FAS-related Autoimmune Lymphoproliferative Syndrome

Mendelian MONDO:1060194 Pathograph 19 Primary Immunodeficiency Autoimmune Disorder Lymphoproliferative Disorder

FAS-related autoimmune lymphoproliferative syndrome is an inborn error of immunity caused by pathogenic FAS variants that impair Fas-mediated apoptosis and disrupt lymphocyte homeostasis. The classical phenotype corresponds to the dominant historical ALPS-Ia form, the most common molecular subtype of ALPS, and is characterized by chronic non-malignant lymphadenopathy or hepatosplenomegaly, autoimmune cytopenias, expansion of alpha-beta double-negative T cells, and lifelong lymphoma predisposition.

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1
Inheritance
4
Pathophys.
10
Phenotypes
19
Pathograph
1
Genes
10
Treatments
2
Subtypes
1
References
2
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
The classical FAS-related ALPS phenotype is usually inherited in an autosomal dominant manner with incomplete penetrance. Many affected families segregate heterozygous FAS death-domain variants, but clinically unaffected carriers can occur. Somatic FAS ALPS is not inherited and should be distinguished from germline FAS ALPS for recurrence-risk counseling.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (4 references)
PMID:21447005 SUPPORT Other
"Majority of patients with ALPS harbor heterozygous germline mutations in the gene for the TNF receptor-family member Fas (CD 95, Apo-1) which are inherited in an autosomal dominant fashion."
Review evidence that the predominant FAS-related ALPS form is due to heterozygous germline FAS variants with dominant transmission.
PMID:12732128 SUPPORT Human Clinical
"The molecular study of these families confirms a diagnosis of ALPS and suggests that the causing defect of this syndrome is compatible with an autosomal dominant inheritance with incomplete penetrance."
Family-based human genetic evidence directly supports autosomal dominant inheritance with incomplete penetrance.
PMID:24398331 SUPPORT Human Clinical
"FAS mutations have a clinical penetrance of <60%"
The NIH natural-history cohort quantifies incomplete clinical penetrance among individuals with FAS mutations.
+ 1 more reference
◆

Subtypes

2
Germline FAS ALPS
Canonical ALPS-FAS caused by germline heterozygous FAS pathogenic variants, usually autosomal dominant with incomplete penetrance. Dominant-negative intracellular death-domain variants tend to have higher penetrance and greater lymphoma risk than haploinsufficient extracellular variants.
Show evidence (1 reference)
PMID:22157362 SUPPORT Other
"disease penetrance appears to be much higher in families with dominant negative intracellular mutations compared with haploinsufficient extracellular mutations."
This review supports separating germline FAS ALPS by dominant-negative versus haploinsufficient variant mechanism and penetrance.
Somatic FAS ALPS
Acquired ALPS-FAS subtype caused by somatic FAS pathogenic variants enriched in selected cell populations, especially alpha-beta double-negative T cells; recurrence counseling differs from germline FAS ALPS.
Show evidence (1 reference)
PMID:22157362 SUPPORT Other
"A significant subset of ALPS patients have somatic FAS mutations, primarily limited to the non-thymic double negative T cell (DNT) compartment."
This supports structuring somatic FAS ALPS separately from inherited germline FAS ALPS.
⚙

Pathophysiology

4
Defective Fas-mediated apoptosis of activated lymphocytes
Pathogenic FAS variants impair signaling through the Fas death receptor and blunt activation-induced cell death of mature lymphocytes. This failure of peripheral deletion is the core molecular lesion underlying FAS-related ALPS.
T cell link alpha-beta T cell link
activation-induced cell death of T cells link ↓ DECREASED extrinsic apoptotic signaling pathway via death domain receptors link ↓ DECREASED
Downstream
Chronic lymphocyte accumulation and double-negative T-cell expansion
Persistence of autoreactive lymphocytes and autoimmune cytopenias
Lymphoma predisposition
Show evidence (2 references)
PMID:12732128 SUPPORT Human Clinical
"In family A, in vitro Fas-mediated apoptosis was absent in the patient and markedly reduced in his father."
Human functional testing directly shows defective Fas-mediated apoptosis in mutation carriers.
PMID:22157362 SUPPORT Other
"Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway."
Review evidence frames the disease as a primary failure of the Fas apoptotic pathway.
Chronic lymphocyte accumulation and double-negative T-cell expansion
Because activated lymphocytes are not efficiently deleted, lymphoid mass accumulates and the characteristic circulating alpha-beta double-negative T cell population expands. Clinically this drives chronic, non-infectious, non-malignant lymphadenopathy and hepatosplenomegaly.
lymphocyte link alpha-beta T cell link
lymphocyte homeostasis link ↓ DECREASED
Show evidence (2 references)
PMID:21885601 SUPPORT Other
"Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy,..."
Review evidence directly links failed apoptotic homeostasis to lymphoid accumulation, lymphadenopathy, and hepatosplenomegaly.
PMID:23850805 SUPPORT Human Clinical
"Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/β(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations."
Prospective cohort evidence anchors expanded alpha-beta double-negative T cells as a characteristic cellular feature of FAS-mutant ALPS.
Persistence of autoreactive lymphocytes and autoimmune cytopenias
Failed deletion of activated lymphocytes allows autoreactive clones to persist, breaking peripheral tolerance and producing immune-mediated destruction of multiple hematopoietic lineages.
T cell link
tolerance induction dependent upon immune response link ↓ DECREASED
Show evidence (2 references)
PMID:21885601 SUPPORT Other
"Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia."
Review evidence identifies the canonical autoimmune cytopenias that arise downstream of failed lymphocyte tolerance.
PMID:20170754 SUPPORT Other
"While ALPS is one of the few autoimmune diseases with a known genetic defect, there remain unanswered questions regarding how a defect in apoptosis results in the observed phenotype."
Review evidence supports the central concept that defective apoptosis drives autoimmune manifestations in ALPS.
Lymphoma predisposition
Defective Fas-mediated apoptosis also weakens deletion of transformed or transformation-prone lymphocytes, creating a lifelong predisposition to lymphoma, especially B-cell and Hodgkin-type malignancies.
B cell link
extrinsic apoptotic signaling pathway via death domain receptors link ↓ DECREASED
Show evidence (2 references)
PMID:15160902 SUPPORT Other
"Individuals with germline mutations in the Fas gene have a high risk to develop non Hodgkin lymphomas (x 14) as well as Hodgkin lymphomas (x 51), in particular NLP Hodgkin lymphoma."
Review evidence quantifies the marked lymphoma predisposition associated with germline FAS mutations.
PMID:21885601 SUPPORT Other
"Some of these patients with FAS mutations affecting the intracellular portion of the FAS protein also have an increased risk of B-cell lymphoma."
Review evidence further links intracellular FAS mutations to B-cell lymphoma risk.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for FAS-related 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

10
Blood 4
Autoimmune hemolytic anemia Autoimmune hemolytic anemia (HP:0001890)
Show evidence (1 reference)
PMID:21885601 SUPPORT Other
"Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia."
Review evidence explicitly lists autoimmune hemolytic anemia among the canonical autoimmune cytopenias of ALPS.
Autoimmune thrombocytopenia Autoimmune thrombocytopenia (HP:0001973)
Show evidence (1 reference)
PMID:21885601 SUPPORT Other
"Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia."
Review evidence explicitly lists immune-mediated thrombocytopenia as a core autoimmune cytopenia in ALPS.
Decreased circulating immunoglobulin concentration OCCASIONAL Decreased circulating immunoglobulin concentration (HP:0004313)
Show evidence (1 reference)
PMID:19214977 PARTIAL Human Clinical
"Noted toxicities included profound and prolonged hypogammaglobulinemia in three patients requiring replacement IVIG"
This supports hypogammaglobulinemia as a clinically important immune finding in ALPS management, especially after rituximab exposure.
Lymphoma Lymphoma (HP:0002665)
Show evidence (1 reference)
PMID:15160902 SUPPORT Other
"Individuals with germline mutations in the Fas gene have a high risk to develop non Hodgkin lymphomas (x 14) as well as Hodgkin lymphomas (x 51), in particular NLP Hodgkin lymphoma."
Review evidence directly supports lymphoma as a major malignant complication of germline FAS-mutant ALPS.
Cardiovascular 2
Lymphadenopathy Lymphadenopathy (HP:0002716)
Show evidence (1 reference)
PMID:21885601 SUPPORT Other
"Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy,..."
Review evidence directly supports chronic non-malignant lymphadenopathy as a hallmark manifestation.
Hepatosplenomegaly Hepatosplenomegaly (HP:0001433)
Show evidence (1 reference)
PMID:21885601 SUPPORT Other
"Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of apoptotic mechanisms to maintain lymphocyte homeostasis, permitting accumulation of lymphoid mass and persistence of autoreactive cells that often manifest in childhood with chronic nonmalignant lymphadenopathy,..."
The same review abstract directly supports hepatosplenomegaly as part of the core lymphoproliferative phenotype.
Immune 1
Recurrent infections OCCASIONAL Recurrent infections (HP:0002719)
Show evidence (1 reference)
PMID:24398331 SUPPORT Human Clinical
"the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma."
The natural-history cohort identifies post-splenectomy sepsis as a major ALPS morbidity and mortality driver.
Other 3
Autoimmune neutropenia Autoimmune neutropenia (HP:0001904)
Show evidence (1 reference)
PMID:21885601 SUPPORT Other
"Cytopenias in these patients can be the result of splenic sequestration as well as autoimmune complications manifesting as autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia."
Review evidence explicitly lists autoimmune neutropenia among the multilineage cytopenias seen in ALPS.
Abnormal double-negative T cell proportion Abnormal double-negative T cell proportion (HP:0031399)
Show evidence (1 reference)
PMID:23993982 SUPPORT Human Clinical
"Biomarkers including elevated CD3+TCRαβ+CD4-CD8- double negative T cells (TCRαβ+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate between ALPS and common variable immunodeficiency (CVID) patients with an overlapping clinical phenotype."
Biomarker study supports elevated alpha-beta double-negative T cells as a distinguishing immunophenotypic feature of ALPS.
Increased circulating immunoglobulin concentration Increased circulating immunoglobulin concentration (HP:0010702)
Show evidence (1 reference)
PMID:22157362 SUPPORT Other
"Our group established that a combination of autoimmune cytopenias and hypergammaglobulinemia are very predictive of ALPS in patients with lymphoproliferation and elevated DNTs."
Review evidence supports hypergammaglobulinemia as a useful immune phenotype and diagnostic-context marker.
🧬

Genetic Associations

1
FAS (CAUSATIVE)
Autosomal dominant
Show evidence (3 references)
PMID:23850805 SUPPORT Human Clinical
"Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative..."
Prospective diagnostic study identifies FAS mutation as the most frequent molecular cause of ALPS.
PMID:12732128 SUPPORT Human Clinical
"Both mutations are located in exon 9 of TNFRSF6 gene, affecting the death domain of the Fas protein."
Human family study shows that pathogenic variants in the FAS death domain are a core mutational mechanism in classical ALPS-Ia.
PMID:22157362 SUPPORT Other
"A number of key observations have been made recently that better define the pathophysiology of ALPS, including the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mechanism of decreased Fas expression, and the description of multiple genetic hits in..."
Review evidence refines the allelic spectrum to include haploinsufficient and somatic FAS-driven disease mechanisms.
💊

Treatments

10
Sirolimus
Action: Pharmacotherapy NCIT:C15986
Agent: sirolimus ↗
mTOR inhibition with sirolimus is an effective steroid-sparing therapy for refractory autoimmune cytopenias and benign lymphoproliferation in ALPS, and can normalize the double-negative T-cell compartment.
Target Phenotypes: lymphadenopathy ↗ autoimmune thrombocytopenia ↗ hepatosplenomegaly ↗
Show evidence (3 references)
PMID:19208097 SUPPORT Human Clinical
"Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response."
Initial clinical series supports sirolimus efficacy against ALPS autoimmune cytopenias.
PMID:19208097 SUPPORT Human Clinical
"Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease."
The same series shows that sirolimus improves lymphoproliferation and the characteristic DNT-cell abnormality.
PMID:26504182 SUPPORT Human Clinical
"All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus."
Prospective trial evidence supports sirolimus as a highly active treatment for ALPS requiring chronic therapy.
Mycophenolate mofetil
Action: Pharmacotherapy NCIT:C15986
Agent: mycophenolate mofetil ↗
Mycophenolate mofetil is an established steroid-sparing immunosuppressive therapy for chronic autoimmune disease manifestations in ALPS, particularly when long-term corticosteroids should be avoided.
Show evidence (1 reference)
PMID:22157362 SUPPORT Other
"mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease."
Review evidence identifies mycophenolate mofetil as one of the two established steroid-sparing agents with marked activity in ALPS.
Corticosteroid pulses for acute autoimmune cytopenias
Action: corticosteroid agent therapy MAXO:0000640
Short corticosteroid pulses are used for acute or severe autoimmune cytopenia flares and selected severe lymphoproliferative complications, but chronic corticosteroid exposure should be minimized by steroid-sparing therapy when prolonged treatment is required.
Target Phenotypes: autoimmune hemolytic anemia ↗ autoimmune thrombocytopenia ↗ autoimmune neutropenia ↗
Show evidence (1 reference)
PMID:22157362 SUPPORT Other
"Most patients respond to short corticosteroid pulses."
This directly supports corticosteroids for acute ALPS autoimmune complications while avoiding chronic toxicity.
Immunoglobulin replacement or adjunct IVIg
Action: immunoglobulin infusion therapy MAXO:0001480
Immunoglobulin infusion is considered for clinically significant hypogammaglobulinemia or as adjunctive therapy in severe autoimmune cytopenia contexts, particularly when B-cell depletion has caused prolonged antibody deficiency.
Target Phenotypes: Decreased circulating immunoglobulin concentration ↗
Show evidence (1 reference)
PMID:19214977 SUPPORT Human Clinical
"profound and prolonged hypogammaglobulinemia in three patients requiring replacement IVIG"
This supports immunoglobulin replacement when ALPS treatment causes clinically significant antibody deficiency.
Rituximab for selected refractory cytopenias
Action: pharmacotherapy MAXO:0000058
Agent: rituximab ↗
Rituximab can be considered only after other immunosuppressive strategies fail or are not tolerated, because ALPS-specific toxicity includes prolonged hypogammaglobulinemia, impaired polysaccharide vaccine responses, and added infection risk, especially in asplenic patients.
Target Phenotypes: autoimmune thrombocytopenia ↗
Show evidence (2 references)
PMID:19214977 PARTIAL Human Clinical
"Seven out of 12 patients responded with stabilization of cytopenia for greater than 6 months."
This supports rituximab activity in selected refractory cytopenias but does not make it first-line therapy.
PMID:19214977 SUPPORT Human Clinical
"Toxicities including hypogammaglobulinemia and neutropenia constitute an additional infection risk burden"
This supports caution and later-line positioning for rituximab in ALPS.
Splenectomy avoidance
Splenectomy should be avoided whenever possible and reserved only as a last resort for life-threatening refractory cytopenias or severe hypersplenism after medical strategies fail, because post-splenectomy sepsis is a major cause of morbidity and mortality in ALPS-FAS.
Show evidence (2 references)
PMID:24398331 SUPPORT Human Clinical
"Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients."
The natural-history cohort identifies splenectomy avoidance as an outcome-improving management principle.
PMID:22157362 SUPPORT Other
"splenectomy should be avoided except in the case of uncontrolled hypersplenism that fails other medical management."
This review supports strict last-resort positioning for splenectomy.
Post-splenectomy antimicrobial prophylaxis and vaccination
Action: penicillin agent therapy MAXO:0000198
If splenectomy has already occurred or is unavoidable, infection-prevention planning should include penicillin prophylaxis, pneumococcal and other asplenia-appropriate vaccination, and urgent evaluation of febrile illness.
Target Phenotypes: Recurrent infections ↗
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1108/ SUPPORT Other
"Vaccinations pre-splenectomy (with consideration of post-splenectomy boost vaccinations) and penicillin prophylaxis are strongly recommended for individuals who undergo splenectomy."
GeneReviews directly supports vaccination and penicillin prophylaxis for individuals with ALPS who undergo splenectomy.
Lymphoma surveillance
Action: surveillance for malignancies MAXO:0001492
Lifelong clinical surveillance for lymphoma should focus on changes in disease pattern, constitutional symptoms, suspicious nodes or masses, CBC trends, LDH, and targeted imaging or biopsy when clinically indicated rather than routine serial PET/CT for stable benign lymphoproliferation.
Target Phenotypes: lymphoma ↗
Show evidence (1 reference)
PMID:22157362 SUPPORT Other
"Rather, we investigate for malignancy if patients develop constitutional symptoms or have a significant change in disease pattern."
This supports clinically triggered lymphoma surveillance and workup rather than indiscriminate routine imaging.
Hematopoietic stem cell transplantation for selected severe disease
Action: hematopoietic stem cell transplantation MAXO:0000747
HSCT is a potential curative option reserved for selected severe, refractory, life-threatening ALPS phenotypes, such as biallelic FAS disease, severe refractory autoimmune cytopenias, lymphoma-associated disease, or major complications of prolonged immunosuppression.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1108/ SUPPORT Other
"Bone marrow (hematopoietic stem cell) transplantation (BMT/HSCT) is currently the only curative treatment for ALPS."
GeneReviews supports HSCT as curative but reserved for selected severe presentations because of transplant risk.
Genetic counseling and family testing
Action: genetic counseling MAXO:0000079
Genetic counseling should distinguish germline autosomal dominant FAS ALPS with incomplete penetrance from somatic FAS ALPS, guide testing of at-risk relatives when a familial variant is known, and discuss genotype-specific penetrance and lymphoma-risk implications.
Show evidence (1 reference)
PMID:22157362 SUPPORT Other
"FAS mutations have variable penetrance, as ALPS patients often have family members with the same genetic alterations and an absent or very mild clinical phenotype"
This supports genotype-specific family counseling and at-risk relative evaluation in germline FAS ALPS.
{ }

Source YAML

click to show 
name: FAS-related Autoimmune Lymphoproliferative Syndrome
creation_date: "2026-04-16T00:00:00Z"
updated_date: "2026-04-19T00:00:00Z"
category: Mendelian
synonyms:
- ALPS-Ia
- autoimmune lymphoproliferative syndrome type IA
- autoimmune lymphoproliferative syndrome type 1A
description: >-
  FAS-related autoimmune lymphoproliferative syndrome is an inborn error of
  immunity caused by pathogenic FAS variants that impair Fas-mediated apoptosis
  and disrupt lymphocyte homeostasis. The classical phenotype corresponds to
  the dominant historical ALPS-Ia form, the most common molecular subtype of
  ALPS, and is characterized by chronic non-malignant lymphadenopathy or
  hepatosplenomegaly, autoimmune cytopenias, expansion of alpha-beta
  double-negative T cells, and lifelong lymphoma predisposition.
disease_term:
  preferred_term: FAS-related autoimmune lymphoproliferative immune disorder
  term:
    id: MONDO:1060194
    label: FAS-related autoimmune lymphoproliferative immune disorder
parents:
- Primary Immunodeficiency
- Autoimmune Disorder
- Lymphoproliferative Disorder
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1108/
  title: Autoimmune Lymphoproliferative Syndrome - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
  findings:
  - statement: >-
      GeneReviews provides the clinical baseline for ALPS diagnosis,
      management, surveillance, and genetic counseling.
    supporting_text: >-
      The diagnosis of ALPS is based on the following: Clinical findings;
      Laboratory abnormalities; Identification of pathogenic variants in genes
      relevant for the Fas pathway of apoptosis.
has_subtypes:
- name: Germline FAS ALPS
  description: >-
    Canonical ALPS-FAS caused by germline heterozygous FAS pathogenic variants,
    usually autosomal dominant with incomplete penetrance. Dominant-negative
    intracellular death-domain variants tend to have higher penetrance and
    greater lymphoma risk than haploinsufficient extracellular variants.
  evidence:
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      disease penetrance appears to be much higher in families with dominant
      negative intracellular mutations compared with haploinsufficient
      extracellular mutations.
    explanation: >-
      This review supports separating germline FAS ALPS by dominant-negative
      versus haploinsufficient variant mechanism and penetrance.
- name: Somatic FAS ALPS
  description: >-
    Acquired ALPS-FAS subtype caused by somatic FAS pathogenic variants enriched
    in selected cell populations, especially alpha-beta double-negative T cells;
    recurrence counseling differs from germline FAS ALPS.
  evidence:
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A significant subset of ALPS patients have somatic FAS mutations,
      primarily limited to the non-thymic double negative T cell (DNT)
      compartment.
    explanation: >-
      This supports structuring somatic FAS ALPS separately from inherited
      germline FAS ALPS.
tracked_issues:
- url: https://github.com/monarch-initiative/mondo/issues/9749
  title: FAS-related autoimmune lymphoproliferative syndrome
  tracked_issue_role: ontology_term_request
  tracked_issue_status: OPEN
  notes: >-
    ClinGen/MONDO term request that introduced the current gene-related disease
    label used here.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    The classical FAS-related ALPS phenotype is usually inherited in an
    autosomal dominant manner with incomplete penetrance. Many affected
    families segregate heterozygous FAS death-domain variants, but clinically
    unaffected carriers can occur. Somatic FAS ALPS is not inherited and should
    be distinguished from germline FAS ALPS for recurrence-risk counseling.
  evidence:
  - reference: PMID:21447005
    reference_title: "Advances in autoimmune lymphoproliferative syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Majority of patients with ALPS harbor heterozygous germline mutations in
      the gene for the TNF receptor-family member Fas (CD 95, Apo-1) which are
      inherited in an autosomal dominant fashion.
    explanation: >-
      Review evidence that the predominant FAS-related ALPS form is due to
      heterozygous germline FAS variants with dominant transmission.
  - reference: PMID:12732128
    reference_title: "[Autoimmune lymphoproliferative syndrome: molecular diagnosis in two families]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The molecular study of these families confirms a diagnosis of ALPS and
      suggests that the causing defect of this syndrome is compatible with an
      autosomal dominant inheritance with incomplete penetrance.
    explanation: >-
      Family-based human genetic evidence directly supports autosomal dominant
      inheritance with incomplete penetrance.
  - reference: PMID:24398331
    reference_title: >-
      Natural history of autoimmune lymphoproliferative syndrome associated
      with FAS gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FAS mutations have a clinical penetrance of <60%
    explanation: >-
      The NIH natural-history cohort quantifies incomplete clinical penetrance
      among individuals with FAS mutations.
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ALPS patients with germline and somatic-variant FAS mutations are
      phenotypically similar in both disease manifestations and laboratory
      abnormalities.
    explanation: >-
      This supports distinguishing inherited germline FAS ALPS from acquired
      somatic FAS ALPS despite overlapping clinical presentations.
genetic:
- name: FAS
  gene_term:
    preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
  association: CAUSATIVE
  features: >-
    Classical disease is usually caused by heterozygous germline FAS variants,
    especially lesions affecting the intracellular death domain, which impair
    receptor-mediated apoptosis of activated lymphocytes. Somatic FAS variants
    also occur, but the dominant germline form remains the canonical
    presentation of historical ALPS-Ia. Dominant-negative intracellular
    variants are associated with higher penetrance and lymphoma risk than
    haploinsufficient extracellular variants, while somatic variants are
    enriched in the double-negative T-cell compartment and generally imply
    sporadic rather than familial recurrence risk.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:23850805
    reference_title: "Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical and genetic heterogeneity renders confirmation or exclusion of
      autoimmune lymphoproliferative syndrome difficult. To re-evaluate and
      improve the currently suggested diagnostic approach to patients with
      suspected FAS mutation, the most frequent cause of autoimmune
      lymphoproliferative syndrome, we prospectively determined 11 biomarkers in
      163 patients with splenomegaly or lymphadenopathy and presumed or proven
      autoimmune cytopenia(s).
    explanation: >-
      Prospective diagnostic study identifies FAS mutation as the most frequent
      molecular cause of ALPS.
  - reference: PMID:12732128
    reference_title: "[Autoimmune lymphoproliferative syndrome: molecular diagnosis in two families]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both mutations are located in exon 9 of TNFRSF6 gene, affecting the death
      domain of the Fas protein.
    explanation: >-
      Human family study shows that pathogenic variants in the FAS death domain
      are a core mutational mechanism in classical ALPS-Ia.
  - reference: PMID:22157362
    reference_title: "New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A number of key observations have been made recently that better define
      the pathophysiology of ALPS, including the characterization of somatic FAS
      variant ALPS, the identification of haploinsufficiency as a mechanism of
      decreased Fas expression, and the description of multiple genetic hits in
      FAS in some families that may explain the variable penetrance of the
      disease.
    explanation: >-
      Review evidence refines the allelic spectrum to include haploinsufficient
      and somatic FAS-driven disease mechanisms.
pathophysiology:
- name: Defective Fas-mediated apoptosis of activated lymphocytes
  description: >-
    Pathogenic FAS variants impair signaling through the Fas death receptor and
    blunt activation-induced cell death of mature lymphocytes. This failure of
    peripheral deletion is the core molecular lesion underlying FAS-related
    ALPS.
  gene:
    preferred_term: FAS
    term:
      id: hgnc:11920
      label: FAS
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: alpha-beta T cell
    term:
      id: CL:0000789
      label: alpha-beta T cell
  biological_processes:
  - preferred_term: activation-induced cell death of T cells
    term:
      id: GO:0006924
      label: activation-induced cell death of T cells
    modifier: DECREASED
  - 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:12732128
    reference_title: "[Autoimmune lymphoproliferative syndrome: molecular diagnosis in two families]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In family A, in vitro Fas-mediated apoptosis was absent in the patient
      and markedly reduced in his father.
    explanation: >-
      Human functional testing directly shows defective Fas-mediated apoptosis
      in mutation carriers.
  - reference: PMID:22157362
    reference_title: "New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted
      lymphocyte homeostasis, resulting from mutations in the Fas apoptotic
      pathway.
    explanation: >-
      Review evidence frames the disease as a primary failure of the Fas
      apoptotic pathway.
  downstream:
  - target: Chronic lymphocyte accumulation and double-negative T-cell expansion
  - target: Persistence of autoreactive lymphocytes and autoimmune cytopenias
  - target: Lymphoma predisposition
- name: Chronic lymphocyte accumulation and double-negative T-cell expansion
  description: >-
    Because activated lymphocytes are not efficiently deleted, lymphoid mass
    accumulates and the characteristic circulating alpha-beta double-negative T
    cell population expands. Clinically this drives chronic, non-infectious,
    non-malignant lymphadenopathy and hepatosplenomegaly.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  - preferred_term: alpha-beta T cell
    term:
      id: CL:0000789
      label: alpha-beta T cell
  biological_processes:
  - preferred_term: lymphocyte homeostasis
    term:
      id: GO:0002260
      label: lymphocyte homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of
      apoptotic mechanisms to maintain lymphocyte homeostasis, permitting
      accumulation of lymphoid mass and persistence of autoreactive cells that
      often manifest in childhood with chronic nonmalignant lymphadenopathy,
      hepatosplenomegaly, and recurring multilineage cytopenias.
    explanation: >-
      Review evidence directly links failed apoptotic homeostasis to lymphoid
      accumulation, lymphadenopathy, and hepatosplenomegaly.
  - reference: PMID:23850805
    reference_title: "Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 98 patients sequenced for FAS mutations in
      CD3(+)TCRα/β(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and
      six had somatic FAS mutations.
    explanation: >-
      Prospective cohort evidence anchors expanded alpha-beta double-negative T
      cells as a characteristic cellular feature of FAS-mutant ALPS.
- name: Persistence of autoreactive lymphocytes and autoimmune cytopenias
  description: >-
    Failed deletion of activated lymphocytes allows autoreactive clones to
    persist, breaking peripheral tolerance and producing immune-mediated
    destruction of multiple hematopoietic lineages.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: tolerance induction dependent upon immune response
    term:
      id: GO:0002461
      label: tolerance induction dependent upon immune response
    modifier: DECREASED
  evidence:
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cytopenias in these patients can be the result of splenic sequestration
      as well as autoimmune complications manifesting as autoimmune hemolytic
      anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia.
    explanation: >-
      Review evidence identifies the canonical autoimmune cytopenias that arise
      downstream of failed lymphocyte tolerance.
  - reference: PMID:20170754
    reference_title: "The autoimmune lymphoproliferative syndrome: A rare disorder providing clues about normal tolerance."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While ALPS is one of the few autoimmune diseases with a known genetic
      defect, there remain unanswered questions regarding how a defect in
      apoptosis results in the observed phenotype.
    explanation: >-
      Review evidence supports the central concept that defective apoptosis
      drives autoimmune manifestations in ALPS.
- name: Lymphoma predisposition
  description: >-
    Defective Fas-mediated apoptosis also weakens deletion of transformed or
    transformation-prone lymphocytes, creating a lifelong predisposition to
    lymphoma, especially B-cell and Hodgkin-type malignancies.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  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:15160902
    reference_title: "Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with germline mutations in the Fas gene have a high risk to
      develop non Hodgkin lymphomas (x 14) as well as Hodgkin lymphomas (x 51),
      in particular NLP Hodgkin lymphoma.
    explanation: >-
      Review evidence quantifies the marked lymphoma predisposition associated
      with germline FAS mutations.
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some of these patients with FAS mutations affecting the intracellular
      portion of the FAS protein also have an increased risk of B-cell
      lymphoma.
    explanation: >-
      Review evidence further links intracellular FAS mutations to B-cell
      lymphoma risk.
phenotypes:
- name: Lymphadenopathy
  description: >-
    Chronic, non-malignant lymph node enlargement is a defining clinical
    manifestation of FAS-related ALPS.
  phenotype_term:
    preferred_term: lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of
      apoptotic mechanisms to maintain lymphocyte homeostasis, permitting
      accumulation of lymphoid mass and persistence of autoreactive cells that
      often manifest in childhood with chronic nonmalignant lymphadenopathy,
      hepatosplenomegaly, and recurring multilineage cytopenias.
    explanation: >-
      Review evidence directly supports chronic non-malignant lymphadenopathy
      as a hallmark manifestation.
- name: Hepatosplenomegaly
  description: >-
    Persistent enlargement of the liver and spleen reflects chronic benign
    lymphoid accumulation.
  phenotype_term:
    preferred_term: hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autoimmune lymphoproliferative syndrome (ALPS) represents a failure of
      apoptotic mechanisms to maintain lymphocyte homeostasis, permitting
      accumulation of lymphoid mass and persistence of autoreactive cells that
      often manifest in childhood with chronic nonmalignant lymphadenopathy,
      hepatosplenomegaly, and recurring multilineage cytopenias.
    explanation: >-
      The same review abstract directly supports hepatosplenomegaly as part of
      the core lymphoproliferative phenotype.
- name: Autoimmune hemolytic anemia
  description: >-
    Immune-mediated red-cell destruction is one of the most common autoimmune
    cytopenias in ALPS.
  phenotype_term:
    preferred_term: autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cytopenias in these patients can be the result of splenic sequestration
      as well as autoimmune complications manifesting as autoimmune hemolytic
      anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia.
    explanation: >-
      Review evidence explicitly lists autoimmune hemolytic anemia among the
      canonical autoimmune cytopenias of ALPS.
- name: Autoimmune thrombocytopenia
  description: >-
    Immune-mediated platelet destruction is a recurrent hematologic
    complication of FAS-related ALPS.
  phenotype_term:
    preferred_term: autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cytopenias in these patients can be the result of splenic sequestration
      as well as autoimmune complications manifesting as autoimmune hemolytic
      anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia.
    explanation: >-
      Review evidence explicitly lists immune-mediated thrombocytopenia as a
      core autoimmune cytopenia in ALPS.
- name: Autoimmune neutropenia
  description: >-
    Autoimmune neutropenia occurs as part of the multilineage cytopenia
    spectrum.
  phenotype_term:
    preferred_term: autoimmune neutropenia
    term:
      id: HP:0001904
      label: Autoimmune neutropenia
  evidence:
  - reference: PMID:21885601
    reference_title: "How I treat autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cytopenias in these patients can be the result of splenic sequestration
      as well as autoimmune complications manifesting as autoimmune hemolytic
      anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia.
    explanation: >-
      Review evidence explicitly lists autoimmune neutropenia among the
      multilineage cytopenias seen in ALPS.
- name: Abnormal double-negative T cell proportion
  description: >-
    Elevated circulating alpha-beta double-negative T cells are a characteristic
    immunophenotypic marker of FAS-related ALPS.
  phenotype_term:
    preferred_term: abnormal double-negative T cell proportion
    term:
      id: HP:0031399
      label: Abnormal double-negative T cell proportion
  evidence:
  - reference: PMID:23993982
    reference_title: "Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biomarkers including elevated CD3+TCRαβ+CD4-CD8- double negative T cells
      (TCRαβ+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate
      between ALPS and common variable immunodeficiency (CVID) patients with an
      overlapping clinical phenotype.
    explanation: >-
      Biomarker study supports elevated alpha-beta double-negative T cells as a
      distinguishing immunophenotypic feature of ALPS.
- name: Increased circulating immunoglobulin concentration
  description: >-
    Polyclonal hypergammaglobulinemia is a supportive immune-laboratory feature
    in ALPS, especially when combined with autoimmune cytopenias,
    lymphoproliferation, and elevated double-negative T cells.
  phenotype_term:
    preferred_term: Increased circulating immunoglobulin concentration
    term:
      id: HP:0010702
      label: Increased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Our group established that a combination of autoimmune cytopenias and
      hypergammaglobulinemia are very predictive of ALPS in patients with
      lymphoproliferation and elevated DNTs.
    explanation: >-
      Review evidence supports hypergammaglobulinemia as a useful immune
      phenotype and diagnostic-context marker.
- name: Decreased circulating immunoglobulin concentration
  description: >-
    Hypogammaglobulinemia is not the defining untreated immune phenotype, but it
    can occur in selected ALPS patients, particularly after B-cell depletion, and
    can drive immunoglobulin replacement needs.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:19214977
    reference_title: >-
      Use of rituximab for refractory cytopenias associated with autoimmune
      lymphoproliferative syndrome (ALPS).
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Noted toxicities included profound and prolonged hypogammaglobulinemia in
      three patients requiring replacement IVIG
    explanation: >-
      This supports hypogammaglobulinemia as a clinically important immune
      finding in ALPS management, especially after rituximab exposure.
- name: Recurrent infections
  description: >-
    Severe infection risk is especially important after splenectomy or
    treatment-related hypogammaglobulinemia; this context drives explicit
    splenectomy avoidance and infection-prevention planning.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:24398331
    reference_title: >-
      Natural history of autoimmune lymphoproliferative syndrome associated
      with FAS gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the major causes of morbidity and mortality in these patients are the
      overwhelming postsplenectomy sepsis and development of lymphoma.
    explanation: >-
      The natural-history cohort identifies post-splenectomy sepsis as a major
      ALPS morbidity and mortality driver.
- name: Lymphoma
  description: >-
    FAS-related ALPS confers increased lifetime risk of both Hodgkin and
    non-Hodgkin lymphoma.
  phenotype_term:
    preferred_term: lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:15160902
    reference_title: "Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals with germline mutations in the Fas gene have a high risk to
      develop non Hodgkin lymphomas (x 14) as well as Hodgkin lymphomas (x 51),
      in particular NLP Hodgkin lymphoma.
    explanation: >-
      Review evidence directly supports lymphoma as a major malignant
      complication of germline FAS-mutant ALPS.
diagnosis:
- name: Revised ALPS diagnostic criteria assessment
  description: >-
    Apply the revised NIH diagnostic-criteria framework: chronic noninfectious,
    nonmalignant lymphoproliferation plus elevated alpha-beta double-negative T
    cells are required, with Fas apoptosis testing, germline or somatic Fas
    pathway variants, biomarkers, histopathology, autoimmune cytopenias, and
    family history used as accessory criteria to classify definitive versus
    probable ALPS.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  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: OTHER
    snippet: >-
      harmonizing the diagnosis and classification of ALPS will foster
      collaborative research and better understanding of the pathogenesis of
      autoimmune cytopenias and B-cell lymphomas.
    explanation: >-
      The NIH workshop report is the formal source for revised ALPS diagnostic
      criteria and classification.
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The first two criteria remain mandatory for diagnosis.
    explanation: >-
      This review summarizes the revised diagnostic algorithm and its mandatory
      criteria.
- name: Flow-cytometric double-negative T-cell quantification
  description: >-
    Flow cytometry is used to quantify circulating CD3-positive
    TCR-alpha-beta-positive CD4-negative CD8-negative T cells, the hallmark
    immunophenotypic abnormality of ALPS.
  diagnosis_term:
    preferred_term: flow cytometry procedure
    term:
      id: MAXO:0035055
      label: flow cytometry procedure
  evidence:
  - reference: PMID:12732128
    reference_title: "[Autoimmune lymphoproliferative syndrome: molecular diagnosis in two families]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To confirm such a diagnosis, immunoglobulin quantification, cellular
      phenotypic analysis by flow cytometry, IL-10 quantification, an apoptosis
      study, and molecular analysis were performed.
    explanation: >-
      Family study directly supports flow-cytometric immunophenotyping in the
      diagnostic workup.
  - reference: PMID:23993982
    reference_title: "Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 95th percentile for TCRαβ+ DNT in healthy controls was used to define
      a normal range up to 2.3% of total lymphocytes or 3.4% of T cells.
    explanation: >-
      Biomarker study provides practical flow-cytometric thresholds for the
      abnormal DNT-cell phenotype.
- name: Serum biomarker analysis
  description: >-
    Serum vitamin B12, soluble Fas ligand, IL-10, and IL-18 help prioritize FAS
    sequencing and support diagnostic classification in patients with
    lymphoproliferation, elevated DNT cells, and autoimmune cytopenias.
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: MAXO:0000018
      label: biomarker analysis
  evidence:
  - reference: PMID:23850805
    reference_title: "Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The best a priori predictor of FAS mutations was the combination of
      vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL,
      respectively), which had a positive predictive value of 92% and a
      negative predictive value of 97%.
    explanation: >-
      Prospective cohort evidence supports vitamin B12 and soluble Fas ligand as
      high-yield biomarkers for selecting patients for FAS testing.
  - reference: PMID:23993982
    reference_title: "Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biomarkers including elevated CD3+TCRαβ+CD4-CD8- double negative T cells
      (TCRαβ+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate
      between ALPS and common variable immunodeficiency (CVID) patients with an
      overlapping clinical phenotype.
    explanation: >-
      Independent biomarker study supports the same laboratory panel for
      differential diagnosis.
- name: Fas-mediated apoptosis assay
  description: >-
    Functional apoptosis testing can confirm impaired Fas signaling in
    suspected cases.
  diagnosis_term:
    preferred_term: apoptosis assay
    term:
      id: MAXO:0035080
      label: apoptosis assay
  evidence:
  - reference: PMID:12732128
    reference_title: "[Autoimmune lymphoproliferative syndrome: molecular diagnosis in two families]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In family A, in vitro Fas-mediated apoptosis was absent in the patient
      and markedly reduced in his father.
    explanation: >-
      Human family study supports apoptosis assays as a functional confirmation
      of defective Fas signaling.
- name: FAS molecular genetic testing
  description: >-
    Molecular testing of FAS confirms the diagnosis and distinguishes germline
    from somatic disease mechanisms. If germline testing is negative but the
    phenotype and DNT expansion remain convincing, sequencing enriched or sorted
    alpha-beta DNT cells can detect somatic FAS ALPS.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:12732128
    reference_title: "[Autoimmune lymphoproliferative syndrome: molecular diagnosis in two families]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The molecular study of these families confirms a diagnosis of ALPS and
      suggests that the causing defect of this syndrome is compatible with an
      autosomal dominant inheritance with incomplete penetrance.
    explanation: >-
      Molecular confirmation of familial FAS variants anchors gene-level testing
      as a core diagnostic modality.
treatments:
- name: Sirolimus
  description: >-
    mTOR inhibition with sirolimus is an effective steroid-sparing therapy for
    refractory autoimmune cytopenias and benign lymphoproliferation in ALPS,
    and can normalize the double-negative T-cell compartment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_phenotypes:
  - preferred_term: lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  - preferred_term: autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  - preferred_term: hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:19208097
    reference_title: "Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients were treated for autoimmune cytopenias; all had a rapid
      complete or near complete response.
    explanation: >-
      Initial clinical series supports sirolimus efficacy against ALPS
      autoimmune cytopenias.
  - reference: PMID:19208097
    reference_title: "Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients had complete resolution of lymphadenopathy and
      splenomegaly and all patients had a reduction in double negative T cells,
      a population hallmark of the disease.
    explanation: >-
      The same series shows that sirolimus improves lymphoproliferation and the
      characteristic DNT-cell abnormality.
  - reference: PMID:26504182
    reference_title: "Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS)
      achieved a durable complete response (CR), including rapid improvement in
      autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3
      months of starting sirolimus.
    explanation: >-
      Prospective trial evidence supports sirolimus as a highly active
      treatment for ALPS requiring chronic therapy.
- name: Mycophenolate mofetil
  description: >-
    Mycophenolate mofetil is an established steroid-sparing immunosuppressive
    therapy for chronic autoimmune disease manifestations in ALPS, particularly
    when long-term corticosteroids should be avoided.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  evidence:
  - reference: PMID:22157362
    reference_title: "New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      mycophenolate mofetil and sirolimus have been demonstrated to have marked
      activity against the disease.
    explanation: >-
      Review evidence identifies mycophenolate mofetil as one of the two
      established steroid-sparing agents with marked activity in ALPS.
- name: Corticosteroid pulses for acute autoimmune cytopenias
  description: >-
    Short corticosteroid pulses are used for acute or severe autoimmune
    cytopenia flares and selected severe lymphoproliferative complications, but
    chronic corticosteroid exposure should be minimized by steroid-sparing
    therapy when prolonged treatment is required.
  treatment_term:
    preferred_term: corticosteroid agent therapy
    term:
      id: MAXO:0000640
      label: corticosteroid agent therapy
  target_phenotypes:
  - preferred_term: autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  - preferred_term: autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  - preferred_term: autoimmune neutropenia
    term:
      id: HP:0001904
      label: Autoimmune neutropenia
  evidence:
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most patients respond to short corticosteroid pulses.
    explanation: >-
      This directly supports corticosteroids for acute ALPS autoimmune
      complications while avoiding chronic toxicity.
- name: Immunoglobulin replacement or adjunct IVIg
  description: >-
    Immunoglobulin infusion is considered for clinically significant
    hypogammaglobulinemia or as adjunctive therapy in severe autoimmune
    cytopenia contexts, particularly when B-cell depletion has caused prolonged
    antibody deficiency.
  treatment_term:
    preferred_term: immunoglobulin infusion therapy
    term:
      id: MAXO:0001480
      label: immunoglobulin infusion therapy
  target_phenotypes:
  - preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:19214977
    reference_title: >-
      Use of rituximab for refractory cytopenias associated with autoimmune
      lymphoproliferative syndrome (ALPS).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      profound and prolonged hypogammaglobulinemia in three patients requiring
      replacement IVIG
    explanation: >-
      This supports immunoglobulin replacement when ALPS treatment causes
      clinically significant antibody deficiency.
- name: Rituximab for selected refractory cytopenias
  description: >-
    Rituximab can be considered only after other immunosuppressive strategies
    fail or are not tolerated, because ALPS-specific toxicity includes prolonged
    hypogammaglobulinemia, impaired polysaccharide vaccine responses, and added
    infection risk, especially in asplenic patients.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_phenotypes:
  - preferred_term: autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:19214977
    reference_title: >-
      Use of rituximab for refractory cytopenias associated with autoimmune
      lymphoproliferative syndrome (ALPS).
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven out of 12 patients responded with stabilization of cytopenia for
      greater than 6 months.
    explanation: >-
      This supports rituximab activity in selected refractory cytopenias but
      does not make it first-line therapy.
  - reference: PMID:19214977
    reference_title: >-
      Use of rituximab for refractory cytopenias associated with autoimmune
      lymphoproliferative syndrome (ALPS).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Toxicities including hypogammaglobulinemia and neutropenia constitute an
      additional infection risk burden
    explanation: >-
      This supports caution and later-line positioning for rituximab in ALPS.
- name: Splenectomy avoidance
  description: >-
    Splenectomy should be avoided whenever possible and reserved only as a last
    resort for life-threatening refractory cytopenias or severe hypersplenism
    after medical strategies fail, because post-splenectomy sepsis is a major
    cause of morbidity and mortality in ALPS-FAS.
  role: Harm avoidance
  evidence:
  - reference: PMID:24398331
    reference_title: >-
      Natural history of autoimmune lymphoproliferative syndrome associated
      with FAS gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Avoiding splenectomy while controlling hypersplenism by using
      corticosteroid-sparing treatments improves the outcome in ALPS-FAS
      patients.
    explanation: >-
      The natural-history cohort identifies splenectomy avoidance as an
      outcome-improving management principle.
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      splenectomy should be avoided except in the case of uncontrolled
      hypersplenism that fails other medical management.
    explanation: >-
      This review supports strict last-resort positioning for splenectomy.
- name: Post-splenectomy antimicrobial prophylaxis and vaccination
  description: >-
    If splenectomy has already occurred or is unavoidable, infection-prevention
    planning should include penicillin prophylaxis, pneumococcal and other
    asplenia-appropriate vaccination, and urgent evaluation of febrile illness.
  treatment_term:
    preferred_term: penicillin agent therapy
    term:
      id: MAXO:0000198
      label: penicillin agent therapy
  target_phenotypes:
  - preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1108/
    reference_title: Autoimmune Lymphoproliferative Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vaccinations pre-splenectomy (with consideration of post-splenectomy
      boost vaccinations) and penicillin prophylaxis are strongly recommended
      for individuals who undergo splenectomy.
    explanation: >-
      GeneReviews directly supports vaccination and penicillin prophylaxis for
      individuals with ALPS who undergo splenectomy.
- name: Lymphoma surveillance
  description: >-
    Lifelong clinical surveillance for lymphoma should focus on changes in
    disease pattern, constitutional symptoms, suspicious nodes or masses, CBC
    trends, LDH, and targeted imaging or biopsy when clinically indicated rather
    than routine serial PET/CT for stable benign lymphoproliferation.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: MAXO:0001492
      label: surveillance for malignancies
  target_phenotypes:
  - preferred_term: lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rather, we investigate for malignancy if patients develop constitutional
      symptoms or have a significant change in disease pattern.
    explanation: >-
      This supports clinically triggered lymphoma surveillance and workup rather
      than indiscriminate routine imaging.
- name: Hematopoietic stem cell transplantation for selected severe disease
  description: >-
    HSCT is a potential curative option reserved for selected severe,
    refractory, life-threatening ALPS phenotypes, such as biallelic FAS disease,
    severe refractory autoimmune cytopenias, lymphoma-associated disease, or
    major complications of prolonged immunosuppression.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1108/
    reference_title: Autoimmune Lymphoproliferative Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Bone marrow (hematopoietic stem cell) transplantation (BMT/HSCT) is
      currently the only curative treatment for ALPS.
    explanation: >-
      GeneReviews supports HSCT as curative but reserved for selected severe
      presentations because of transplant risk.
- name: Genetic counseling and family testing
  description: >-
    Genetic counseling should distinguish germline autosomal dominant FAS ALPS
    with incomplete penetrance from somatic FAS ALPS, guide testing of at-risk
    relatives when a familial variant is known, and discuss genotype-specific
    penetrance and lymphoma-risk implications.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:22157362
    reference_title: >-
      New advances in the diagnosis and treatment of autoimmune
      lymphoproliferative syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FAS mutations have variable penetrance, as ALPS patients often have
      family members with the same genetic alterations and an absent or very
      mild clinical phenotype
    explanation: >-
      This supports genotype-specific family counseling and at-risk relative
      evaluation in germline FAS ALPS.
notes: >-
  This entry follows the current MONDO gene-related label for
  FAS-related autoimmune lymphoproliferative syndrome while preserving the
  historical ALPS-Ia synonym set. Rare biallelic or fetal-onset FAS phenotypes
  are part of the broader FAS disease spectrum, but this curation emphasizes
  the classical dominant apoptosis-defect syndrome requested in MONDO NTR
  9749.
📚

References & Deep Research

References

1
url:https://www.ncbi.nlm.nih.gov/books/NBK1108/
Autoimmune Lymphoproliferative Syndrome - GeneReviews® - NCBI Bookshelf
1 finding
GeneReviews provides the clinical baseline for ALPS diagnosis, management, surveillance, and genetic counseling.
"The diagnosis of ALPS is based on the following: Clinical findings; Laboratory abnormalities; Identification of pathogenic variants in genes relevant for the Fas pathway of apoptosis."

Deep Research

2
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 39 citations 2026-04-16T12:37:47.669853

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: FAS-related Autoimmune Lymphoproliferative Syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on FAS-related Autoimmune Lymphoproliferative Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: FAS-related Autoimmune Lymphoproliferative Syndrome (ALPS-FAS)

Executive summary

FAS-related autoimmune lymphoproliferative syndrome (ALPS-FAS) is an inborn error of immunity (primary immune regulatory disorder) caused by impaired FAS-mediated apoptosis (extrinsic apoptotic pathway), leading to chronic nonmalignant lymphoproliferation, autoimmune cytopenias, characteristic expansion of TCRαβ+ CD4−CD8− double-negative T cells (DNTs), and elevated risk of lymphoma. Recent (2023–2024) work emphasizes (i) biomarker-driven case finding (especially sFASL with vitamin B12 and DNTs), (ii) practical NGS panel yields in large referral cohorts, and (iii) recognition of complex genetic architectures including somatic “second hits” (e.g., somatic loss of heterozygosity) that can be missed by standard exome sequencing. (rao2024beyondfascinatingadvances pages 1-3, fernandez2024lookingforalps pages 1-2, xu2024genetictestingin pages 1-2)

Key evidence statistics from recent/major cohorts - NGS panel yield (Cincinnati Children’s, 2014–2023 submissions): 62/802 (7.7%) definite molecular diagnoses; 52/802 (6.5%) with pathogenic/likely pathogenic germline FAS variants; 17/37 (46%) diagnostic FAS variants were novel. Diagnostic yield increased to 30% among those meeting abnormal ALPS immunology criteria. (xu2024genetictestingin pages 1-2, xu2024genetictestingin pages 4-6) - Rapamycin/sirolimus outcomes (28 ALPS-FAS patients): 79% complete remission and 21% partial remission at 6–9 months; relapse occurred rapidly upon stopping therapy. (klemann2017evolutionofdisease pages 6-10)

Target disease

  • Disease name: FAS-related Autoimmune Lymphoproliferative Syndrome
  • Category: Mendelian (inborn error of immunity / primary immune regulatory disorder)
  • MONDO ID: Not available from retrieved sources in this run.

1. Disease information

1.1 What is the disease?

ALPS is a rare immune dysregulation disorder characterized by defective FAS signaling and consequent failure of FAS-mediated lymphocyte apoptosis, producing chronic, nonmalignant lymphoproliferation with autoimmunity (often autoimmune cytopenias) and expansion of αβ DNT cells, with increased risk of malignancy (notably lymphoma). (elgharbawy2023casereportneonatal pages 1-2, fernandez2024lookingforalps pages 1-2, rao2024beyondfascinatingadvances pages 1-3)

Direct abstract quote (definition): “Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder caused by defect of the extrinsic apoptotic pathway.” (Pediatric Allergy and Immunology; May 2024; https://doi.org/10.1111/pai.14135) (fernandez2024lookingforalps pages 1-2)

1.2 Key identifiers

Curated disease identifiers were not directly retrievable from OMIM/Orphanet/MeSH/ICD/MONDO within the documents available to this run.

1.3 Synonyms / alternative names

  • Autoimmune lymphoproliferative syndrome (ALPS) (elgharbawy2023casereportneonatal pages 1-2, fernandez2024lookingforalps pages 1-2)
  • ALPS-FAS (germline FAS pathogenic variants) (fernandez2024lookingforalps pages 1-2, xu2024genetictestingin pages 1-2)
  • ALPS-sFAS (somatic FAS pathogenic variants) (fernandez2024lookingforalps pages 1-2, rao2024beyondfascinatingadvances pages 1-3)
  • “FAS deficiency” / “FAS-pathway apoptosis defect” (rao2011howitreat pages 2-3, rao2024beyondfascinatingadvances pages 1-3)

1.4 Evidence sources

Most information summarized here comes from aggregated disease-level resources (cohorts, consensus criteria papers, expert reviews) rather than single EHR-derived observations, though illustrative case reports are included for severe biallelic disease and sirolimus response. (price2014naturalhistoryof pages 3-4, klemann2017evolutionofdisease pages 6-10, elgharbawy2023casereportneonatal pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: Pathogenic variants affecting the FAS-mediated extrinsic apoptotic pathway, most commonly FAS (TNFRSF6) variants that abrogate FAS expression or function, resulting in impaired activation-induced cell death and defective termination of immune responses. (rao2024beyondfascinatingadvances pages 1-3, rieuxlaucat2018theautoimmunelymphoproliferative pages 1-2, casamayorpolo2021immunologicevaluationand pages 3-5)

2.2 Risk factors

Genetic risk factors

  • Germline FAS variants (typically autosomal dominant with incomplete penetrance). In the NIH natural history cohort, penetrance among mutation-positive individuals was variable and sex-dependent (69% males vs 46% females among mutation carriers reported in the excerpt). (price2014naturalhistoryof pages 3-4)
  • Somatic FAS defects (ALPS-sFAS) and second-hit mechanisms in monoallelic disease, including somatic loss of heterozygosity (sLOH) reported as common in expert synthesis. (rao2024beyondfascinatingadvances pages 1-3)

Recent diagnostic-yield data: In a 2024 NGS panel study of 802 referrals, 52/802 (6.5%) had diagnostic germline FAS pathogenic/likely pathogenic variants; 46% of diagnostic FAS variants were novel. (xu2024genetictestingin pages 1-2, xu2024genetictestingin pages 4-6)

Environmental/infectious risk factors

No specific environmental toxin/lifestyle risk factors were identified in the retrieved ALPS-FAS sources. Infection risk is clinically relevant as a complication/modifier, especially post-splenectomy, but not a primary etiologic trigger in available evidence. (price2014naturalhistoryof pages 1-3, rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6)

2.3 Protective factors

Not specifically identified in the retrieved evidence.

2.4 Gene–environment interactions

Not well characterized in the retrieved ALPS-FAS sources; contemporary reviews of inborn errors of immunity emphasize that penetrance/expressivity can reflect multiple factors over time, including somatic events and environmental exposures, but ALPS-FAS-specific quantitative GxE data were not retrieved here. (rao2024beyondfascinatingadvances pages 1-3)

3. Phenotypes

3.1 Core clinical phenotypes (with frequency when available)

Key phenotypes (HPO suggestions in parentheses): - Chronic lymphadenopathy (~96%) (HP:0002716) (rao2011howitreat pages 2-3) - Splenomegaly (~95%) (HP:0001744) (rao2011howitreat pages 2-3) - Hepatomegaly (~72%) (HP:0002240) (rao2011howitreat pages 2-3) - Autoimmune cytopenias (HP:0001871) - Autoimmune hemolytic anemia ~29% (HP:0001890) (rao2011howitreat pages 2-3) - Immune thrombocytopenia ~23% (HP:0001873) (rao2011howitreat pages 2-3) - Neutropenia ~19% (HP:0001875) (rao2011howitreat pages 2-3) - Polyclonal hypergammaglobulinemia (HP:0004315); in NIH cohort, IgG elevated in 58%, IgA in 45%, IgM in 10% (HP:0004313/HP:0004312 patterns) (price2014naturalhistoryof pages 6-7)

Additional lab/immune abnormalities reported in the NIH cohort include DAT positivity (40%), RF positivity (32%), eosinophilia (24%), and elevated monocyte count (38%). (price2014naturalhistoryof pages 6-7)

3.2 Age of onset and course

  • Usually early childhood onset; one review excerpt reports a median age of onset of ~3 years. (rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6)
  • Rare severe cases can present neonatally with biallelic loss-of-function FAS variants. (elgharbawy2023casereportneonatal pages 1-2)
  • Disease course is typically chronic (>6 months) with fluctuating activity and risk of autoimmune relapses; stopping mTOR inhibition can lead to rapid relapse in treated patients. (klemann2017evolutionofdisease pages 6-10, price2014naturalhistoryof pages 3-4)

3.3 Quality of life impact / complications

Formal QoL instruments were not retrieved. Clinically impactful complications include refractory cytopenias requiring immunosuppression, organomegaly, infection risk, and malignancy surveillance burden. Reviews emphasize avoidance of splenectomy when possible due to septicemia risk and loss of anti-polysaccharide responses. (rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6, price2014naturalhistoryof pages 1-3)

4. Genetic / molecular information

4.1 Causal genes

  • FAS (TNFRSF6) is the principal causal gene for ALPS-FAS. (fernandez2024lookingforalps pages 1-2, xu2024genetictestingin pages 1-2)
  • Other extrinsic apoptosis pathway genes associated with ALPS spectrum (not FAS-related subtype specifically) include FASLG, FADD, CASP10, though they are much less frequent. (fernandez2024lookingforalps pages 1-2, price2014naturalhistoryof pages 3-4)

4.2 Pathogenic variants (classes and examples)

  • In a 2024 referral cohort, most diagnostic FAS variants were truncating or missense variants located in the intracellular domain, often the death domain. (xu2024genetictestingin pages 4-6)
  • Severe early-onset disease can be caused by biallelic loss-of-function variants: e.g., a neonatal case with FAS exon 9 c.775del leading to p.(Ile259*). (elgharbawy2023casereportneonatal pages 1-2)

4.3 Germline vs somatic origin

  • Germline FAS variants are common; somatic FAS variants also occur and may require analysis of sorted DNTs or sensitive sequencing approaches. (rieuxlaucat2018theautoimmunelymphoproliferative pages 7-8, rao2024beyondfascinatingadvances pages 1-3)
  • In expert synthesis, somatic second hits such as sLOH (often via uniparental disomy) are highlighted and can be missed by exome sequencing. (rao2024beyondfascinatingadvances pages 1-3)

4.4 Modifier genes and debated genes

A 2024 Cell Death & Disease study challenges the role of common CASP10 variants in ALPS pathogenesis, concluding caspase-10 is dispensable for FAS-mediated apoptosis and CASP10 defects are unlikely to contribute to ALPS when they do not impair apoptosis. (consonni2024studyofthe pages 1-2)

5. Environmental information

No ALPS-FAS-specific environmental toxin/lifestyle/infectious causal triggers were identified in the retrieved evidence. The key clinically relevant “environmental” dimension is infectious risk under immunosuppression and after splenectomy. (rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6, price2014naturalhistoryof pages 1-3)

6. Mechanism / pathophysiology

6.1 Causal chain (from trigger to manifestations)

  1. FAS ligation and signaling failure: Normally, FAS–FASL interaction triggers receptor trimerization and recruitment of FADD and initiator procaspase-8/10 into the DISC, leading to initiator caspase activation and effector caspase cascade. (rieuxlaucat2018theautoimmunelymphoproliferative pages 1-2, casamayorpolo2021immunologicevaluationand pages 3-5)
  2. Defective activation-induced cell death (AICD): Failure to eliminate activated lymphocytes impairs immune contraction and tolerance. (lambert2021presentationanddiagnosis pages 3-4, casamayorpolo2021immunologicevaluationand pages 3-5)
  3. Accumulation/expansion of DNT cells and autoreactive lymphocytes: This manifests as lymphadenopathy/splenomegaly and autoimmune cytopenias. (bride2017autoimmunelymphoproliferativesyndrome pages 1-3, rao2011howitreat pages 2-3)
  4. Downstream proliferative signaling: DNT subsets show evidence of proliferative/survival pathway engagement (mTOR, STAT3), supporting targeted mTOR inhibition as therapy. (lambert2021presentationanddiagnosis pages 3-4, klemann2017evolutionofdisease pages 6-10)

6.2 Pathways and processes (ontology suggestions)

  • GO: extrinsic apoptotic signaling pathway (GO:0097191)
  • GO: activation-induced cell death of T cells (concept supported; see AICD discussion) (lambert2021presentationanddiagnosis pages 3-4)
  • GO: regulation of lymphocyte apoptosis / immune tolerance (mechanistic basis) (casamayorpolo2021immunologicevaluationand pages 3-5)
  • CL: double negative T cell (TCRαβ+ CD4−CD8−; pathogenic expansion) (xu2024genetictestingin pages 1-2, price2014naturalhistoryof pages 3-4)

6.3 Model organisms / experimental systems

Murine Fas/FasL-deficient models recapitulate key ALPS-like features (lymphoproliferation, autoimmunity, DNT accumulation), including MRL/lpr (Fas-deficient) and MRL/gld (FasL-deficient) models. (bride2017autoimmunelymphoproliferativesyndrome pages 1-3, rieuxlaucat2018theautoimmunelymphoproliferative pages 1-2)

A 2024 modifier study in Faslpr mice (iScience, Nov 2024) shows that altering B-cell apoptosis/activation regulators (EAF2) can modulate lymphoproliferation and nephritis, illustrating potential modifier pathways (Akt/survival genes) in a Fas-deficient background. (luan2024eaf2deficiencyattenuates pages 1-2)

7. Anatomical structures affected

7.1 Organ/system level (UBERON suggestions)

Primary: - Spleen (UBERON:0002106) – splenomegaly/hypersplenism, sequestration cytopenias (rao2011howitreat pages 2-3) - Lymph nodes (UBERON:0000029) – chronic lymphadenopathy (rao2011howitreat pages 2-3) Secondary/variable: - Liver (UBERON:0002107) – hepatomegaly; occasional liver dysfunction (rao2011howitreat pages 2-3) - Bone marrow / hematologic system – autoimmune cytopenias (rao2011howitreat pages 2-3)

7.2 Tissue/cell level (CL suggestions)

  • TCRαβ DNT cells (CL: T cell subset concept) (xu2024genetictestingin pages 1-2, price2014naturalhistoryof pages 3-4)
  • Activated T cells undergoing (failed) AICD; B cell activation/plasma cells in models (luan2024eaf2deficiencyattenuates pages 1-2)

7.3 Subcellular level (GO-CC suggestions)

  • Death-inducing signaling complex (DISC) (complex; DISC discussed mechanistically) (rieuxlaucat2018theautoimmunelymphoproliferative pages 1-2)

8. Temporal development

  • Onset: most often pediatric with chronic course; median onset ~3 years in one review excerpt; severe biallelic disease can present neonatally. (rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6, elgharbawy2023casereportneonatal pages 1-2)
  • Progression/course: chronic lymphoproliferation and episodic/relapsing autoimmune cytopenias; long-term malignancy surveillance required. (price2014naturalhistoryof pages 3-4, rao2011howitreat pages 2-3)

9. Inheritance and population

9.1 Inheritance pattern

  • Typical ALPS-FAS: autosomal dominant with incomplete penetrance (price2014naturalhistoryof pages 3-4)
  • Rare severe biallelic FAS loss-of-function can follow autosomal recessive inheritance (as in the neonatal homozygous truncating case report). (elgharbawy2023casereportneonatal pages 1-2)

9.2 Penetrance/expressivity

  • NIH cohort data indicate variable penetrance with sex differences among mutation carriers (69% males vs 46% females in excerpt). (price2014naturalhistoryof pages 3-4)
  • 2024 expert review emphasizes somatic second hits (including sLOH) and complex variants that may explain variable expression and diagnostic gaps. (rao2024beyondfascinatingadvances pages 1-3)

9.3 Epidemiology (incidence/prevalence)

No population incidence/prevalence estimates were identified in the retrieved sources for this run.

10. Diagnostics

10.1 Standardized diagnostic criteria (NIH 2009 revised)

NIH 2009 revised criteria (as reproduced in the ALPS-FAS natural history study) define: - Required criteria: chronic (>6 months) nonmalignant, noninfectious lymphadenopathy and/or splenomegaly; plus elevated TCRαβ DNT cells (>1.5% of total lymphocytes or >2.5% of CD3+ lymphocytes) with normal/elevated lymphocyte count. (price2014naturalhistoryof pages 3-4) - Primary accessory: defective FAS-induced apoptosis or pathogenic germline/somatic mutation in FAS/FASL/FADD/CASP10. (price2014naturalhistoryof pages 3-4) - Secondary accessory: elevated biomarkers including sFASL (>200 pg/mL), IL-10 (>20 pg/mL), vitamin B12 (>1500 pg/mL), typical histopathology, autoimmune cytopenias, hypergammaglobulinemia, family history. (price2014naturalhistoryof pages 3-4)

Visual evidence: Table 1 (cropped) in Price et al. 2014 reproduces these thresholds and criteria components. (price2014naturalhistoryof media e08f037f)

10.2 Biomarkers and real-world screening strategies (recent)

A 2024 pediatric study screened 398 patients with autoimmune cytopenia/lymphoproliferation using DNT cells plus sFASL; sFASL correlated strongly with vitamin B12, and sFASL with vitamin B12 were “the most discriminating biomarkers” among confirmed cases in their cohort. (fernandez2024lookingforalps pages 1-2)

10.3 Genetic testing approaches

A 15-gene ALPS NGS panel experience (802 cases) showed a 7.7% definite diagnostic yield overall, increasing to 30% when abnormal ALPS immunology criteria were met; it also identified non-FAS ALPID diagnoses (ADA2, CTLA4, KRAS, MAGT1, NRAS) in 1.2%. (xu2024genetictestingin pages 1-2)

10.4 Differential diagnosis

Differentials include ALPS-like/autoimmune lymphoproliferative immunodeficiency (ALPID) conditions with overlapping lymphoproliferation and cytopenias, including RAS pathway disorders and CTLA4/LRBA-related immune dysregulation (highlighted in the 2024 NGS panel cohort). (xu2024genetictestingin pages 1-2)

11. Outcome / prognosis

11.1 Morbidity and mortality drivers

In the NIH natural history study, major morbidity/mortality drivers include overwhelming postsplenectomy sepsis and development of lymphoma; thus, avoiding splenectomy when possible and using steroid-sparing approaches is emphasized. (price2014naturalhistoryof pages 1-3)

11.2 Malignancy risk

ALPS-FAS carries increased lymphoma risk; clinical warning features include systemic symptoms and sudden focal lymph node enlargement in established lymphadenopathy. (price2014naturalhistoryof pages 6-7)

No specific numeric lifetime lymphoma incidence was extracted from the retrieved excerpts (the full paper contains SEER O/E analyses but exact values were not captured in the evidence snippets). (price2014naturalhistoryof pages 3-4)

12. Treatment

12.1 Pharmacotherapy (current practice and evidence)

mTOR inhibition (sirolimus/rapamycin) - In a 28-patient ALPS-FAS cohort, rapamycin achieved complete remission in 79% and partial remission in 21% at 6–9 months; all who stopped relapsed rapidly; biomarker normalization was incomplete in many (e.g., DNT normalized in 33%). (klemann2017evolutionofdisease pages 6-10) - A 2024 ASH Hematology review notes rapamycin (sirolimus) and mycophenolate mofetil as long-term steroid-sparing measures used successfully over two decades. (rao2024beyondfascinatingadvances pages 1-3)

Mycophenolate mofetil (MMF) Used as a steroid-sparing agent in ALPS management in expert review summaries. (rao2024beyondfascinatingadvances pages 1-3)

Supportive / avoidance strategies Avoid splenectomy when possible due to infection risk; management includes surveillance for malignancy. (rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6, price2014naturalhistoryof pages 1-3)

12.2 Real-world implementations (recent case reports)

A 2023 neonatal severe ALPS-FAS case with homozygous truncating FAS variant improved clinically with sirolimus with “obvious reduction” in DNT percentage. (elgharbawy2023casereportneonatal pages 1-2)

12.3 Clinical trials (registered)

  • NCT00392951 (CHOP; started Dec 2006; completed Feb 2016; results posted Dec 6, 2017): Phase 1/2 pilot of oral sirolimus for refractory autoimmune cytopenias including ALPS; targeted trough 5–15 ng/mL; primary outcome grade 3–4 toxicities over 6 months; secondary outcomes included CR/PR response and lymphoproliferation response. https://clinicaltrials.gov/study/NCT00392951 (NCT00392951 chunk 1)
  • NCT02579967 (NCI; started Nov 19, 2015; recruiting): Phase 2 allo-BMT trial for primary immunodeficiencies listing “Autoimmune Lymphoproliferative” among conditions; primary endpoint aGVHD-free, graft-failure–free survival at day +180. https://clinicaltrials.gov/study/NCT02579967 (NCT02579967 chunk 1, NCT02579967 chunk 2)

Emerging targeted therapy direction: PI3Kδ inhibition is highlighted as a successful paradigm in related IEIs (leniolisib FDA-licensed in 2023 for APDS), and preclinical work supports evaluation in ALPS (NCT06549114 referenced in murine work; not retrievable as a full CT record in this run). (rao2024beyondfascinatingadvances pages 1-3)

12.4 MAXO suggestions (treatment/action ontology)

  • mTOR inhibitor therapy (sirolimus/rapamycin) (supported by rapamycin cohort and trial) (klemann2017evolutionofdisease pages 6-10, NCT00392951 chunk 1)
  • Immunosuppressive therapy (MMF; steroids) (rao2024beyondfascinatingadvances pages 1-3)
  • Hematopoietic stem cell transplantation / allo-BMT (for severe PID/immune dysregulation in selected cases) (NCT02579967 chunk 1)

13. Prevention

Primary prevention is not generally applicable for Mendelian ALPS-FAS beyond reproductive options. Secondary/tertiary prevention includes: - Genetic counseling and cascade testing of relatives; family studies can identify at-risk family members and assist variant classification. (xu2024genetictestingin pages 1-2) - Avoidance of splenectomy when possible and infection prophylaxis strategies as clinically indicated. (rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6, price2014naturalhistoryof pages 1-3)

14. Other species / natural disease

No naturally occurring veterinary ALPS-FAS cases were retrieved in obtainable texts in this run.

15. Model organisms

15.1 Core models

  • MRL/lpr (Fas-deficient) and MRL/gld (FasL-deficient) mice recapitulate lymphoproliferation, autoimmunity, DNT expansion, and organ pathology (e.g., glomerulonephritis) relevant to ALPS mechanisms. (bride2017autoimmunelymphoproliferativesyndrome pages 1-3, rieuxlaucat2018theautoimmunelymphoproliferative pages 1-2)

15.2 Recent model-organism development (2024)

A 2024 iScience study used Faslpr mice to demonstrate that EAF2 deficiency can attenuate autoimmune disease features by modulating B-cell activation and apoptosis, providing a modifier pathway example in a Fas-deficient background. (luan2024eaf2deficiencyattenuates pages 1-2)

Recent developments (2023–2024 focus) and expert analysis

  1. Biomarker strategy refinement: A 2024 study argues that existing ALPS criteria are sensitive but have low PPV and supports combined biochemical marker screening, particularly sFASL with vitamin B12 (plus DNTs). (fernandez2024lookingforalps pages 1-2)
  2. Large-scale NGS diagnostic yield: The 2024 802-patient NGS panel experience quantifies real-world yields and highlights that adding immunology pre-screening increases molecular diagnostic efficiency (30% yield in immunology-abnormal subgroup). (xu2024genetictestingin pages 1-2)
  3. Complex genetics and “missed” variants: 2024 ASH Hematology review emphasizes that promoter/deep intronic variants, deletions/duplications, and somatic second hits (including sLOH) can be missed by exome sequencing, motivating extended testing strategies. (rao2024beyondfascinatingadvances pages 1-3)

Structured reference table (diagnostics/genetics)

The following table compacts the core naming, NIH criteria, key biomarkers, and genetics for ALPS-FAS.

Domain Summary Key thresholds/details Supporting citations
Disease name / synonyms FAS-related Autoimmune Lymphoproliferative Syndrome; commonly referred to as ALPS-FAS or autoimmune lymphoproliferative syndrome due to FAS defect/deficiency. Core disease concept: inborn error of immunity with defective Fas-mediated apoptosis causing chronic nonmalignant lymphoproliferation, autoimmune cytopenias, expanded αβ double-negative T cells, and increased lymphoma risk. Usually childhood-onset, but presentation can occur at any age. (rao2024beyondfascinatingadvances pages 1-3, xu2024genetictestingin pages 1-2, fernandez2024lookingforalps pages 1-2)
NIH 2009 required criteria Both are required for ALPS diagnosis framework. 1) Chronic >6 months, nonmalignant, noninfectious lymphadenopathy and/or splenomegaly. 2) Elevated CD3+ TCRαβ+ CD4− CD8− DNT cells with normal/elevated lymphocyte counts: >1.5% of total lymphocytes or >2.5% of CD3+ lymphocytes. (price2014naturalhistoryof pages 3-4, rao2011howitreat pages 2-3)
NIH 2009 primary accessory criteria Supports definitive diagnosis when combined with both required criteria. 1) Defective Fas-mediated apoptosis in 2 separate assays; or 2) pathogenic somatic or germline mutation in FAS, FASLG, FADD, or CASP10. (price2014naturalhistoryof pages 3-4, rao2011howitreat pages 2-3)
NIH 2009 secondary accessory criteria Supports probable diagnosis when combined with both required criteria. Elevated sFASL >200 pg/mL, IL-10 >20 pg/mL, vitamin B12 >1500 pg/mL/ng/L; typical immunohistopathology; autoimmune cytopenias with elevated IgG/polyclonal hypergammaglobulinemia; family history of nonmalignant/noninfectious lymphoproliferation. IL-18 >500 pg/mL is also noted in later diagnostic summaries. (price2014naturalhistoryof pages 3-4, rao2011howitreat pages 2-3, fernandez2024lookingforalps pages 1-2)
Key biomarker: DNT cells Hallmark immunophenotypic marker of ALPS-FAS; reflects expansion of apoptosis-resistant αβ T cells and is central to screening/diagnosis. Often markedly elevated in ALPS-FAS; in one molecularly defined cohort median 7.5% in ALPS-FAS vs 2.7% in ALPS-U. Flow panel cutoffs used clinically include TCRαβ DNT >2% or >68 cells/µL. (xu2024genetictestingin pages 1-2, molnar2020keydiagnosticmarkers pages 17-19)
Key biomarker: soluble Fas ligand (sFASL) Indicates Fas-pathway dysregulation; especially useful for predicting FAS-mutated disease when paired with apoptosis testing. NIH threshold >200 pg/mL; ALPS-FAS can show very high values, with molecular cohort median >1000 pg/mL versus 152 pg/mL in ALPS-U. (fernandez2024lookingforalps pages 1-2, molnar2020keydiagnosticmarkers pages 17-19)
Key biomarker: IL-10 Reflects immune activation/lymphoproliferative dysregulation; useful supportive biomarker but less specific than sFASL for FAS-mutant disease. NIH threshold >20 pg/mL. Elevated in ALPS generally; in one comparison it was less discriminatory between ALPS-FAS and ALPS-U than sFASL or apoptosis testing. (fernandez2024lookingforalps pages 1-2, rao2011howitreat pages 2-3, molnar2020keydiagnosticmarkers pages 17-19)
Key biomarker: vitamin B12 Readily measurable supportive biomarker; often persistently elevated in ALPS-FAS and useful in biomarker-based triage for FAS testing. NIH threshold >1500 pg/mL/ng/L. Price et al. identified elevated vitamin B12 as a reliable biomarker of ALPS-FAS. (price2014naturalhistoryof pages 3-4, price2014naturalhistoryof pages 1-3, fernandez2024lookingforalps pages 1-2)
Genetics summary: germline FAS Major genetic cause of ALPS. Most diagnosed molecular cases are due to germline FAS pathogenic/likely pathogenic variants, often affecting the intracellular death domain; inheritance usually autosomal dominant with incomplete penetrance, though recessive severe early-onset cases occur. In a 2024 cohort of 802 referred patients, 62/802 (7.7%) had definite molecular diagnoses; 52/62 (84%) had germline FAS variants, including 37 unique variants, 46% novel. Penetrance in an NIH natural-history cohort was <60% overall; sex difference reported 69% males vs 46% females. (xu2024genetictestingin pages 1-2, xu2024genetictestingin pages 4-6, price2014naturalhistoryof pages 1-3, price2014naturalhistoryof pages 3-4)
Genetics summary: somatic FAS / ALPS-sFAS A clinically important subset has somatic FAS variants, often enriched in sorted DNT cells, explaining apparently mutation-negative blood testing and delayed diagnosis. Somatic FAS changes reported in about 15–20% of ALPS patients in recent summaries; testing sorted DNT cells may be required when whole blood is negative or variant allele fraction is low. (rao2024beyondfascinatingadvances pages 1-3, fernandez2024lookingforalps pages 1-2)
Genetics summary: second hits / sLOH Additional somatic events can worsen penetrance and disease expression in monoallelic FAS disease. Somatic loss of heterozygosity (sLOH), often due to uniparental disomy duplicating the mutated allele, is reported in roughly 80% of relevant somatic-event cases in recent expert review summaries. (rao2024beyondfascinatingadvances pages 1-3)

Table: This table compacts the core disease labels, NIH 2009 diagnostic framework, biomarker interpretation, and genetics of FAS-related autoimmune lymphoproliferative syndrome. It is useful as a quick reference for case curation and knowledge-base population.

Evidence gaps / not available in retrieved sources

  • Curated cross-ontology identifiers (OMIM/Orphanet/MeSH/ICD/MONDO) were not directly extractable in this run.
  • Population-level prevalence/incidence estimates were not present in retrieved excerpts.
  • QoL statistics (EQ-5D/SF-36/PROMIS) were not identified in retrieved ALPS-FAS sources.

Key primary literature and authoritative sources (with dates/URLs)

  • Price et al. Blood (Mar 2014): Natural history of ALPS-FAS; includes NIH 2009 criteria table and cohort lab frequencies. https://doi.org/10.1182/blood-2013-10-535393 (price2014naturalhistoryof pages 3-4, price2014naturalhistoryof pages 6-7)
  • Xu et al. Journal of Clinical Immunology (Jul 2024): 802-patient ALPS NGS panel diagnostic yield. https://doi.org/10.1007/s10875-024-01772-z (xu2024genetictestingin pages 1-2)
  • Rao et al. ASH Hematology (Dec 2024): Expert review on advances in diagnosis/management; emphasizes complex genetics and sLOH. https://doi.org/10.1182/hematology.2024000537 (rao2024beyondfascinatingadvances pages 1-3)
  • Fernandez & Touzot Pediatric Allergy and Immunology (May 2024): Combined biomarker assessment (DNT+sFASL) in a screened pediatric cohort. https://doi.org/10.1111/pai.14135 (fernandez2024lookingforalps pages 1-2)
  • Klemann et al. Haematologica (Feb 2017): Rapamycin outcomes and biomarker evolution in 28 ALPS-FAS patients. https://doi.org/10.3324/haematol.2016.153411 (klemann2017evolutionofdisease pages 6-10)
  • ClinicalTrials.gov NCT00392951 (results posted Dec 6, 2017; last update Nov 19, 2019): Sirolimus for autoimmune disease of blood cells including ALPS. https://clinicaltrials.gov/study/NCT00392951 (NCT00392951 chunk 1)

References

  1. (rao2024beyondfascinatingadvances pages 1-3): V. Koneti Rao, Stefania Pittaluga, and Gulbu Uzel. Beyond fascinating: advances in diagnosis and management of autoimmune lymphoproliferative syndrome and activated pi3 kinase δ syndrome. Hematology, 2024:126-136, Dec 2024. URL: https://doi.org/10.1182/hematology.2024000537, doi:10.1182/hematology.2024000537. This article has 9 citations and is from a peer-reviewed journal.

  2. (fernandez2024lookingforalps pages 1-2): Isabel Fernandez and Fabien Touzot. Looking for alps: the value of a combined assessment of biochemical markers. Pediatric Allergy and Immunology, May 2024. URL: https://doi.org/10.1111/pai.14135, doi:10.1111/pai.14135. This article has 0 citations and is from a domain leading peer-reviewed journal.

  3. (xu2024genetictestingin pages 1-2): Xinxiu Xu, James Denton, Yaning Wu, Jie Liu, Qiaoning Guan, D. Brian Dawson, Jack Bleesing, and Wenying Zhang. Genetic testing in patients with autoimmune lymphoproliferative syndrome: experience of 802 patients at cincinnati children’s hospital medical center. Journal of Clinical Immunology, Jul 2024. URL: https://doi.org/10.1007/s10875-024-01772-z, doi:10.1007/s10875-024-01772-z. This article has 4 citations and is from a domain leading peer-reviewed journal.

  4. (xu2024genetictestingin pages 4-6): Xinxiu Xu, James Denton, Yaning Wu, Jie Liu, Qiaoning Guan, D. Brian Dawson, Jack Bleesing, and Wenying Zhang. Genetic testing in patients with autoimmune lymphoproliferative syndrome: experience of 802 patients at cincinnati children’s hospital medical center. Journal of Clinical Immunology, Jul 2024. URL: https://doi.org/10.1007/s10875-024-01772-z, doi:10.1007/s10875-024-01772-z. This article has 4 citations and is from a domain leading peer-reviewed journal.

  5. (klemann2017evolutionofdisease pages 6-10): Christian Klemann, Myrian Esquivel, Aude Magerus-Chatinet, Myriam R. Lorenz, Ilka Fuchs, Nathalie Neveux, Martin Castelle, Jan Rohr, Claudia Bettoni da Cunha, Martin Ebinger, Robin Kobbe, Bernhard Kremens, Florian Kollert, Eleonora Gambineri, Kai Lehmberg, Markus G. Seidel, Kathrin Siepermann, Thomas Voelker, Volker Schuster, Sigune Goldacker, Klaus Schwarz, Carsten Speckmann, Capucine Picard, Alain Fischer, Frederic Rieux-Laucat, Stephan Ehl, Anne Rensing-Ehl, and Benedicte Neven. Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome. Haematologica, 102:e52-e56, Feb 2017. URL: https://doi.org/10.3324/haematol.2016.153411, doi:10.3324/haematol.2016.153411. This article has 68 citations.

  6. (elgharbawy2023casereportneonatal pages 1-2): Fawzia M. Elgharbawy, Mohammed Yousuf Karim, Dina Sameh Soliman, Amel Siddik Hassan, Anoop Sudarsanan, and Ashraf Gad. Case report: neonatal autoimmune lymphoproliferative syndrome with a novel pathogenic homozygous fas variant effectively treated with sirolimus. Frontiers in Pediatrics, Apr 2023. URL: https://doi.org/10.3389/fped.2023.1150179, doi:10.3389/fped.2023.1150179. This article has 4 citations.

  7. (rao2011howitreat pages 2-3): V. Koneti Rao and João Bosco Oliveira. How i treat autoimmune lymphoproliferative syndrome. Blood, 118 22:5741-51, Nov 2011. URL: https://doi.org/10.1182/blood-2011-07-325217, doi:10.1182/blood-2011-07-325217. This article has 240 citations and is from a highest quality peer-reviewed journal.

  8. (price2014naturalhistoryof pages 3-4): Susan Price, Pamela A. Shaw, Amy Seitz, Gyan Joshi, Joie Davis, Julie E. Niemela, Katie Perkins, Ronald L. Hornung, Les Folio, Philip S. Rosenberg, Jennifer M. Puck, Amy P. Hsu, Bernice Lo, Stefania Pittaluga, Elaine S. Jaffe, Thomas A. Fleisher, V. Koneti Rao, and Michael J. Lenardo. Natural history of autoimmune lymphoproliferative syndrome associated with fas gene mutations. Blood, 123 13:1989-99, Mar 2014. URL: https://doi.org/10.1182/blood-2013-10-535393, doi:10.1182/blood-2013-10-535393. This article has 270 citations and is from a highest quality peer-reviewed journal.

  9. (rieuxlaucat2018theautoimmunelymphoproliferative pages 1-2): Frédéric Rieux-Laucat, Aude Magérus-Chatinet, and Bénédicte Neven. The autoimmune lymphoproliferative syndrome with defective fas or fas-ligand functions. Journal of Clinical Immunology, 38:558-568, Jun 2018. URL: https://doi.org/10.1007/s10875-018-0523-x, doi:10.1007/s10875-018-0523-x. This article has 100 citations and is from a domain leading peer-reviewed journal.

  10. (casamayorpolo2021immunologicevaluationand pages 3-5): Laura Casamayor-Polo, Marta López-Nevado, Estela Paz-Artal, Alberto Anel, Frederic Rieux-Laucat, and Luis M. Allende. Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (alps). Critical Reviews in Clinical Laboratory Sciences, 58:253-274, Dec 2021. URL: https://doi.org/10.1080/10408363.2020.1855623, doi:10.1080/10408363.2020.1855623. This article has 29 citations and is from a peer-reviewed journal.

  11. (price2014naturalhistoryof pages 1-3): Susan Price, Pamela A. Shaw, Amy Seitz, Gyan Joshi, Joie Davis, Julie E. Niemela, Katie Perkins, Ronald L. Hornung, Les Folio, Philip S. Rosenberg, Jennifer M. Puck, Amy P. Hsu, Bernice Lo, Stefania Pittaluga, Elaine S. Jaffe, Thomas A. Fleisher, V. Koneti Rao, and Michael J. Lenardo. Natural history of autoimmune lymphoproliferative syndrome associated with fas gene mutations. Blood, 123 13:1989-99, Mar 2014. URL: https://doi.org/10.1182/blood-2013-10-535393, doi:10.1182/blood-2013-10-535393. This article has 270 citations and is from a highest quality peer-reviewed journal.

  12. (rieuxlaucat2018theautoimmunelymphoproliferative pages 5-6): Frédéric Rieux-Laucat, Aude Magérus-Chatinet, and Bénédicte Neven. The autoimmune lymphoproliferative syndrome with defective fas or fas-ligand functions. Journal of Clinical Immunology, 38:558-568, Jun 2018. URL: https://doi.org/10.1007/s10875-018-0523-x, doi:10.1007/s10875-018-0523-x. This article has 100 citations and is from a domain leading peer-reviewed journal.

  13. (price2014naturalhistoryof pages 6-7): Susan Price, Pamela A. Shaw, Amy Seitz, Gyan Joshi, Joie Davis, Julie E. Niemela, Katie Perkins, Ronald L. Hornung, Les Folio, Philip S. Rosenberg, Jennifer M. Puck, Amy P. Hsu, Bernice Lo, Stefania Pittaluga, Elaine S. Jaffe, Thomas A. Fleisher, V. Koneti Rao, and Michael J. Lenardo. Natural history of autoimmune lymphoproliferative syndrome associated with fas gene mutations. Blood, 123 13:1989-99, Mar 2014. URL: https://doi.org/10.1182/blood-2013-10-535393, doi:10.1182/blood-2013-10-535393. This article has 270 citations and is from a highest quality peer-reviewed journal.

  14. (rieuxlaucat2018theautoimmunelymphoproliferative pages 7-8): Frédéric Rieux-Laucat, Aude Magérus-Chatinet, and Bénédicte Neven. The autoimmune lymphoproliferative syndrome with defective fas or fas-ligand functions. Journal of Clinical Immunology, 38:558-568, Jun 2018. URL: https://doi.org/10.1007/s10875-018-0523-x, doi:10.1007/s10875-018-0523-x. This article has 100 citations and is from a domain leading peer-reviewed journal.

  15. (consonni2024studyofthe pages 1-2): Filippo Consonni, Solange Moreno, Blanca Vinuales Colell, Marie-Claude Stolzenberg, Alicia Fernandes, Mélanie Parisot, Cécile Masson, Nathalie Neveux, Jérémie Rosain, Sarah Bamberger, Marie-Gabrielle Vigue, Marion Malphettes, Pierre Quartier, Capucine Picard, Frédéric Rieux-Laucat, and Aude Magerus. Study of the potential role of caspase-10 mutations in the development of autoimmune lymphoproliferative syndrome. Cell Death & Disease, May 2024. URL: https://doi.org/10.1038/s41419-024-06679-6, doi:10.1038/s41419-024-06679-6. This article has 7 citations and is from a peer-reviewed journal.

  16. (lambert2021presentationanddiagnosis pages 3-4): Michele P. Lambert. Presentation and diagnosis of autoimmune lymphoproliferative syndrome (alps). Expert Review of Clinical Immunology, 17:1163-1173, Sep 2021. URL: https://doi.org/10.1080/1744666x.2021.1978842, doi:10.1080/1744666x.2021.1978842. This article has 27 citations and is from a peer-reviewed journal.

  17. (bride2017autoimmunelymphoproliferativesyndrome pages 1-3): Karen Bride and David Teachey. Autoimmune lymphoproliferative syndrome: more than a fascinating disease. F1000Research, 6:1928, Nov 2017. URL: https://doi.org/10.12688/f1000research.11545.1, doi:10.12688/f1000research.11545.1. This article has 129 citations and is from a peer-reviewed journal.

  18. (luan2024eaf2deficiencyattenuates pages 1-2): Yingying Luan, Qing Min, Runyun Zhang, Zichao Wen, Xin Meng, Ziying Hu, Xiaoqian Feng, Meiping Yu, Lulu Dong, and Ji-Yang Wang. Eaf2 deficiency attenuates autoimmune disease in faslpr mice by modulating b cell activation and apoptosis. iScience, 27:111220, Nov 2024. URL: https://doi.org/10.1016/j.isci.2024.111220, doi:10.1016/j.isci.2024.111220. This article has 1 citations and is from a peer-reviewed journal.

  19. (price2014naturalhistoryof media e08f037f): Susan Price, Pamela A. Shaw, Amy Seitz, Gyan Joshi, Joie Davis, Julie E. Niemela, Katie Perkins, Ronald L. Hornung, Les Folio, Philip S. Rosenberg, Jennifer M. Puck, Amy P. Hsu, Bernice Lo, Stefania Pittaluga, Elaine S. Jaffe, Thomas A. Fleisher, V. Koneti Rao, and Michael J. Lenardo. Natural history of autoimmune lymphoproliferative syndrome associated with fas gene mutations. Blood, 123 13:1989-99, Mar 2014. URL: https://doi.org/10.1182/blood-2013-10-535393, doi:10.1182/blood-2013-10-535393. This article has 270 citations and is from a highest quality peer-reviewed journal.

  20. (NCT00392951 chunk 1): Sirolimus for Autoimmune Disease of Blood Cells. Children's Hospital of Philadelphia. 2006. ClinicalTrials.gov Identifier: NCT00392951

  21. (NCT02579967 chunk 1): Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies. National Cancer Institute (NCI). 2015. ClinicalTrials.gov Identifier: NCT02579967

  22. (NCT02579967 chunk 2): Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies. National Cancer Institute (NCI). 2015. ClinicalTrials.gov Identifier: NCT02579967

  23. (molnar2020keydiagnosticmarkers pages 17-19): Emese Molnár, Nesrine Radwan, Gábor Kovács, Hajnalka Andrikovics, Frances Henriquez, Anton Zarafov, Matthew Hayman, Daniela Linzner, Adrian J. Thrasher, Matthew Buckland, Siobhan O. Burns, and Kimberly C. Gilmour. Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis. Blood, 136:1933-1945, Oct 2020. URL: https://doi.org/10.1182/blood.2020005486, doi:10.1182/blood.2020005486. This article has 44 citations and is from a highest quality peer-reviewed journal.

Manual Pubmed Review ▸
FAS-related Autoimmune Lymphoproliferative Syndrome: Mechanistic Summary
n/a 10 citations 2026-04-16T19:39:00Z

FAS-related Autoimmune Lymphoproliferative Syndrome: Mechanistic Summary

Disease scope and terminology

FAS-related autoimmune lymphoproliferative syndrome corresponds to the classical FAS-driven ALPS spectrum and aligns with the newer MONDO label MONDO:1060194 FAS-related autoimmune lymphoproliferative syndrome. In historical literature, the dominant form is usually called ALPS-Ia or autoimmune lymphoproliferative syndrome type 1A.

Genetics and inheritance

The dominant clinical form is usually caused by heterozygous germline FAS variants, especially lesions affecting the intracellular death domain. Published family studies support autosomal dominant inheritance with incomplete penetrance. Reviews consistently describe FAS as the most frequent molecular cause of ALPS.

Core pathophysiology

FAS-related ALPS is fundamentally a disorder of defective Fas-mediated apoptosis. Failure of activation-induced lymphocyte deletion disrupts lymphocyte homeostasis, allowing survival of autoreactive lymphocytes and expansion of the characteristic alpha-beta double-negative T-cell population. This mechanistically explains the triad of:

  • chronic benign lymphoproliferation
  • autoimmune cytopenias
  • lymphoma predisposition

Hallmark clinical phenotype

The core phenotype includes:

  • chronic non-malignant lymphadenopathy
  • hepatosplenomegaly
  • autoimmune cytopenias, especially autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia
  • elevated circulating alpha-beta double-negative T cells
  • increased lifetime risk of Hodgkin and non-Hodgkin lymphoma

Diagnosis

Diagnosis is supported by:

  • flow-cytometric quantification of CD3+TCR-alpha-beta+CD4-CD8- cells
  • serum biomarker assessment including vitamin B12, soluble Fas ligand, and IL-10
  • functional apoptosis assays demonstrating impaired Fas-mediated apoptosis
  • confirmatory FAS molecular genetic testing

Treatment

The strongest treatment evidence identified here supports sirolimus as a highly effective steroid-sparing therapy for refractory autoimmune cytopenias and benign lymphoproliferation in ALPS. Reviews also describe mycophenolate mofetil as active, but sirolimus has the clearest direct response data.

References

  • PMID:12732128
  • PMID:15160902
  • PMID:19208097
  • PMID:20170754
  • PMID:21447005
  • PMID:21885601
  • PMID:22157362
  • PMID:23850805
  • PMID:23993982
  • PMID:26504182