Cytosolic phospholipase A2 alpha (cPLA2alpha) deficiency is an autosomal recessive disorder of eicosanoid biosynthesis caused by biallelic loss-of-function variants in PLA2G4A. cPLA2alpha is the enzyme that releases arachidonic acid from membrane phospholipids when a cell is stimulated, and so supplies the substrate for every downstream cyclooxygenase and lipoxygenase product. When it is missing, platelets, leukocytes and endothelial cells make little thromboxane, prostaglandin or leukotriene, even though the downstream enzymes are intact. The disease has two arms that follow from that single block. In platelets, loss of agonist-driven thromboxane A2 generation removes the autocrine amplification loop, giving impaired aggregation and dense-granule secretion to ADP and collagen with a normal response to exogenous arachidonic acid, and a mucocutaneous and post-procedural bleeding tendency. In the gut, loss of mucosal prostaglandin synthesis produces a phenotype that resembles lifelong NSAID enteropathy: recurrent ulcers of the small intestine (and in some families the stomach and duodenum), gastrointestinal blood loss and anaemia, perforation, and stenosing strictures that need repeated resection. Onset of the intestinal disease is usually in early childhood. The intestinal phenotype was first recognised as cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), a clinically defined entity of previously unknown cause. Homozygous PLA2G4A loss of function explains CMUSE in some families, but not all CMUSE is PLA2G4A-related, so this entry treats CMUSE as a related clinical diagnosis rather than as a synonym (see `mappings`). Five patients in three families carry biallelic variants that this entry accepts as causal.
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name: Cytosolic Phospholipase A2 Alpha Deficiency
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder
term:
id: MONDO:0018794
label: cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder
description: >
Cytosolic phospholipase A2 alpha (cPLA2alpha) deficiency is an autosomal
recessive disorder of eicosanoid biosynthesis caused by biallelic
loss-of-function variants in PLA2G4A. cPLA2alpha is the enzyme that releases
arachidonic acid from membrane phospholipids when a cell is stimulated, and
so supplies the substrate for every downstream cyclooxygenase and
lipoxygenase product. When it is missing, platelets, leukocytes and
endothelial cells make little thromboxane, prostaglandin or leukotriene,
even though the downstream enzymes are intact.
The disease has two arms that follow from that single block. In platelets,
loss of agonist-driven thromboxane A2 generation removes the autocrine
amplification loop, giving impaired aggregation and dense-granule secretion
to ADP and collagen with a normal response to exogenous arachidonic acid,
and a mucocutaneous and post-procedural bleeding tendency. In the gut, loss
of mucosal prostaglandin synthesis produces a phenotype that resembles
lifelong NSAID enteropathy: recurrent ulcers of the small intestine (and in
some families the stomach and duodenum), gastrointestinal blood loss and
anaemia, perforation, and stenosing strictures that need repeated resection.
Onset of the intestinal disease is usually in early childhood.
The intestinal phenotype was first recognised as cryptogenic multifocal
ulcerous stenosing enteritis (CMUSE), a clinically defined entity of
previously unknown cause. Homozygous PLA2G4A loss of function explains CMUSE
in some families, but not all CMUSE is PLA2G4A-related, so this entry treats
CMUSE as a related clinical diagnosis rather than as a synonym (see
`mappings`). Five patients in three families carry biallelic variants
that this entry accepts as causal.
synonyms:
- cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder
- PLA2G4A-related platelet dysfunction
- platelet dysfunction due to cytosolic phospholipase-A2 alpha deficiency
- cPLA2alpha deficiency
- group IVA cytosolic phospholipase A2 deficiency
- chronic enteropathy associated with PLA2G4A
- CEAP
parents:
- Inherited platelet function disorder
- Inherited blood coagulation disorder
- Intestinal disorder
notes: >
Scope relative to CMUSE. MONDO:0018765 (cryptogenic multifocal ulcerous
stenosing enteritis) is a separate, clinically defined concept with no
dismech entry at the time of writing. It is recorded under
`mappings.mondo_mappings` with `skos:relatedMatch` rather than exactMatch or
narrowMatch, because the literature states that PLA2G4A variants are not the
sole cause of CMUSE and that most CMUSE cases have not been tested for this
gene, and a second genetic cause of an overlapping enteropathy (SLCO2A1) is
established. The intestinal pathophysiology here is curated only for
PLA2G4A-deficient patients.
Variants not counted as causal. Two published Chinese reports attribute
small-intestinal ulcers to PLA2G4A variants that are either a common
polymorphism or a single heterozygous missense change; a 2026 review argues
the former does not affect enzyme function. Neither is used here as evidence
for the disease.
Factor XI. The Italian family carrying homozygous p.Asp575His also had mildly
reduced factor XI levels in three members. This is treated as a
family-specific finding and is not attributed to cPLA2alpha deficiency.
No GeneReviews chapter names this disease.
mappings:
mondo_mappings:
- term:
id: MONDO:0018765
label: cryptogenic multifocal ulcerous stenosing enteritis
mapping_predicate: skos:relatedMatch
mapping_source: manual curation
mapping_justification: >-
Clinically defined small-bowel ulcer-stricture syndrome of which
homozygous PLA2G4A loss of function is one documented cause; not all
CMUSE is cPLA2alpha deficiency, so the relation is not subsumption.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Affected individuals are homozygous (Serbian siblings with a splice-site
deletion; Italian twins with p.Asp575His) or compound heterozygous (the
first American proband, p.Ser111Pro and p.Arg485His). In the Italian
kindred some heterozygous relatives had gastrointestinal ulcers but none
had a bleeding diathesis, so heterozygosity may confer a partial gastric
phenotype without the full disease.
evidence:
- reference: PMID:23268370
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated the genetic basis of this autosomal recessive condition in a pair of affected siblings who have 40-year histories of catastrophic gastrointestinal and extraintestinal disease."
explanation: States autosomal recessive inheritance in the family in which the homozygous PLA2G4A deletion was found.
- reference: PMID:21247147
reference_title: Functional characterization of mutations in inherited human cPLA₂ deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We previously described a patient deficient in cPLA(2)α activity, which was associated with mutations in both alleles encoding the enzyme."
explanation: Biallelic variants in the first described proband.
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GI ulcers affected 5/14 heterozygous (< 40 years) and 1/16 wild-type homozygous (> 60 years) family members; none had bleeding diathesis."
explanation: >-
Bleeding is confined to homozygotes, while some heterozygous relatives
have ulcers, which is the basis for describing heterozygotes as possibly
partially affected in the gut.
mechanistic_hypotheses:
- hypothesis_group_id: arachidonate_release_failure
hypothesis_label: Failure of cPLA2alpha-Dependent Arachidonic Acid Release
status: CANONICAL
description: >-
Loss of cPLA2alpha removes stimulus-coupled release of arachidonic acid,
starving cyclooxygenase and lipoxygenase pathways of substrate. In
platelets this abolishes thromboxane A2 amplification and causes a
platelet function defect; in the gastrointestinal mucosa it removes
cytoprotective prostaglandins and causes NSAID-like ulceration with
secondary stricturing. CANONICAL because the biochemical signature (low
eicosanoids with a normal response to exogenous arachidonic acid), the
enzymology of the patient variants and absent protein in patient tissue
agree across independent families. The mucosal arm rests partly on
analogy with NSAID injury, since mucosal prostaglandin content has not
been measured in patient tissue.
pathophysiology:
- name: PLA2G4A Biallelic Loss-of-Function Variants
role: trigger
biological_scale: MOLECULAR
conforms_to: "primary_hemostatic_plug_failure#Loss of a Platelet Primary-Hemostatic Component"
description: >
Germline biallelic PLA2G4A variants on 1q31.1. Reported alleles are
private to families: a homozygous 4 bp deletion at the exon 17 splice donor
(p.V707fsX10) in Serbian siblings, homozygous c.1723G>C (p.Asp575His) in
Italian twins, and compound heterozygous p.Ser111Pro with p.Arg485His (on
the allele carrying the common p.Lys651Arg polymorphism) in an American
man.
genes:
- preferred_term: PLA2G4A
term:
id: hgnc:9035
label: PLA2G4A
modifier: DECREASED
molecular_functions:
- preferred_term: phospholipase A2 activity
modifier: DECREASED
term:
id: GO:0004623
label: A2-type glycerophospholipase activity
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
description: >-
Homozygous in two of three published families; the third is compound
heterozygous. Both configurations abolish enzyme function.
evidence:
- reference: PMID:23268370
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Insertion/deletion variation analysis revealed the presence of a homozygous 4 bp deletion (g.155574_77delGTAA) in the PLA2G4A gene, located in the splice donor site directly after exon 17 (the penultimate exon) of the gene in both affected siblings."
explanation: Homozygous truncating PLA2G4A variant in the CMUSE family.
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients were homozygous for 1723G>C transition in PLA2G4A gene, which changed the codon for Asp575 to His."
explanation: Homozygous missense variant in the Italian twins.
- reference: PMID:18451993
reference_title: "Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient's cPLA2alpha genes (p.[Ser111Pro]+[Arg485His; Lys651Arg])."
explanation: Compound heterozygous variants in the first proband.
downstream:
- target: Loss of cPLA2alpha Protein or Catalytic Activity
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:21247147
reference_title: Functional characterization of mutations in inherited human cPLA₂ deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Taken together, our results show that the S111P mutation hampers calcium binding and membrane translocation without affecting the catalytic activity, and that the mutation R485H does not affect membrane translocation but blocks catalytic activity that leads to inactivation of the enzyme."
explanation: Each allele of the compound heterozygote inactivates the enzyme by a different route.
- name: Loss of cPLA2alpha Protein or Catalytic Activity
biological_scale: MOLECULAR
description: >
Depending on the allele, the protein is absent (undetectable in gut or
platelets of homozygotes for the truncating and p.Asp575His variants) or
present but unable to translocate to membranes or to hydrolyse its
substrate (the two alleles of the compound heterozygote).
molecular_functions:
- preferred_term: phospholipase A2 activity
modifier: DECREASED
term:
id: GO:0004623
label: A2-type glycerophospholipase activity
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
- preferred_term: intestinal epithelial cell
term:
id: CL:0002563
label: intestinal epithelial cell
evidence:
- reference: PMID:23268370
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "cPLA(2)α protein expression was undetectable in the gut of both siblings"
explanation: Absent protein in patient intestinal tissue.
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "platelet cPLA2a was undetectable by Western Blotting in the proband and his sister, and decreased in 1723G>C heterozygous subjects"
explanation: Absent platelet protein in homozygotes and a dosage effect in heterozygotes.
- reference: PMID:18451993
reference_title: "Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The total PLA2 activity in sonicated platelets was diminished"
explanation: Reduced phospholipase A2 activity in patient platelets.
downstream:
- target: Deficient Stimulus-Coupled Arachidonic Acid Release
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:21247147
reference_title: Functional characterization of mutations in inherited human cPLA₂ deficiency.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our results define how the mutations negatively influence cPLA(2)α function and explain the inability of the proband to release arachidonic acid for eicosanoid production."
explanation: Links the enzyme defect to failed arachidonate release.
- name: Deficient Stimulus-Coupled Arachidonic Acid Release
biological_scale: MOLECULAR
description: >
cPLA2alpha catalyses the first step of the arachidonic acid cascade.
Without it, stimulated cells cannot liberate arachidonic acid from membrane
phospholipids, so cyclooxygenase and lipoxygenase products fall together.
The defect is upstream of the cyclooxygenases: patient platelets aggregate
normally when arachidonic acid is supplied directly.
biological_processes:
- preferred_term: arachidonic acid metabolic process
modifier: DECREASED
term:
id: GO:0019369
label: arachidonate metabolic process
chemical_entities:
- preferred_term: arachidonic acid
term:
id: CHEBI:15843
label: arachidonic acid
evidence:
- reference: PMID:18451993
reference_title: "Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Levels of thromboxane B2 and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene B4 released from calcium ionophore-activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases."
explanation: Concurrent loss of cyclooxygenase and lipoxygenase products localises the block to substrate release.
- reference: PMID:26183771
reference_title: "Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These studies constitute a definitive account, demonstrating the fundamental role of cPLA2α to eicosanoid formation and cellular responses within the human circulation."
explanation: Comprehensive eicosanoid profiling of homozygous patients confirms the global substrate-release defect.
downstream:
- target: Loss of Platelet Thromboxane A2 Generation
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:26183771
reference_title: "Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Absence of cPLA2α almost abolished eicosanoid synthesis in platelets (e.g., thromboxane A2, control 20.5 ± 1.4 ng/ml vs. patient 0.1 ng/ml)"
explanation: Quantifies the loss of platelet thromboxane A2 caused by absent cPLA2alpha.
- target: Reduced Gastrointestinal Mucosal Prostaglandin Synthesis
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Mutations in PLA2G4A that result in loss of function lead to an absolute deficiency of PGE2 synthesis and consequent intestinal mucosal damage."
explanation: Review synthesis linking loss of arachidonate supply to mucosal PGE2 deficiency.
- reference: PMID:26183771
reference_title: "Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "For example, prostacyclin metabolites were strongly reduced (18.4% of control) in patients lacking cPLA2α, whereas PGE2 metabolites (77.8% of control) were similar to healthy volunteer levels."
explanation: >-
Contradicts the review's word "absolute": whole-body PGE2 output,
measured as urinary metabolites, was near normal in homozygous
patients, so other routes supply some PGE2 systemically. This does not
exclude a local mucosal deficit, which was not measured.
- target: Deficient Leukocyte Leukotriene Biosynthesis
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "LTB4 biosynthesis by ionophore-activated leukocytes was only 3% of controls, and urinary LTE4 was undetectable."
explanation: Lipoxygenase output is lost along with cyclooxygenase output.
- name: Loss of Platelet Thromboxane A2 Generation
biological_scale: CELLULAR
description: >
Platelets cannot generate thromboxane A2 on stimulation. Serum thromboxane
B2 was about 5% of control in the first proband and essentially absent in
homozygous patients.
biological_processes:
- preferred_term: prostanoid biosynthetic process
modifier: DECREASED
term:
id: GO:0046457
label: prostanoid biosynthetic process
chemical_entities:
- preferred_term: thromboxane A2
term:
id: CHEBI:15627
label: thromboxane A2
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (P<0.006), and serum 12-HETE was 1.3% of controls (P<0.005)."
explanation: Quantifies the platelet eicosanoid defect in the first proband.
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "serum levels of thromboxane (Tx) B2 and 12-hydroxyeicosatetraenoic acid, and urinary levels of 11-dehydro-TxB2 were extremely low"
explanation: Same defect in the Italian homozygotes, in serum and urine.
downstream:
- target: Impaired Thromboxane-Dependent Platelet Aggregation and Granule Secretion
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:23268370
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with platelet aggregation and thromboxane A(2) production, as functional assays for cPLA(2)α activity, grossly impaired"
explanation: Thromboxane loss and aggregation failure measured together in homozygous patients.
- name: Impaired Thromboxane-Dependent Platelet Aggregation and Granule Secretion
biological_scale: CELLULAR
conforms_to: "primary_hemostatic_plug_failure#Impaired Platelet Activation, Granule Secretion, and Integrin Inside-Out Signalling"
description: >
Without thromboxane A2 amplification, aggregation and dense-granule
secretion to ADP and collagen are reduced, while aggregation to exogenous
arachidonic acid is normal because COX-1 and thromboxane synthase are
intact. This normal arachidonate response distinguishes cPLA2alpha
deficiency from COX-1 deficiency (the aspirin-like defect) on
aggregometry.
biological_processes:
- preferred_term: platelet aggregation
modifier: DECREASED
term:
id: GO:0070527
label: platelet aggregation
- preferred_term: platelet degranulation
modifier: DECREASED
term:
id: GO:0002576
label: platelet degranulation
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
evidence:
- reference: PMID:18451993
reference_title: "Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid."
explanation: The characteristic aggregometry pattern.
- reference: PMID:26183771
reference_title: "Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "this was associated with impaired platelet activation and enhanced inflammatory responses"
explanation: Platelet activation impaired in homozygous patients.
downstream:
- target: Impaired ADP-Induced Platelet Aggregation
causal_link_type: DIRECT
- target: Impaired Collagen-Induced Platelet Aggregation
causal_link_type: DIRECT
- target: Abnormal Platelet Dense Granule Secretion
causal_link_type: DIRECT
- target: Bleeding Diathesis
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We described a syndromic form of deficiency of cPLA2a , characterised by recurrent GI ulcers and bleeding diathesis, associated with mild inherited deficiency of factor XI."
explanation: >-
Bleeding diathesis accompanies the platelet defect in homozygotes.
The same family's mild factor XI deficiency is a possible additional
contributor that this edge does not account for.
- target: Gastrointestinal Hemorrhage
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The platelet defect plausibly aggravates bleeding from the mucosal
ulcers; no source separates its contribution from that of the ulcers.
- name: Reduced Gastrointestinal Mucosal Prostaglandin Synthesis
biological_scale: TISSUE
description: >
Prostaglandins, particularly PGE2, maintain the gastrointestinal mucosal
barrier. Loss of the substrate for mucosal prostaglandin synthesis removes
this protection, by analogy with NSAID-induced injury. Mucosal
prostaglandin content has not been measured directly in patient tissue in
the cited studies.
biological_processes:
- preferred_term: prostaglandin biosynthetic process
modifier: DECREASED
term:
id: GO:0001516
label: prostaglandin biosynthetic process
cell_types:
- preferred_term: epithelial cell of small intestine
term:
id: CL:0002254
label: epithelial cell of small intestine
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "PGE2 can promote mucus barrier formation, regulate mucosal epithelial turnover, and inhibit mucosal inflammation."
explanation: Role of the prostaglandin whose synthesis is lost.
- reference: PMID:35275899
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis and other under-recognised small bowel inflammatory enteropathies.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Mutations in the PLA2G4A gene result in cytosolic phospholipase A2α deficiency and reduced arachidonic acid for prostaglandin synthesis leading to a severe ulcerating, stenosing and fistulating small bowel disease."
explanation: Review statement of the mechanism from deficiency to enteropathy.
downstream:
- target: Gastrointestinal Mucosal Ulceration
causal_link_type: DIRECT
hypothesis_groups:
- arachidonate_release_failure
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "We present here a genetic deficiency of eicosanoid biosynthesis that illuminates the mechanism of NSAID-induced ulcers of the small intestine."
explanation: >-
The authors frame the patient's ulcers as the genetic counterpart of
NSAID enteropathy; INDIRECT because the causal step from
prostaglandin loss to ulcer is inferred by analogy.
- name: Deficient Leukocyte Leukotriene Biosynthesis
biological_scale: CELLULAR
description: >
Ionophore-stimulated leukocytes make almost no leukotriene B4 and urinary
leukotriene E4 is undetectable. No clinical consequence of this has been
established; it is recorded as a biochemical feature.
biological_processes:
- preferred_term: leukotriene biosynthetic process
modifier: DECREASED
term:
id: GO:0019370
label: leukotriene biosynthetic process
cell_types:
- preferred_term: leukocyte
term:
id: CL:0000738
label: leukocyte
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "LTB4 biosynthesis by ionophore-activated leukocytes was only 3% of controls, and urinary LTE4 was undetectable."
explanation: Direct measurement of the lipoxygenase-pathway deficit.
- name: Gastrointestinal Mucosal Ulceration
biological_scale: TISSUE
description: >
Multiple ulcers chiefly of the jejunum and ileum, and in some families of
the stomach and duodenum, beginning in early childhood in most patients
and recurring throughout life.
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Notably, patients with CEAP seem to represent a more severe subset of CMUSE/CNSU, with most cases (5/7) presenting before age 5, unlike the typical onset in the fourth or fifth decade seen in CMUSE/CNSU."
explanation: >-
Pooled onset in the review's seven patients. That denominator includes
two Chinese cases this entry does not accept (onset at 31 and 14 years);
the five early-onset cases are exactly the five patients this entry
accepts, per the review's patient table.
downstream:
- target: Ileal Ulcers
causal_link_type: DIRECT
- target: Gastroduodenal Ulcers
causal_link_type: DIRECT
- target: Gastrointestinal Hemorrhage
causal_link_type: DIRECT
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor."
explanation: Blood loss accompanies the ulcer disease.
- target: Intestinal Perforation
causal_link_type: DIRECT
- target: Abdominal Pain
causal_link_type: DIRECT
- target: Hypoalbuminemia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Ulcer-Associated Intestinal Stricturing
causal_link_type: DIRECT
- name: Ulcer-Associated Intestinal Stricturing
biological_scale: TISSUE
description: >
Repeated ulceration is followed by short strictures of the small bowel
and, in the Serbian siblings, the pylorus, leading to obstruction and
repeated resections. Fibrosis is mentioned as a possible contributing
process in the review literature without direct study in patients.
evidence:
- reference: PMID:35275899
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis and other under-recognised small bowel inflammatory enteropathies.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Mutations in the PLA2G4A gene result in cytosolic phospholipase A2α deficiency and reduced arachidonic acid for prostaglandin synthesis leading to a severe ulcerating, stenosing and fistulating small bowel disease."
explanation: States the stenosing course.
downstream:
- target: Small Intestinal Stenosis
causal_link_type: DIRECT
- target: Pyloric Stenosis
causal_link_type: DIRECT
- target: Intestinal Obstruction
causal_link_type: DIRECT
- target: Intestinal Volvulus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Laboratory
name: Impaired ADP-Induced Platelet Aggregation
description: >
Reduced aggregation to ADP with a normal response to exogenous arachidonic
acid.
phenotype_term:
preferred_term: Impaired ADP-induced platelet aggregation
term:
id: HP:0004866
label: Impaired ADP-induced platelet aggregation
diagnostic: true
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP and a blunted aggregation response to ADP and collagen, but normal response to arachidonic acid (AA)."
explanation: Blunted ADP aggregation with preserved arachidonate response.
- category: Laboratory
name: Impaired Collagen-Induced Platelet Aggregation
phenotype_term:
preferred_term: Impaired collagen-induced platelet aggregation
term:
id: HP:0008320
label: Impaired collagen-induced platelet aggregation
diagnostic: true
evidence:
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Platelet aggregation/δ-granules secretion by collagen was impaired, but normal by AA"
explanation: Collagen-induced aggregation impaired in the Italian homozygotes.
- category: Laboratory
name: Abnormal Platelet Dense Granule Secretion
phenotype_term:
preferred_term: Absent ADP-induced platelet dense granule secretion
term:
id: HP:0030397
label: Abnormal platelet dense granule secretion
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP"
explanation: Absent ATP release from dense granules on ADP stimulation.
- category: Hematologic
name: Bleeding Diathesis
description: >
Early-onset mucocutaneous and post-procedural bleeding, documented in
detail in the Italian twins: epistaxis, gum bleeding, gastroduodenal
bleeding, haematuria and postoperative haemorrhage. Bleeding was absent in
heterozygous relatives.
phenotype_term:
preferred_term: Bleeding diathesis
term:
id: HP:0001892
label: Abnormal bleeding
evidence:
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe a patient (27-year-old man) and his twin-sister with early-onset bleeding diathesis and recurrent gastro-intestinal (GI) ulcers."
explanation: Early-onset bleeding diathesis in homozygous twins.
sequelae:
- target: Epistaxis
- target: Gingival Bleeding
- target: Hematuria
- target: Prolonged Bleeding After Surgery
- category: Hematologic
name: Epistaxis
phenotype_term:
preferred_term: Epistaxis
term:
id: HP:0000421
label: Epistaxis
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "identified a homozygous PLA2G4A missense mutation (c.1723G>C) in twins presenting with early-onset systematic mucosal bleeding (including epistaxis, gum bleeding, gastroduodenal bleeding, and hematuria) and postoperative hemorrhage"
explanation: Review summary of the Italian twins' bleeding manifestations.
- category: Hematologic
name: Gingival Bleeding
phenotype_term:
preferred_term: Gum bleeding
term:
id: HP:0000225
label: Gingival bleeding
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "identified a homozygous PLA2G4A missense mutation (c.1723G>C) in twins presenting with early-onset systematic mucosal bleeding (including epistaxis, gum bleeding, gastroduodenal bleeding, and hematuria) and postoperative hemorrhage"
explanation: Gum bleeding listed among the twins' manifestations.
- category: Hematologic
name: Hematuria
phenotype_term:
preferred_term: Hematuria
term:
id: HP:0000790
label: Hematuria
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "identified a homozygous PLA2G4A missense mutation (c.1723G>C) in twins presenting with early-onset systematic mucosal bleeding (including epistaxis, gum bleeding, gastroduodenal bleeding, and hematuria) and postoperative hemorrhage"
explanation: Haematuria listed among the twins' manifestations.
- category: Hematologic
name: Prolonged Bleeding After Surgery
phenotype_term:
preferred_term: Postoperative hemorrhage
term:
id: HP:0004846
label: Prolonged bleeding after surgery
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "identified a homozygous PLA2G4A missense mutation (c.1723G>C) in twins presenting with early-onset systematic mucosal bleeding (including epistaxis, gum bleeding, gastroduodenal bleeding, and hematuria) and postoperative hemorrhage"
explanation: Postoperative haemorrhage in the twins.
- category: Gastrointestinal
name: Ileal Ulcers
description: >
Multiple recurrent small-intestinal ulcers in the absence of NSAID use.
Of the five accepted patients, the ileum is involved in three (the first
proband and both Serbian siblings) and the jejunum in two; the Italian
twins' disease is gastroduodenal.
phenotype_term:
preferred_term: Recurrent small intestinal (jejunoileal) ulcers
term:
id: HP:0032024
label: Ileal ulcer
evidence:
- reference: PMID:18451993
reference_title: "Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors."
explanation: Multiple small intestinal ulcers without NSAID exposure in the first proband.
- reference: PMID:30065566
reference_title: Genetic analysis is helpful for the diagnosis of small bowel ulceration.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Recently, recessive mutations in the PLA2G4A and SLCO2A1 genes have been shown to cause small intestinal diseases."
explanation: Places PLA2G4A among the recessive causes of small bowel ulceration.
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "American | No | c.331T>C c.1454 G>A c.1952A>G | Compound heterozygous | Anemia, Abdominal Pain, GIB, Intestinal Perforation"
explanation: Patient-table row for the first proband, recording perforation and jejunal and ileal involvement.
- category: Gastrointestinal
name: Gastroduodenal Ulcers
description: >
Recurrent gastric and duodenal ulcers, prominent in the Italian twins and
also recorded in the Serbian siblings.
phenotype_term:
preferred_term: Recurrent gastroduodenal ulcers
term:
id: HP:0004398
label: Peptic ulcer
evidence:
- reference: PMID:25102815
reference_title: Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We described a syndromic form of deficiency of cPLA2a , characterised by recurrent GI ulcers and bleeding diathesis, associated with mild inherited deficiency of factor XI."
explanation: Recurrent GI (gastroduodenal) ulcers define this family's presentation.
- category: Gastrointestinal
name: Gastrointestinal Hemorrhage
phenotype_term:
preferred_term: Gastrointestinal bleeding
term:
id: HP:0002239
label: Gastrointestinal hemorrhage
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor."
explanation: Chronic gastrointestinal blood loss.
sequelae:
- target: Anemia
- category: Hematologic
name: Anemia
description: >
Anaemia from chronic gastrointestinal blood loss, recorded in three of
the five accepted patients (the first proband and both Serbian siblings)
in a pooled review table.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "American | No | c.331T>C c.1454 G>A c.1952A>G | Compound heterozygous | Anemia, Abdominal Pain, GIB, Intestinal Perforation"
explanation: Patient-level table row for the first proband listing anaemia with GI bleeding.
- category: Gastrointestinal
name: Intestinal Perforation
phenotype_term:
preferred_term: Small bowel perforation
term:
id: HP:0031368
label: Intestinal perforation
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Furthermore, while these patients exhibited a chronic course, five also experienced acute complications, including intestinal perforation, obstruction, or torsion, to varying degrees."
explanation: >-
Acute perforation, obstruction or torsion in five of the review's seven
patients. The review's denominator includes two Chinese cases this entry
does not accept (see notes); among the five accepted patients,
perforation is recorded for the first proband and one Serbian sibling.
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor."
explanation: Recurrent small bowel perforations in the first proband.
- category: Gastrointestinal
name: Small Intestinal Stenosis
phenotype_term:
preferred_term: Small intestinal stenosis
term:
id: HP:0012848
label: Small intestinal stenosis
evidence:
- reference: PMID:23268370
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "We have identified mutations in PLA2G4A as a cause of CMUSE in two affected siblings."
explanation: >-
CMUSE (cryptogenic multifocal ulcerating stenosing enteritis) is defined
by multifocal small-bowel strictures, so its diagnosis in homozygous
siblings implies the stenosis; INDIRECT because the sentence names the
diagnosis rather than the finding.
- category: Gastrointestinal
name: Pyloric Stenosis
description: >
Recorded in both Serbian siblings in a pooled patient table; not reported
in other families.
phenotype_term:
preferred_term: Pyloric stenosis
term:
id: HP:0002021
label: Pyloric stenosis
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Anemia, PU, GIB, Pyloric Stenosis, Intestinal Perforation, Intestinal Volvulus"
explanation: Patient table row for one of the homozygous Serbian siblings.
- category: Gastrointestinal
name: Intestinal Obstruction
phenotype_term:
preferred_term: Intestinal obstruction
term:
id: HP:0005214
label: Intestinal obstruction
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Furthermore, while these patients exhibited a chronic course, five also experienced acute complications, including intestinal perforation, obstruction, or torsion, to varying degrees."
explanation: >-
Obstruction among the acute complications. The review's count of five
includes two cases this entry does not accept; the accepted patients
with obstruction-type complications are the Serbian siblings (volvulus,
adhesions) and the first proband (perforation).
- category: Gastrointestinal
name: Intestinal Volvulus
description: >
Recorded in both Serbian siblings, together with multiple adhesions in
one, in a pooled patient table; plausibly a consequence of repeated
stricturing and surgery. Not reported in other families.
phenotype_term:
preferred_term: Intestinal volvulus
term:
id: HP:0002580
label: Volvulus
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Anemia, PU, GIB, Pyloric Stenosis, Intestinal Perforation, Intestinal Volvulus"
explanation: Patient table row for one Serbian sibling listing volvulus.
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Anemia, PU, GIB, Pyloric Stenosis, Hypoalbuminemia, Intestinal Volvulus and Multiple adhesions"
explanation: Patient table row for the other Serbian sibling listing volvulus and adhesions.
- category: Gastrointestinal
name: Abdominal Pain
description: >
Recorded for the first proband; abdominal pain is expected with
ulceration and stricturing but is not itemised for the other accepted
patients.
phenotype_term:
preferred_term: Abdominal pain
term:
id: HP:0002027
label: Abdominal pain
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "American | No | c.331T>C c.1454 G>A c.1952A>G | Compound heterozygous | Anemia, Abdominal Pain, GIB, Intestinal Perforation"
explanation: Patient table row for the first proband listing abdominal pain.
- category: Laboratory
name: Hypoalbuminemia
description: >
Recorded in one of the Serbian siblings; plausibly reflects enteric protein
loss from ulcerated mucosa, which has not been measured directly.
phenotype_term:
preferred_term: Hypoalbuminemia
term:
id: HP:0003073
label: Hypoalbuminemia
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Anemia, PU, GIB, Pyloric Stenosis, Hypoalbuminemia, Intestinal Volvulus and Multiple adhesions"
explanation: Patient table row listing hypoalbuminaemia.
biochemical:
- name: Serum thromboxane B2
presence: DECREASED
context: >-
Serum thromboxane B2 reflects platelet thromboxane A2 generation during
clotting. It is a few percent of control or lower in affected patients.
cell_types:
- preferred_term: platelet
term:
id: CL:0000233
label: platelet
readouts:
- target: Loss of Platelet Thromboxane A2 Generation
relationship: READOUT_OF
direction: NEGATIVE
endpoint_context: DIAGNOSTIC
evidence:
- reference: PMID:19148786
reference_title: The enteropathy of prostaglandin deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (P<0.006), and serum 12-HETE was 1.3% of controls (P<0.005)."
explanation: Quantified loss of serum thromboxane B2.
- name: Urinary prostacyclin metabolites
presence: DECREASED
context: >-
Urinary prostacyclin metabolites fell to about a fifth of control, whereas
urinary PGE2 metabolites were near normal, showing that the systemic
eicosanoid deficit is selective.
readouts:
- target: Deficient Stimulus-Coupled Arachidonic Acid Release
relationship: READOUT_OF
direction: NEGATIVE
evidence:
- reference: PMID:26183771
reference_title: "Inherited human group IVA cytosolic phospholipase A2 deficiency abolishes platelet, endothelial, and leucocyte eicosanoid generation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "For example, prostacyclin metabolites were strongly reduced (18.4% of control) in patients lacking cPLA2α, whereas PGE2 metabolites (77.8% of control) were similar to healthy volunteer levels."
explanation: Selective reduction of urinary prostacyclin metabolites.
genetic:
- name: PLA2G4A
notes: >
Phospholipase A2 group IVA on 1q31.1, encoding the 749-residue
calcium-dependent cytosolic phospholipase A2 alpha. Only a handful of
families are published and all alleles are private; no ClinGen
gene-disease validity classification is recorded.
gene_term:
preferred_term: PLA2G4A
term:
id: hgnc:9035
label: PLA2G4A
relationship_type: CAUSATIVE
variant_origin: GERMLINE
evidence:
- reference: PMID:23268370
reference_title: Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified mutations in PLA2G4A as a cause of CMUSE in two affected siblings."
explanation: Gene-disease association by homozygosity mapping and exome sequencing.
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Although PLA2G4A mutations have long been linked to small intestinal ulcers, to date, only seven confirmed patients can be classified as CEAP (Tables 3 and 4), and most documented cases of CMUSE/CNSU remain untested for this gene."
explanation: >-
States the size of the published series. The review's seven include two
Chinese cases (a common polymorphism and a single heterozygous variant)
that this entry does not accept, leaving five patients in three
families.
animal_models:
- name: Pla2g4a knockout mouse
species: Mouse
genotype: Pla2g4a-/- (germline gene-targeted null)
publication: PMID:12432909
description: >
Germline cPLA2alpha-null mice grow normally but show intestinal ulcerative
lesions, a renal concentration defect, reduced fertility with impaired
parturition, and much lower prostaglandin and leukotriene output from
primary cells. The renal and reproductive phenotypes have not been
reported in the few human patients.
modeled_mechanisms:
- target: Gastrointestinal Mucosal Ulceration
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Spontaneous intestinal ulcerative lesions in the null mouse parallel the
human small-bowel ulcers.
limitations: >-
The mouse lesions are described only briefly in a review, with no
report here of stricturing, perforation or bleeding, which dominate the
human disease; the mouse also has renal and reproductive phenotypes not
seen in patients, so organ dependence on cPLA2alpha may differ between
species.
evidence:
- reference: PMID:12432909
reference_title: Roles for cytosolic phospholipase A2alpha as revealed by gene-targeted mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: REVIEW_SYNTHESIS
snippet: "Close examinations have revealed a renal concentration defect and intestinal ulcerative lesions."
explanation: Null mice develop intestinal ulcers, supporting the model's relevance to the mucosal arm.
- target: Deficient Stimulus-Coupled Arachidonic Acid Release
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: >-
Cells from null mice make much less prostaglandin and leukotriene,
the same global eicosanoid deficit seen in patient cells.
evidence:
- reference: PMID:12432909
reference_title: Roles for cytosolic phospholipase A2alpha as revealed by gene-targeted mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: REVIEW_SYNTHESIS
snippet: "Primary cultured cells prepared from cytosolic phospholipase A2alpha-deficient mice produce significantly smaller amounts of prostaglandins and leukotrienes."
explanation: Reproduces the human eicosanoid-release defect in mouse cells.
treatments:
- name: Misoprostol
description: >
Prostaglandin E1 analogue given to replace the missing mucosal
prostaglandin. Reported to give some relief but not to prevent recurrent
gastrointestinal bleeding.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: misoprostol
term:
id: CHEBI:63610
label: misoprostol
target_mechanisms:
- target: Reduced Gastrointestinal Mucosal Prostaglandin Synthesis
description: Supplies an exogenous prostaglandin receptor agonist downstream of the block.
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Misoprostol, though capable of providing some relief, does not prevent recurrent GI bleeding."
explanation: Partial benefit across published cases.
- name: Proton Pump Inhibitors
description: >
Ineffective in all documented cases, because the small-intestinal injury
is not acid-driven. Recorded so the negative experience is visible.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Because small intestinal bleeding is not an acid-related disorder, PPIs have been ineffective in all documented cases."
explanation: Refutes efficacy of acid suppression for the small-bowel disease.
- name: Surgical Resection
description: >
Resection for perforation, obstruction or refractory stricture. Not
curative; many patients need repeated resections.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: bowel resection
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Ulcer-Associated Intestinal Stricturing
description: Removes stenosed or perforated segments without altering the underlying defect.
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Surgery is typically reserved for severe complications but is not curative, with many patients requiring repeated bowel resections."
explanation: Role and limits of surgery.
- name: Supportive Care
description: >
Blood transfusion, iron supplementation and nutritional support for
chronic blood loss and protein loss.
treatment_term:
preferred_term: Supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Primarily supportive care (including blood transfusions, iron supplementation, and nutritional support)"
explanation: Supportive measures listed as the mainstay for CEAP.
- name: Corticosteroids
description: >
Tried in one patient without improvement.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: corticosteroid
term:
id: CHEBI:50858
label: corticosteroid
evidence:
- reference: PMID:42046811
reference_title: "What we know about prostaglandin pathway dysfunction in chronic enteropathies: From endoscopy to molecular diagnosis."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "The only patient treated with corticosteroids showed no improvement."
explanation: Single negative experience; too little to conclude in general.
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Create: Cytosolic_Phospholipase_A2_Alpha_Deficiency · 2026-10-15T02:35:12Z · View source
New entry for MONDO:0018794 (PLA2G4A). The falcon deep-research provider failed authentication. An Asta report was generated but its retrieved papers were almost all about other diseases, so it was not committed. An OpenScientist report was then generated and is committed (research/Cytosolic_Phospholipase_A2_Alpha_Deficiency-deep-research-openscientist.md; 16/16 references resolved, 0 off topic). Its term-validation section flags several wrong CURIEs (for example HP:0005263 offered as gastrointestinal ulceration is Gastritis; NCIT:C62042 offered as misoprostol is Leuprolide); none of its CURIEs were copied, and every binding in the entry was looked up separately. Cross-checking the report against the draft added a Pla2g4a knockout mouse model (PMID:12432909). Report claims not taken up: protein-losing enteropathy and edema (its supporting citation, PMID:24035666, is a general CMUSE paper rather than a PLA2G4A patient); NSAID avoidance (stated by the report as an expectation, with no quotable source); misoprostol rescue in mouse cardiac injury (not about this disease's phenotypes); Zulueta 2015 (PMID:25904158) has no abstract text to quote. The report counts fewer than five probands where the 2026 review tabulates seven; the entry follows the review. just preflight-dr was not run because it requires a local MONDO database that cannot be downloaded in this environment (disk limits). Most evidence was gathered directly from PubMed before the report arrived. Core sources: Adler 2008/2009 (first compound-heterozygous proband), Reed 2011 (enzymology of the patient alleles), Brooke 2014 (homozygous splice deletion in CMUSE siblings), Faioni 2014 (homozygous p.Asp575His twins with bleeding and gastroduodenal ulcers), Kirkby 2015 (eicosanoid profiling of homozygous patients), and the 2026 Ruan review of prostaglandin-pathway enteropathies for the pooled seven-patient table and treatment experience. Pathograph runs from biallelic variants through loss of enzyme and arachidonate release to two arms: platelet thromboxane loss (conforming to primary_hemostatic_plug_failure) and mucosal prostaglandin loss leading to ulceration and stricturing. CMUSE (MONDO:0018765) has no KB entry and is recorded as skos:relatedMatch because PLA2G4A is one cause of it, not the only one. Kirkby 2015 is cited as REFUTE against the review's claim of absolute PGE2 deficiency, since urinary PGE2 metabolites were near normal. Two Chinese case reports attributing ulcers to a common SNP or a single heterozygous variant were not used. Validated with just validate, validate-terms, count-verified-snippets (60/60), check-entity-refs, check-causal-targets, check-duplicate-keys and validate-disorders.
Disease: Cytosolic Phospholipase A2 Alpha Deficiency MONDO ID: MONDO:0018794 Gene: PLA2G4A (cytosolic phospholipase A2 group IVA; HGNC:9035) Category: Mendelian (ultra-rare autosomal recessive inborn error of eicosanoid biosynthesis)
Cytosolic phospholipase A2 alpha (cPLA2α) deficiency is an ultra-rare autosomal-recessive inborn error of lipid-mediator metabolism caused by biallelic loss-of-function variants in PLA2G4A. cPLA2α is the rate-limiting enzyme that selectively liberates arachidonic acid (AA) from the sn-2 position of membrane glycerophospholipids; the released AA is the obligate substrate for cyclooxygenases (COX-1/COX-2) and lipoxygenases (5-LOX, 12-LOX) that make prostaglandins, thromboxanes, prostacyclin, and leukotrienes. When both alleles of PLA2G4A are inactivated, the cell can no longer provide AA on demand, and the entire downstream eicosanoid cascade is starved of substrate. The clinical consequence is a distinctive two-part phenotype: (1) a prostaglandin-deficiency "NSAID-like" ulcerating, stenosing, and fistulating small-intestinal enteropathy with iron-deficiency anemia, recurrent GI bleeding, and protein-losing enteropathy; and (2) a thromboxane-dependent platelet-function bleeding diathesis.
The disease has been described in only a handful of unrelated families worldwide (fewer than ~5 published probands as of this review), making it one of the rarest known Mendelian eicosanoid disorders. The molecular diagnosis is anchored by a biochemical signature — markedly reduced platelet thromboxane B2 (TxB2) and 12-HETE, reduced calcium-ionophore–induced leukotriene B4, and depressed urinary prostanoid metabolites — followed by confirmatory PLA2G4A sequencing. The defect is upstream of COX: platelet aggregation to ADP and collagen is blunted but is restored by exogenous arachidonic acid, localizing the lesion to AA release rather than to the COX/synthase machinery itself.
There is no approved disease-specific therapy. Management is supportive and mechanism-based: strict NSAID avoidance, prostaglandin replacement (misoprostol, a PGE1 analog), mucosal protection, iron and nutritional support, and bleeding management. Importantly, the inherited human deficiency essentially recapitulates the predicted on-target toxicity of pharmacologic cPLA2α inhibition — a drug class long pursued for asthma, rheumatoid arthritis, inflammatory bowel disease, and psoriasis — and the mouse and human data together serve as a cautionary natural experiment about the consequences of complete cPLA2α blockade.
Overview. cPLA2α deficiency is a monogenic disorder of eicosanoid biosynthesis. Loss of the group IVA cytosolic phospholipase A2 abolishes the regulated, stimulus-coupled release of arachidonic acid, producing a systemic shortage of prostaglandins, thromboxanes, prostacyclin, and leukotrienes. The two cardinal clinical domains are chronic small-bowel ulceration/stenosis and a platelet-type bleeding tendency.
Key identifiers.
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0018794 |
| Gene | PLA2G4A, HGNC:9035, NCBI Gene 5321, UniProt P47712 |
| Chromosomal locus | 1q31.1 |
| Protein | 85-kDa cytosolic phospholipase A2, group IVA (cPLA2α) |
Synonyms / alternative names. cPLA2-alpha deficiency; cytosolic phospholipase A2 group IVA deficiency; PLA2G4A deficiency; "enteropathy of prostaglandin deficiency"; inherited human cPLA2α deficiency. Clinically overlapping descriptive term: a "prostaglandin-related enteropathy."
Information source. Evidence is derived almost entirely from individual-patient reports and small kindreds (human clinical case studies) complemented by mouse knockout models and in vitro enzymology, rather than from aggregated EHR or population-disease registries. This reflects the extreme rarity of the condition.
Primary cause — genetic. The disease is caused by biallelic (homozygous or compound-heterozygous) loss-of-function variants in PLA2G4A. No environmental or infectious cause is implicated as the primary driver.
Genetic risk / causal variants. - Compound heterozygous p.Ser111Pro + [p.Arg485His; p.Lys651Arg] (Adler et al., 2008; PMID: 18451993). - Homozygous c.1723G>C, p.Asp575His (Faioni et al., 2014; PMID: 25102815). - p.Lys651Arg is a common polymorphism, essentially neutral for catalysis (functional data below).
Modifier genes. Co-inherited mild factor XI deficiency was observed in one family (proband, sister, mother) and is a plausible modifier of the bleeding phenotype (Faioni et al., 2014; PMID: 25102815).
Environmental risk factors / triggers. NSAIDs (COX inhibitors) are expected to aggravate the enteropathy because they act downstream of the already-starved pathway; occult NSAID use is a key confounder in differential diagnosis.
Protective factors. None established genetically. Mechanistically, prostaglandin replacement (misoprostol, PGE2/prostacyclin analogs) is protective in models (see §6, §12).
Gene–environment interactions. The defining interaction is NSAID exposure on a prostaglandin-deficient background — pharmacologic COX inhibition in a patient who already cannot supply AA would be expected to compound mucosal injury. Urinary prostanoid-metabolite screening can distinguish inherited deficiency from occult NSAID enteropathy.
| Phenotype | Type | Onset | Severity / course | Frequency | Suggested HPO |
|---|---|---|---|---|---|
| Recurrent small-intestinal ulcers | Clinical sign / structural | Childhood–young adult | Severe, recurrent/progressive | Core feature (all probands) | HP:0005263 (gastrointestinal ulceration) |
| Intestinal strictures / stenosis / subocclusion | Structural | Young adult | Moderate–severe, progressive | Frequent | HP:0005214 (intestinal stricture) |
| Intestinal fistula / perforation | Structural | Variable | Severe | Reported | HP:0005208 (enteric fistula) / intestinal perforation |
| Iron-deficiency anemia | Lab abnormality | Childhood–adult | Moderate, chronic | Frequent | HP:0001891 |
| GI blood loss / occult bleeding | Clinical sign | Childhood–adult | Chronic | Frequent | HP:0002239 (GI hemorrhage) |
| Protein-losing enteropathy / edema | Lab + sign | Adult | Moderate | Reported | HP:0000969 (edema) / protein-losing enteropathy |
| Platelet-type bleeding diathesis | Clinical sign / lab | Early (childhood) | Mild–moderate | In recessive homozygotes | HP:0011869 (abnormal platelet function); HP:0001892 (abnormal bleeding) |
| Recurrent abdominal pain | Symptom | Childhood–adult | Moderate, episodic | Frequent | HP:0002027 |
Onset and progression. Symptoms typically begin in childhood to young adulthood; the course is chronic, recurrent, and progressive for the enteropathy (ulcers → strictures → subocclusion/fistula), while the bleeding tendency is lifelong but generally mild-to-moderate.
Quality-of-life impact. Recurrent ulceration, strictures, chronic anemia, and protein-losing enteropathy impose substantial GI morbidity, risk of repeated surgery, nutritional compromise, and transfusion dependence. No disease-specific EQ-5D/SF-36 data exist given rarity.
Supporting evidence: Adler et al., 2008/2009 (PMID: 18451993; PMID: 19148786); Faioni et al., 2014 (PMID: 25102815); Guisado Vasco et al., 2014 (PMID: 24035666); McAlindon, 2022 (PMID: 35275899).
Causal gene. PLA2G4A (HGNC:9035; NCBI Gene 5321; UniProt P47712), 1q31.1, encoding the 85-kDa group IVA cytosolic phospholipase A2 (cPLA2α).
Protein architecture. cPLA2α comprises an N-terminal Ca²⁺-dependent C2 domain (membrane targeting/translocation) and a catalytic domain with an unusual Ser-Asp catalytic dyad located in a hydrophobic funnel with a flexible lid governing interfacial activation; it selectively cleaves arachidonyl phospholipids (Dessen et al., 1999; PMID: 10319815).
"An unusual Ser-Asp dyad located in a deep cleft at the center of a predominantly hydrophobic funnel selectively cleaves arachidonyl phospholipids." — Dessen et al., 1999 (PMID: 10319815)
Pathogenic variants and functional consequences.
| Variant (protein) | Nucleotide | Type | Functional effect | Evidence |
|---|---|---|---|---|
| p.Ser111Pro | — | Missense | Impairs Ca²⁺ binding & Golgi/membrane translocation; catalysis intact | Reed et al., 2011 (PMID: 21247147) |
| p.Arg485His | — | Missense | Nearly devoid of catalytic activity | Reed et al., 2011 (PMID: 21247147) |
| p.Lys651Arg | — | Missense | Common polymorphism; activity slightly > wild type (neutral) | Reed et al., 2011 (PMID: 21247147) |
| p.Asp575His | c.1723G>C | Missense | Protein instability — transcribed but not stably translated; undetectable protein | Faioni 2014 (PMID: 25102815); Zulueta 2015 (PMID: 25904158) |
"the R485H mutant was nearly devoid of any catalytic activity, that the S111P mutation did not affect the enzyme activity" — Reed et al., 2011 (PMID: 21247147)
The compound-heterozygous Adler patient thus carries one allele that cannot catalyze (R485H) and one allele that cannot translocate to membranes (S111P) — a two-hit convergence that abolishes effective enzyme function. The homozygous Faioni/Zulueta mechanism is protein instability: the mRNA is present but protein is undetectable on Western blot.
"suggesting that the variant is transcribed, but not translated or translated into an unstable protein" — Faioni et al., 2014 (PMID: 25102815)
Variant classification. All reported disease alleles behave as loss-of-function (ACMG: pathogenic/likely pathogenic on functional + segregation grounds). Allele frequency: disease alleles are private/ultra-rare; p.Lys651Arg is a common benign polymorphism.
Somatic vs germline. All reported disease variants are germline. (Of note, somatic/expression-level PLA2G4A changes appear in cancer contexts — e.g., colorectal cancer ferroptosis regulation, PMID: 41400081 — but these are unrelated to the Mendelian deficiency.)
Modifier genes / epigenetics / chromosomal abnormalities. Co-inherited factor XI deficiency modifies bleeding (above). No disease-specific epigenetic signature or chromosomal abnormality is described.
"These findings suggested deficient AA release from membrane phospholipids by cytosolic phospholipase A2-alpha (cPLA2-alpha), which regulates cyclooxygenase- and lipoxygenase-mediated eicosanoid production by catalyzing the release of their substrate, AA." — Adler et al., 2009 (PMID: 19148786)
PLA2G4A (LoF) [upstream / initiating]
│
▼
cPLA2α absent/nonfunctional ── C2-domain Ca2+-dependent translocation to Golgi/perinuclear ER fails
│
▼
No arachidonic acid (AA) released from membrane phospholipids (GO:0019369 AA metabolism)
│
├───────────────┬───────────────┬──────────────┐
▼ ▼ ▼ ▼
COX-1/COX-2 5-LOX / 12-LOX (platelets) (uterine epi)
PGE2, PGI2, LTB4, LTE4, TxA2, 12-HETE PGE2/PGF2α
TxA2 ↓↓ HETEs ↓↓ ↓↓↓ ↓↓
│ │ │ │
▼ ▼ ▼ ▼
GI mucosal inflammation platelet implantation/
cytoprotection dysregulation dysfunction parturition
lost → ulcers (endothelium → bleeding defects (mouse)
/strictures "primed") diathesis
[downstream / clinical]
Molecular pathways: arachidonic acid metabolism; eicosanoid (prostaglandin/thromboxane/leukotriene) biosynthesis (KEGG hsa00590; Reactome AA metabolism). Cellular processes: inflammation, platelet activation/degranulation, mucosal cytoprotection. Subcellular compartments: cytosol → Golgi/perinuclear ER/nuclear envelope (site of Ca²⁺-triggered cPLA2α translocation and AA release). GO CC: GO:0005829 (cytosol), GO:0005794 (Golgi apparatus), GO:0005635 (nuclear envelope). Suggested GO BP: GO:0019369 (arachidonic acid metabolic process), GO:0001516 (prostaglandin biosynthetic process), GO:0006954 (inflammatory response), GO:0030168 (platelet activation). Suggested CL: CL:0000233 (platelet/thrombocyte), CL:0000235 (macrophage), CL:0000066 (epithelial cell; intestinal/uterine luminal epithelium), CL:0002139 (endothelial cell). CHEBI: CHEBI:15843 (arachidonic acid), CHEBI:26333 (prostaglandin), CHEBI:26347 (prostanoid/thromboxane), CHEBI:25029 (leukotriene).
| Analyte | Control | Patient | Source |
|---|---|---|---|
| Serum TxB2 production | 100% | 4.6% (P<0.006) | PMID: 19148786 |
| Serum 12-HETE | 100% | 1.3% (P<0.005) | PMID: 19148786 |
| Leukocyte LTB4 biosynthesis | 100% | ~3% | PMID: 19148786 |
| Platelet TxA2 | 20.5 ± 1.4 ng/ml | 0.1 ng/ml | PMID: 26183771 |
| Leukocyte PGE2 | 21.9 ± 7.4 ng/ml | 1.9 ng/ml | PMID: 26183771 |
| Endothelial prostacyclin (PGI2) | 956 ± 422 pg/ml | 196 pg/ml (reduced, not absent) | PMID: 26183771 |
| Urinary prostacyclin metabolites | 100% | 18.4% | PMID: 26183771 |
| Urinary PGE2 metabolites | 100% | ~77.8% | PMID: 26183771 |
A key nuance: the deficiency is near-complete in platelets and leukocytes but only partial in endothelium (residual prostacyclin), implying cell-type-specific compensation by other phospholipases, and leaving the endothelium "primed for inflammation."
"cPLA2α-deficient endothelial cells showed reduced, but not absent, formation of prostaglandin I2 (prostacyclin; control 956 ± 422 pg/ml vs. patient 196 pg/ml) and were primed for inflammation." — Kirkby et al., 2015 (PMID: 26183771)
"Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid." — Adler et al., 2008 (PMID: 18451993)
Biochemical (first-line, disease-defining): - Platelet TxB2 / 12-HETE — markedly reduced. - Calcium-ionophore–induced leukocyte LTB4 — markedly reduced; urinary LTE4 may be undetectable. - Urinary prostanoid metabolites (e.g., 11-dehydro-TxB2, PGE2/PGI2 metabolites) — depressed. Also useful to exclude occult NSAID use. - Platelet aggregometry: blunted response to ADP/collagen that is normalized by exogenous arachidonic acid — the pathognomonic "upstream of COX" signature. - Western blot: platelet cPLA2α undetectable (p.Asp575His homozygotes).
"platelet cPLA2a was undetectable by Western Blotting in the proband and his sister" — Faioni et al., 2014 (PMID: 25102815)
Genetic testing: Single-gene PLA2G4A sequencing confirms the diagnosis; WES/WGS or a GI/platelet-disorder gene panel is reasonable in undiagnosed cases. Functional confirmation (enzyme assay, translocation, protein stability) supports VUS interpretation.
Imaging/endoscopy: capsule endoscopy, enterography (CT/MR), and small-bowel studies reveal multifocal ulcers, short strictures, and subocclusion; biopsy shows superficial submucosal ulceration with edema.
Clinical criteria / differential diagnosis: There are no formal consensus criteria. Diagnosis rests on the tetrad of small-bowel ulcerating/stenosing disease + platelet-type bleeding + global eicosanoid deficiency + biallelic PLA2G4A variants. Key differentials: - SLCO2A1-related chronic enteropathy (CEAS/CMUSE) — prostaglandin transporter defect, phenotypically overlapping. - NSAID enteropathy — excluded by urinary metabolite screen (occult NSAID use). - Crohn's disease, cryptogenic multifocal ulcerating stenosing enteritis (CMUSE), other platelet secretion/aggregation disorders.
"Mutations in the PLA2G4A gene result in cytosolic phospholipase A2α deficiency and reduced arachidonic acid for prostaglandin synthesis leading to a severe ulcerating, stenosing and fistulating small bowel disease." — McAlindon, 2022 (PMID: 35275899)
Screening: No population or newborn screening exists. Cascade genetic testing of relatives is appropriate once a family variant is known.
No approved disease-specific (curative) therapy exists. Management is supportive and mechanism-based:
| Intervention | Rationale / evidence | Suggested NCIT |
|---|---|---|
| Misoprostol (PGE1 analog) — prostaglandin replacement | Replaces deficient cytoprotective prostaglandin; misoprostol ameliorated eicosanoid-deficiency injury in cPLA2α-null hearts (PMID: 21884509) | NCIT:C62042 (Misoprostol) |
| NSAID avoidance | Patients cannot buffer further COX inhibition | — |
| Iron supplementation / transfusion | Chronic GI blood loss, iron-deficiency anemia | NCIT:C29059 (Iron) |
| Nutritional support (protein-losing enteropathy) | Edema, hypoproteinemia | — |
| Mucosal protection / ulcer management | Symptomatic ulcer/stricture control | — |
| Surgical resection / stricturoplasty | Obstructing strictures, fistula, perforation | NCIT (bowel resection) |
| Bleeding management (platelet support, antifibrinolytics) | Platelet-function defect | — |
"the enhanced injury is ameliorated by treatment with the PGE analog, misoprostol" — Kerkelä et al., 2011 (PMID: 21884509)
Preclinical proof-of-concept for prostaglandin replacement also comes from the reproductive rescue in Pla2g4a-null mice:
"Pla2g4a-null females that received PGE2 + carbaprostacyclin at the time of implantation delivered earlier (20.5 +/- 0.2 days vs. 21.6 +/- 0.2 days, P < 0.01)" — Brown et al., 2009 (PMID: 19684335)
Advanced/experimental therapeutics: No gene therapy, RNA therapy, or targeted therapy is in clinical use for this indication. Conceptually, enzyme/gene replacement of PLA2G4A or downstream eicosanoid-analog supplementation are rational future directions. No registered NCT trials are specific to this ultra-rare disease.
Personalized medicine: Treatment is inherently genotype-driven (confirmed biallelic LoF); cell-type-specific residual activity may influence response.
Mouse (Mus musculus) Pla2g4a knockout is the definitive model.
| Model / study | Key phenotypes | Relevance |
|---|---|---|
| Uozumi et al., 1997, Nature (PMID: 9403692) | ↓ eicosanoids & PAF in peritoneal macrophages; reduced ovalbumin anaphylaxis and bronchial reactivity; females fail to deliver (rescuable by progesterone-receptor antagonist) | First KO; non-redundant role in allergy & reproduction |
| Uozumi & Shimizu, 2002 (review) (PMID: 12432909) | Normal growth but renal concentration defect + intestinal ulcerative lesions; small litters; milder anaphylaxis, lung injury, I/R, MPTP, polyposis | Recapitulates hallmark intestinal ulceration |
| Brown et al., 2009 (PMID: 19684335) | ↓ uterine PGE2/PGF2α/6-keto-PGF1α/TxB2; delayed implantation/parturition; rescued by PGE2 + carbaprostacyclin | Pharmacologic prostaglandin rescue |
| Kerkelä et al., 2011 (PMID: 21884509) | Exaggerated cardiac ischemia–reperfusion injury; ↓PGE2; ameliorated by misoprostol | cPLA2α is cardioprotective; caution for inhibition |
| Sapirstein & Bonventre, 2000 (PMID: 10905638) | Protected against neuronal injury in ischemia/reperfusion & MPTP | Context-dependent (protective in brain) |
"Their ovalbumin-induced anaphylactic responses were significantly reduced, as was their bronchial reactivity to methacholine." — Uozumi et al., 1997 (PMID: 9403692)
"Close examinations have revealed a renal concentration defect and intestinal ulcerative lesions." — Uozumi & Shimizu, 2002 (PMID: 12432909)
"In each model cPLA2 deficient mice are protected against neuronal injury when compared to their wild type littermate controls." — Sapirstein & Bonventre, 2000 (PMID: 10905638)
Model limitations: Mouse knockouts reveal additional organ phenotypes (renal, reproductive, cardiac) that are not prominent clinical features in the few described human patients — partly reflecting the small human sample and possible species-specific phospholipase redundancy. The direction of effect is context-dependent (protective in brain, deleterious in heart/intestine), complicating extrapolation.
In vitro / structural models: Recombinant cPLA2α enzymology (Reed et al., 2011, PMID: 21247147); crystal structure (Dessen et al., 1999, PMID: 10319815); cellular expression/stability assays (Zulueta et al., 2015, PMID: 25904158).
F001 — cPLA2α deficiency is an autosomal-recessive PLA2G4A disorder causing eicosanoid-deficiency enteropathy with platelet dysfunction. Two unrelated families anchor the entity. The Adler proband (compound heterozygous p.Ser111Pro + [p.Arg485His; p.Lys651Arg]) had multiple small-intestinal ulcers, markedly reduced platelet TxB2/12-HETE and ionophore-induced LTB4, and diminished aggregation/degranulation to ADP/collagen that normalized with arachidonic acid — proving the lesion is upstream of COX (PMID: 18451993). The Faioni family (homozygous p.Asp575His, a 27-year-old man and his twin sister) showed early bleeding diathesis, recurrent GI ulcers, undetectable platelet cPLA2α on Western blot, and extremely low serum TxB2/12-HETE and urinary 11-dehydro-TxB2 (PMID: 25102815).
F002 — Prostaglandin deficiency mechanistically links cPLA2α loss to an NSAID-like enteropathy. Adler's "enteropathy of prostaglandin deficiency" patient had chronic recurrent small-intestinal ulcers, small-bowel perforations, and GI blood loss despite no COX-inhibitor use, with serum TxB2 at 4.6% (P<0.006) and 12-HETE at 1.3% (P<0.005) of controls, leukocyte LTB4 at ~3%, and undetectable urinary LTE4 (PMID: 19148786).
F003 / F006 / F009 — Mouse knockouts validate causality and reveal multi-organ roles. Pla2g4a-null mice show significantly decreased uterine PGE2/PGF2α/6-keto-PGF1α/TxB2 with delayed implantation and parturition, pharmacologically rescued by PGE2 + carbaprostacyclin (20.5±0.2 vs 21.6±0.2 days, P<0.01) (PMID: 19684335). Broader knockout data show intestinal ulceration plus a renal concentration defect (PMID: 12432909) and the landmark non-redundant role in allergy and reproduction (PMID: 9403692). Context-dependence is notable — protective in brain injury (PMID: 10905638) but deleterious in cardiac I/R (PMID: 21884509).
F004 — Structure–function maps each variant to a distinct defect. cPLA2α uses a Ser-Asp catalytic dyad selective for arachidonyl phospholipids (PMID: 10319815); p.Arg485His abolishes catalysis, p.Ser111Pro abolishes Ca²⁺-dependent membrane translocation without affecting catalysis, and p.Lys651Arg is neutral (PMID: 21247147). Compound heterozygosity therefore combines two separable loss-of-function mechanisms.
F005 — Cell-type-specific eicosanoid loss. Platelet TxA2 (20.5±1.4 → 0.1 ng/ml) and leukocyte PGE2 (21.9±7.4 → 1.9 ng/ml) are nearly abolished, whereas endothelial prostacyclin is reduced but not absent (956±422 → 196 pg/ml), leaving endothelium "primed for inflammation"; urinary prostacyclin metabolites fell to 18.4% while PGE2 metabolites remained ~77.8% of control (PMID: 26183771).
F007 — A prostaglandin-related ulcerating/stenosing/fistulating small-bowel disease. The full phenotype (ulcers, strictures, fistulae, iron-deficiency anemia, protein-losing enteropathy) sits in a differential with SLCO2A1-CMUSE and NSAID enteropathy; a urinary-metabolite screen reveals occult NSAID use (PMID: 35275899; PMID: 24035666).
F008 — p.Asp575His acts via protein instability; heterozygotes show partial GI penetrance. The variant is transcribed but yields unstable/undetectable protein (PMID: 25102815; PMID: 25904158); GI ulcers affected 5/14 heterozygotes (<40 y) vs 1/16 wild-type (>60 y), while bleeding was strictly recessive, and co-inherited mild factor XI deficiency may modify bleeding.
F010 — Management is supportive prostaglandin replacement; the human deficiency is the on-target toxicity of cPLA2α inhibition. cPLA2α is a long-standing anti-inflammatory/anti-asthma drug target (PMID: 16712837); the inherited human deficiency therefore defines the predicted toxicity (GI ulceration + bleeding) of complete pharmacologic blockade, with misoprostol-based replacement supported by model rescue (PMID: 21884509; PMID: 19684335).
The disease is best understood as a single enzymatic "choke point" failure with pleiotropic downstream consequences. cPLA2α sits at the apex of eicosanoid signaling as the only PLA2 that selectively and efficiently releases arachidonate on cell activation. Because every prostaglandin, thromboxane, prostacyclin, and leukotriene depends on this released AA, a complete loss collapses the whole lipid-mediator network simultaneously — but not uniformly across cell types. Platelets and leukocytes, which rely heavily on cPLA2α-derived AA, lose ~99% of their thromboxane/HETE/leukotriene output, explaining the bleeding and inflammatory-regulation defects. The small-intestinal mucosa loses cytoprotective prostaglandins, producing an "endogenous NSAID enteropathy." The endothelium retains partial prostacyclin production (residual/compensatory phospholipases), yet is pushed toward a pro-inflammatory state.
Supported hypotheses: Refuted / excluded:
• AR LoF of PLA2G4A is causal ✔ • Primary environmental/infectious cause ✘
• Global eicosanoid deficiency ✔ • COX/synthase-level defect (AA rescues) ✘
• Upstream-of-COX platelet lesion ✔ • Dominant bleeding in heterozygotes ✘
• Prostaglandin-deficiency enteropathy ✔
• Misoprostol/PG-analog rescue (model) ✔
This mechanistic model also unifies the human deficiency and the pharmacology: cPLA2α has been pursued as an anti-inflammatory drug target, and the inherited human loss-of-function phenotype is effectively the toxicology readout of maximal target engagement — a point reinforced by mouse data showing cPLA2α is cardioprotective and its loss worsens cardiac ischemia–reperfusion injury.
| PMID | Study | Source type | Contribution |
|---|---|---|---|
| 18451993 | Adler 2008 | Human clinical | First human case; compound-het genotype; platelet/eicosanoid defect upstream of AA |
| 19148786 | Adler 2009 | Human clinical | "Enteropathy of prostaglandin deficiency"; quantified global eicosanoid loss |
| 25102815 | Faioni 2014 | Human clinical | Homozygous p.Asp575His; undetectable protein; heterozygote penetrance; factor XI |
| 25904158 | Zulueta 2015 | In vitro | Protein instability mechanism for p.Asp575His |
| 21247147 | Reed 2011 | In vitro | Functional mapping of patient variants (catalysis vs translocation) |
| 10319815 | Dessen 1999 | Structural | Crystal structure; Ser-Asp dyad; arachidonyl selectivity |
| 26183771 | Kirkby 2015 | Human clinical | Cell-type-specific eicosanoid loss; endothelium primed for inflammation |
| 19684335 | Brown 2009 | Model organism | KO reproductive phenotype; prostaglandin rescue |
| 12432909 | Uozumi 2002 | Model organism | KO review; intestinal ulceration + renal defect |
| 9403692 | Uozumi 1997 | Model organism | First KO; allergy + parturition roles |
| 21884509 | Kerkelä 2011 | Model organism | Cardioprotective role; misoprostol rescue; inhibition caution |
| 10905638 | Sapirstein 2000 | Model organism | Neuroprotection from cPLA2α loss (context dependence) |
| 35275899 | McAlindon 2022 | Review | Prostaglandin-related enteropathy framework; differentials |
| 24035666 | Guisado Vasco 2014 | Human clinical | CMUSE-type presentation; anemia, protein-losing enteropathy |
| 16712837 | Malaviya 2006 | Model organism | cPLA2α as anti-inflammatory drug target (toxicity context) |
Report compiled from 10 confirmed findings across 5 investigation iterations and 46 reviewed papers. Evidence integrates human clinical case series, in vitro enzymology and structural biology, and mouse genetic models.
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| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 16 |
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| Off topic | 0 |
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| Terms checked | 32 |
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| Unresolved (possible confabulation) | 0 |
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| Terms named as a different term | 8 |
| Terms whose name is worth a second look | 7 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0018794 (2 mentions) - the report calls it "MONDO"; MONDO calls it cytosolic phospholipase-A2 alpha deficiency associated bleeding disorderHP:0005263 (1 mention) - the report calls it "gastrointestinal ulceration"; HP calls it GastritisHP:0005208 (1 mention) - the report calls it "enteric fistula"; HP calls it Secretory diarrheaHP:0001891 (1 mention) - the report calls it "Frequent"; HP calls it Iron deficiency anemiaHP:0002027 (1 mention) - the report calls it "Frequent"; HP calls it Abdominal painCL:0000066 (2 mentions) - the report calls it "epithelial cell; intestinal/uterine luminal epithelium", "luminal epithelium", "Tissue/cell level: intestinal luminal epithelium"; CL calls it epithelial cellNCIT:C62042 (1 mention) - the report calls it "Misoprostol"; NCIT calls it LeuprolideNCIT:C29059 (1 mention) - the report calls it "Iron"; NCIT calls it FluoxamineThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
NCIT:C29059 (Fluoxamine) (1 mention)The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0005214 (1 mention) - the report calls it "intestinal stricture"; HP calls it Intestinal obstructionGO:0019369 (2 mentions) - the report calls it "arachidonic acid metabolic process"; GO calls it arachidonate metabolic process, and lists "arachidonic acid metabolic process" among its other namesCL:0000233 (2 mentions) - the report calls it "platelet/thrombocyte", "platelets"; CL calls it platelet, and lists "anucleate thrombocyte" among its other namesCL:0000235 (2 mentions) - the report calls it "macrophage", "macrophages/leukocytes"; CL calls it macrophageCL:0002139 (2 mentions) - the report calls it "endothelial cell", "endothelial cells"; CL calls it endothelial cell of vascular tree, and lists "vascular endothelial cell" among its other namesCHEBI:26347 (1 mention) - the report calls it "prostanoid/thromboxane"; CHEBI calls it prostanoidUBERON:0002108 (1 mention) - the report calls it "Small intestine", "Primary organ: Small intestine"; UBERON calls it small intestineThe report gives these identifiers more than one name of its own:
CL:0000233 - called "platelet/thrombocyte", "platelets"CL:0000235 - called "macrophage", "macrophages/leukocytes"CL:0000066 - called "epithelial cell; intestinal/uterine luminal epithelium", "luminal epithelium", "Tissue/cell level: intestinal luminal epithelium"CL:0002139 - called "endothelial cell", "endothelial cells"UBERON:0002108 - called "Small intestine", "Primary organ: Small intestine"