoproliferative syndrome (ALPS): report from the 2009 NIH International
        Workshop.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosis resulting in an accumulation of lymphocytes and childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, and an increased risk of B-cell lymphoma."
      explanation: >-
        Lists the clinical consequences of the apoptosis defect as a single causal
        statement, including the raised lymphoma risk.

- name: Chronic Lymphoproliferation, Autoimmune Cytopenias and Lymphoma Risk
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical syndrome. Lymphadenopathy and splenomegaly are chronic, non-malignant
    and non-infectious, which is what distinguishes ALPS from the lymphoma and infection
    it mimics; the cytopenias are immune-mediated and multilineage; and the lymphoma
    risk persists for life, so resolution of childhood lymphoproliferation does not end
    surveillance.
  evidence:
  - reference: PMID:20538792
    reference_title: >-
      Revised diagnostic criteria and classification for the autoimmune
      lymphoproliferative syndrome (ALPS): report from the 2009 NIH International
      Workshop.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune lymphoproliferative syndrome (ALPS) is a human genetic disorder of lymphocyte apoptosis resulting in an accumulation of lymphocytes and childhood onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, and an increased risk of B-cell lymphoma."
    explanation: >-
      The definitional statement of the clinical phenotype from the criteria paper.

phenotypes:
- category: Clinical
  name: Chronic Lymphadenopathy
  description: >-
    Chronic, non-malignant, non-infectious lymph node enlargement, typically of
    childhood onset and often the presenting complaint.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
    temporality: CHRONIC
- category: Clinical
  name: Splenomegaly
  description: Chronic splenic enlargement from accumulated lymphocytes.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
    temporality: CHRONIC
- category: Hematologic
  name: Autoimmune Hemolytic Anemia
  description: >-
    Immune-mediated destruction of erythrocytes, one component of the characteristic
    multilineage autoimmune cytopenia.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
- category: Hematologic
  name: Autoimmune Thrombocytopenia
  description: Immune-mediated destruction of platelets.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia

diagnosis:
- name: Alpha-Beta Double-Negative T Cell Quantification
  description: >-
    Flow-cytometric measurement of circulating CD3+ TCR-alpha/beta+ CD4- CD8- T cells.
    An expanded double-negative T-cell population in the presence of chronic
    non-malignant lymphoproliferation is the required cellular criterion for ALPS, and
    the same compartment is where somatic FAS variants are found — so sorting it before
    sequencing is what makes ALPS-sFAS detectable.
  evidence:
  - reference: PMID:36621650
    reference_title: >-
      Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers."
    explanation: >-
      Names expanded double-negative T cells and elevated serum biomarkers as the
      characteristic diagnostic profile of ALPS.

discussions:
- discussion_id: alps_scope_after_2009_reclassification
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Defective Fas-Mediated Lymphocyte Apoptosis"
  prompt: >-
    Which ALPS-like disorders belong inside the ALPS concept, and which are separate
    diseases that merely share its phenotype?
  rationale: >-
    The 2009 NIH revision narrowed ALPS to defects of the Fas apoptosis pathway and
    moved several conditions that had carried ALPS type numbers out of the syndrome —
    caspase-8 deficiency (historically ALPS type IIb) and RAS-associated autoimmune
    leukoproliferative disease (historically ALPS type IV) are the clearest cases,
    PRKCD-related type 3 disease is a third, and CTLA4 haploinsufficiency and CD27
    deficiency reach an ALPS-like phenotype without a Fas-pathway lesion at all. MONDO
    still carries several of these as descendants of
    `MONDO:0017979`, so the ontology and the clinical classification disagree. This
    entry follows the narrow Fas-pathway definition and binds only Fas-pathway subtypes,
    but the boundary is a curation decision rather than a settled fact, and it
    determines whether the KB's ALPS-like entries should be members here or siblings.
  evidence:
  - reference: PMID:29911256
    reference_title: >-
      The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand
      Functions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The related apoptosis defect accounts for the accumulation of autoreactive lymphocytes as well as for specific clinical and biological features that distinguish the ALPS-FAS from other monogenic defects of this apoptosis pathway, such as FADD and CASPASE 8 deficiencies."
    explanation: >-
      Explicitly distinguishes ALPS-FAS from other monogenic defects of the same
      apoptosis pathway, which is the distinction the scope question turns on.

notes: >
  Scope. A thin root over an already-curated subtree.
  `FAS-related_Autoimmune_Lymphoproliferative_Syndrome.yaml` holds the FAS-specific
  pathophysiology, diagnostics and treatment in depth; this entry binds MONDO:0017979
  and carries the genotype classification axis and the shared apoptosis-defect chain
  once. No treatment section is curated here on purpose — management (sirolimus,
  mycophenolate, the avoidance of splenectomy) is subtype- and severity-driven and is
  already curated on the FAS entry.

  Subtype term binding. ALPS-FAS and ALPS-CASP10 are bound to MONDO terms whose causal
  gene was verified against the MONDO record (`RO:0004003` HGNC:11920 FAS and HGNC:1500
  CASP10 respectively). ALPS-sFAS and ALPS-U are deliberately left unbound: MONDO does
  not separate the somatic form from FAS-related ALPS, and ALPS-U is by definition a
  residual category. ALPS-FASLG is likewise unbound — no MONDO term was found that
  specifically denotes the FASLG form.

  Deliberately excluded. Caspase-8 deficiency (MONDO:0011804, historically ALPS type
  IIb) and RAS-associated autoimmune leukoproliferative disease (MONDO:0013767,
  historically ALPS type IV, NRAS/KRAS) are MONDO descendants of ALPS but were moved out
  of the syndrome by the 2009 reclassification and are not curated as subtypes here.
  CTLA4 haploinsufficiency (MONDO:0014493) is likewise a MONDO descendant but is an
  ALPS-like disorder of a different mechanism and already has its own entry. The
  remaining two MONDO descendants, type 3 ALPS (MONDO:8000023) and its PRKCD-caused form
  (MONDO:8000024), are also excluded: PRKCD deficiency is conventionally an ALPS-like
  disorder rather than one of the 2009 NIH Fas-pathway subtypes. The exclusion list is
  therefore complete against MONDO's current descendants of MONDO:0017979. See the
  `alps_scope_after_2009_reclassification` discussion.