Periodic Fever, Immunodeficiency, and Thrombocytopenia Syndrome

Mendelian MONDO:0007883 Pathograph 21 Show in embeddings browser Inborn Errors of Immunity

Periodic fever, immunodeficiency, and thrombocytopenia syndrome (PFIT) is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in WDR1, which encodes actin-interacting protein 1 (Aip1), the cofactor that accelerates cofilin-mediated severing and depolymerisation of actin filaments. PFIT is an "actinopathy": one defect in actin filament turnover produces three clinically unrelated-looking problems at once. In monocytes it permits inflammasome hyperactivation and excess interleukin-18 release, giving periodic fever with an extreme acute-phase response; in neutrophils it abolishes the polarisation and chemotaxis needed to reach a site of infection, giving recurrent infection, severe stomatitis and poor wound healing despite normal microbial killing; and in megakaryocytes it blocks the maturation step needed for platelet shedding, giving thrombocytopenia. The autoinflammatory arm is driven by IL-18 rather than IL-1-beta, which is why IL-1 blockade is at best partially effective and allogeneic haematopoietic stem cell transplantation, which replaces the whole mutant haematopoietic compartment, is the treatment that has worked.

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1
Inheritance
9
Pathophys.
13
Phenotypes
2
Gaps
21
Pathograph
1
Genes
2
Medical Actions
2
Differentials
1
Models
7
References
1
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive. Affected individuals carry biallelic WDR1 variants; heterozygous relatives are clinically normal.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:27557945 SUPPORT Human Clinical
"Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive."
States the inheritance mode and the segregation observation it rests on.
PMID:27994071 SUPPORT Human Clinical
"We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia."
The index family is a consanguineous kindred with a homozygous variant in two affected siblings, consistent with recessive inheritance.
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Discussions and Knowledge Gaps

2
Does mutant WDR1 sequester pyrin in patient monocytes, or is the aggregate an artefact of overexpression in HEK293T cells?
KNOWLEDGE GAP pfit_pyrin_sequestration_evidence
Attached to
pathophysiology#Pyrin Sequestration by Mutant WDR1 Aggregates
The link from impaired actin turnover to inflammasome activation is the load-bearing step of the autoinflammatory arm, and it rests on a single co-transfection experiment in a heterologous cell line, reported by its authors with two hedges in one sentence. Patient monocytes show increased caspase-1 cleavage, so something activates the inflammasome; whether it is pyrin sequestration by aggregates is untested in a patient-derived cell. The node is marked PROVISIONAL for this reason.
Proposed experiments
Pyrin localisation in patient-derived monocytes
pfit_pyrin_localisation_patient_monocytes
Image endogenous pyrin and WDR1 in patient monocytes or patient-iPSC-derived macrophages at physiological expression, and ask whether pyrin co-localises with WDR1 aggregates.
Readouts
Pyrin and WDR1 co-localisation
pathophysiology#Pyrin Sequestration by Mutant WDR1 Aggregates
Direction: INCREASED
Interpretation: Co-localisation at endogenous expression would move the node off PROVISIONAL.
If PFIT autoinflammation is IL-18-driven, why did anakinra have any effect at all, and would IL-18 blockade work better?
CONTROVERSY pfit_il18_versus_il1_target
Attached to
pathophysiology#Excess Interleukin-18 Production treatments#Interleukin-1 Blockade with Anakinra
The cytokine data are unambiguous that IL-18 and not IL-1-beta is raised, yet anakinra produced a transient steroid-sparing effect. The authors themselves raise the possibility that anakinra partially antagonises IL-18, which would reconcile the two observations, but no PFIT patient has been treated with a specific IL-18 blocker such as recombinant IL-18-binding protein. Until one is, the mechanistic model predicts a therapy that has never been tested in this disease.
⚙

Pathophysiology

9
Biallelic WDR1 Loss of Function
Biallelic WDR1 variants reduce the function of actin-interacting protein 1 (Aip1). The index PFIT family carries a homozygous missense substitution affecting both transcripts; the neutrophil-dysfunction families carry biallelic variants affecting distinct antiparallel beta-strands of the protein.
Genetic context WDR1 hgnc:12754 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns WDR1 (hgnc:12754). hgnc:12754 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Impaired Cofilin-Mediated Actin Filament Disassembly Aip1 is the accelerator of cofilin-mediated filament severing, so reduced Aip1 function slows actin filament turnover.
Show evidence (2 references)
PMID:27994071 SUPPORT Human Clinical
"In conclusion, homozygous missense L153F/L293F mutation in the actin regulatory gene WDR1 causes a new AID in humans, with periodic fevers, immunodeficiency, and intermittent thrombocytopenia (PFIT)."
Names the causal gene, the zygosity and the substitution, and asserts causation for the syndrome this entry describes.
PMID:27557945 SUPPORT Human Clinical
"Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients."
Independent confirmation of biallelic WDR1 variants in a separate cohort of four children from three families.
Impaired Cofilin-Mediated Actin Filament Disassembly
Aip1/WDR1 preferentially disassembles cofilin-decorated actin filaments. With Aip1 function reduced, filaments that cofilin has already decorated are not cleared, and polymerised actin accumulates. Patient neutrophils carry roughly four times the normal F-actin content.
actin filament depolymerization GO:0030042 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin filament depolymerization (GO:0030042). GO:0030042 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Immunological Synapse Formation in Lymphocytes B-cell and T-cell immunological synapses depend on Aip1-driven actin turnover.
Pyrin Sequestration by Mutant WDR1 Aggregates Mutant WDR1 protein aggregates, and the aggregates appear to trap pyrin.
Defective Neutrophil Motility and Polarization Neutrophil chemotaxis and polarisation depend on continuous actin turnover at the leading edge.
Defective Megakaryocyte Maturation and Platelet Shedding Megakaryocyte maturation and proplatelet shedding require cofilin/Aip1 actin dynamics.
Show evidence (5 references)
PMID:29056508 SUPPORT Other
"AIP1 preferentially promotes disassembly of ADF/cofilin-decorated actin filaments but exhibits minimal effects on bare actin filaments."
States the specific biochemical activity that is lost, and that it is selective for cofilin-decorated filaments rather than actin generally.
PMID:27557945 SUPPORT Human Clinical
"Neutrophil F-actin was elevated fourfold, suggesting an abnormality in F-actin regulation."
Quantifies the accumulation of polymerised actin in patient cells, the direct cellular readout of failed depolymerisation.
PMID:27994071 SUPPORT Human Clinical
"We found impaired actin dynamics in patient immune cells."
Confirms the same actin-dynamics defect in the independent PFIT family.
+ 2 more references
Pyrin Sequestration by Mutant WDR1 Aggregates
Mechanism confidence: Provisional
In HEK293T cells co-transfected with pyrin and mutant WDR1, the mutant protein forms aggregates that accumulate pyrin. The proposal is that this concentrates pyrin and so nucleates inflammasome assembly. This is an overexpression experiment in a heterologous cell line and the authors themselves state it only as a possibility, so the node is marked PROVISIONAL rather than asserted.
Downstream
Inflammasome Hyperactivation in Monocytes Concentrating pyrin is proposed to lower the threshold for inflammasome assembly.
Show evidence (1 reference)
PMID:27994071 SUPPORT INDIRECT In Vitro
"Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly."
The only direct observation behind this node, and the reason it is PROVISIONAL: "appeared to" and "could potentially" are the authors' own hedges, and the experiment is transfected HEK293T cells rather than patient monocytes.
Inflammasome Hyperactivation in Monocytes
Patient monocytes show increased caspase-1 cleavage, the biochemical signature of inflammasome activation.
Monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
inflammasome-mediated signaling pathway GO:0141084 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammasome-mediated signaling pathway (GO:0141084). GO:0141084 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Excess Interleukin-18 Production Activated caspase-1 matures pro-IL-18.
Show evidence (1 reference)
PMID:27994071 SUPPORT Human Clinical
"We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity."
Measured in patient cells rather than a model system, which is why this node is asserted while the pyrin-sequestration node above is provisional.
Excess Interleukin-18 Production
The autoinflammatory arm of PFIT runs through IL-18, not IL-1-beta. Serum IL-18 is high without a matching rise in IL-18-binding protein, so free bioactive IL-18 is increased, and patient cells secrete more IL-18 but not more IL-1-beta in culture. This is the mechanistic reason IL-1 blockade is only partially effective.
positive regulation of interleukin-18 production GO:0032741 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of interleukin-18 production (GO:0032741). GO:0032741 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Recurrent fever Systemic IL-18-driven autoinflammation manifests as periodic febrile episodes with an extreme acute-phase response.
Increased circulating interleukin 18 concentration The directly measured serum correlate of this node.
Show evidence (1 reference)
PMID:27994071 SUPPORT Human Clinical
"Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture."
Establishes both halves of the claim: IL-18 is elevated and unbuffered by its binding protein, and IL-1-beta is not elevated.
Defective Neutrophil Motility and Polarization
Patient neutrophils cannot polarise, spread or move directionally, yet kill staphylococci normally once contact is made and mount an increased oxidative burst. The defect is therefore in getting to the infection, not in dealing with it, which is the distinctive shape of this immunodeficiency. Neutrophil nuclear lobes herniate and cytosolic regions are agranular. This node is contested across cohorts, and the REFUTE items below record it. The motility defect is the Kuhns cohort's central finding, but the founding PFIT family was measured in a Dunn chamber and showed no difference in velocity or chemotactic index, with the authors concluding that neutrophil dysfunction alone cannot account for the phenotype. The node is kept because the defect is real where it was found, not because the disagreement is settled.
Neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
neutrophil chemotaxis GO:0030593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neutrophil chemotaxis (GO:0030593). GO:0030593 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Wdr1 hypomorphic (rd/rd) mouse Mouse partially recapitulates Wdr1 mutant mouse neutrophils show impaired cytoskeletal responses and accumulate polymerised actin, as human patient neutrophils do.
Downstream
Impaired Innate Host Defense at Barrier Surfaces Neutrophils that cannot reach a site of infection cannot clear it.
Impaired neutrophil chemotaxis
Abnormal neutrophil morphology
Show evidence (4 references)
PMID:27994071 REFUTE Human Clinical
"We further assessed neutrophil migratory function from patient IV-4 using a modified Dunn chamber, and found no significant difference in velocity or chemotactic index (Fig. 5, A–C)."
The founding PFIT family, measured directly, showed no migration defect. This contradicts the node for that cohort and is why the description calls the finding contested rather than settled.
PMID:27994071 REFUTE Human Clinical
"The neutrophil defects in these patients appeared relatively mild, as respiratory burst and phagocytosis were normal (Table S1)."
The same paper grades the neutrophil abnormalities as mild, against the node's claim of a defining motility failure.
PMID:27557945 SUPPORT Human Clinical
"Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation."
Establishes the selective motility defect with preserved killing, the claim this node makes.
+ 1 more reference
Impaired Innate Host Defense at Barrier Surfaces
Failure of neutrophil recruitment produces recurrent infection and, strikingly, severe oral inflammation that can scar to oral stenosis, plus impaired wound healing.
Downstream
Recurrent bacterial infections
Stomatitis
Poor wound healing
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
Lists the clinical consequences this node groups, in the cohort in which they were described.
Defective Immunological Synapse Formation in Lymphocytes
The arm of the disease that the founding reports missed. Patient T cells accumulate atypical actin structures at the immunological synapse, with reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. The B-cell compartment is affected more severely still: peripheral B lymphopenia, few marrow B-cell progenitors, no switched memory B cells, reduced clonal diversity, abnormal spreading, and increased apoptosis on receptor stimulation. So the immunodeficiency in PFIT is not only a neutrophil delivery problem; it has an adaptive component with its own mechanism at the same molecular step.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
immunological synapse GO:0001772 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves immunological synapse (GO:0001772). GO:0001772 is a cellular component from the Gene Ontology.
Downstream
Decreased total B cell count
Impaired Innate Host Defense at Barrier Surfaces Loss of switched memory B cells and B lymphopenia add an antibody-side contribution to the same clinical infection burden.
Show evidence (3 references)
PMID:29751004 SUPPORT Human Clinical
"However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation."
The T-cell half of this node, measured in patient cells.
PMID:29751004 SUPPORT Human Clinical
"WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis..."
The B-cell half, and the observation that it is the more severely affected compartment.
PMID:29751004 SUPPORT Human Clinical
"Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses."
States the mechanism this node asserts: actin turnover at the synapse.
Defective Megakaryocyte Maturation and Platelet Shedding
Bone marrow from a PFIT patient contained small atypical megakaryocytes that had failed to develop a demarcating membrane system, the structure from which proplatelets are extended. Thrombocytopenia in PFIT is therefore a production defect at the shedding step, not peripheral destruction.
Megakaryocyte CL:0000556 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Megakaryocyte (CL:0000556). CL:0000556 is a cell type from the Cell Ontology.
platelet formation GO:0030220 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased platelet formation (GO:0030220). GO:0030220 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Wdr1 hypomorphic (rd/rd) mouse Mouse recapitulates The mouse establishes the causal chain from Wdr1 hypomorphism through megakaryocyte maturation failure to defective platelet shedding.
Downstream
Thrombocytopenia
Show evidence (4 references)
PMID:27994071 SUPPORT Human Clinical
"We observed ultrastructural abnormalities of megakaryocytes in patient IV-4 (Fig"
Records that the megakaryocyte abnormality was observed in patient marrow. Quoted short because the sentence continues into a figure callout; the morphological detail is in the next item.
PMID:27994071 SUPPORT Human Clinical
"revealing occasional small, atypical megakaryocytes, with no nucleus and failure of the development of the demarcating membrane system."
The specific ultrastructural lesion: absent demarcating membrane system, which is the structure proplatelet shedding requires.
PMID:17515402 SUPPORT INDIRECT Model Organism
"Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding."
The mouse experiment that establishes the causal step the human ultrastructure is read against. Indirect because it is a mouse hypomorph, and because platelet size transfers only partly: of the two index siblings, one had mean platelet volume consistently above the reference range and the other consistently within it, so the human phenotype is variable rather than uniformly normocytic. The next evidence item records that measurement.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Periodic Fever, Immunodeficiency, and Thrombocytopenia 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

13
Blood 5
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873), qualified as temporality recurrent. HP:0001873 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:27994071 SUPPORT Human Clinical
"Both developed severe inflammatory responses to (presumed) viral infections, with moderate thrombocytopenia."
Documents thrombocytopenia and its association with inflammatory episodes.
Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total neutrophil count (HP:0001875), qualified as severity mild. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
Reports the neutropenia and grades it mild.
Abnormal neutrophil morphology HP:0011992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal neutrophil morphology (HP:0011992). HP:0011992 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"All patients studied had similar distinctive neutrophil herniation of the nuclear lobes and agranular regions within the cytosol."
Describes the morphological abnormality and states it was present in all patients studied.
Decreased total B cell count HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29751004 SUPPORT Human Clinical
"WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis..."
Reports the B lymphopenia this phenotype records.
Impaired neutrophil chemotaxis HP:0040238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired neutrophil chemotaxis (HP:0040238). HP:0040238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation."
The direct measurement of impaired chemotaxis in patient neutrophils.
Head and Neck 1
Stomatitis HP:0010280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stomatitis (HP:0010280). HP:0010280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
Names severe stomatitis with oral stenosis among the presenting features.
Immune 3
Increased circulating interleukin 18 concentration HP:0034447 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating interleukin 18 concentration (HP:0034447). HP:0034447 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27994071 SUPPORT Human Clinical
"Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture."
Reports the elevated serum IL-18 measurement directly.
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29751004 SUPPORT Human Clinical
"Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis."
Names respiratory tract infections as a presenting feature in the six-patient lymphoid cohort.
Recurrent bacterial infections HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718), qualified as temporality recurrent. HP:0002718 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
Recurrent infection is the presenting feature of the four-child cohort.
Integument 2
Poor wound healing HP:0001058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor wound healing (HP:0001058). HP:0001058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
Names impaired wound healing among the presenting features.
Skin ulcer HP:0200042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin ulcer (HP:0200042). HP:0200042 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29751004 SUPPORT Human Clinical
"Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis."
Names skin ulceration among the presenting features of the third cohort.
Metabolism 1
Recurrent fever HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954), qualified as temporality recurrent. HP:0001954 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:27994071 SUPPORT Human Clinical
"Both had periodic fevers lasting 3"
Documents the periodic fever and its duration. Quoted short because the source writes the range with an en-dash inside a long compound sentence; the periodicity and acute-phase detail are carried by the laboratory phenotypes below.
Other 1
Reduced circulating follicular helper T cells
Show evidence (1 reference)
PMID:29751004 SUPPORT Human Clinical
"T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset."
Reports normal T-cell development with the follicular helper subset as the stated exception.
🧬

Genetic Associations

1
WDR1
Gene: WDR1 hgnc:12754 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WDR1 (hgnc:12754). hgnc:12754 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:27557945 SUPPORT Human Clinical
"Mutations in WDR1 affect neutrophil morphology, motility, and function, causing a novel primary immunodeficiency."
States the gene-disease relationship for the immunodeficiency arm.
PMID:17515402 SUPPORT INDIRECT Model Organism
"While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles."
Supports the notes claim that only hypomorphic alleles are compatible with life. Indirect: the lethality is established in mouse, not human.
💊

Medical Actions

2
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic haematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic haematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
Replacing the mutant haematopoietic compartment addresses all three arms of the disease at once, because the neutrophil, monocyte and megakaryocyte defects are all cell-intrinsic to bone-marrow-derived cells. One PFIT patient transplanted at age 8 remained well and off all medication three years later, and transplantation corrected the immunological defect in one patient of the neutrophil-dysfunction cohort.
Mechanism Target:
Defective Neutrophil Motility and Polarization — Donor-derived neutrophils carry wild-type WDR1 and migrate normally.
Inflammasome Hyperactivation in Monocytes — Donor-derived monocytes remove the source of excess IL-18.
Show evidence (4 references)
PMID:27994071 SUPPORT Human Clinical
"Patient IV-4 successfully underwent allogeneic hematopoietic stem cell transplantation (HSCT) at age 8, and remains well, off all medication, 3 yr later."
The single reported durable outcome in PFIT, and the basis for treating transplantation as definitive rather than supportive.
PMID:27994071 SUPPORT Human Clinical
"Given that severe autoinflammation coexists with immunodeficiency and thrombocytopenia in PFIT, for the time being, we suggest that HSCT is the most appropriate treatment."
The authors' explicit treatment recommendation, and their reasoning that it is the coexistence of the three arms that makes transplant the answer.
PMID:27557945 SUPPORT Human Clinical
"Allogeneic stem cell transplantation corrected the immunologic defect in 1 patient."
An independent transplant outcome in the second cohort, restricted to the immunological arm.
+ 1 more reference
Interleukin-1 Blockade with Anakinra
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anakinra NCIT:C38717 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anakinra (NCIT:C38717). NCIT:C38717 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Anakinra produced only a transient steroid-sparing effect and did not control the autoinflammatory episodes; the patient treated with it died at 14 of sterile systemic inflammation and multiorgan failure. This is the expected result if the driver is IL-18 rather than IL-1-beta, and the entry carries it as a REFUTE item against the IL-1 hypothesis rather than as a recommended therapy.
Show evidence (2 references)
PMID:27994071 REFUTE Human Clinical
"Ultimately, however, this did not control the episodes of autoinflammation, and this patient died at 14 yr of age from sterile systemic inflammation and multiorgan failure."
Refutes IL-1 blockade as adequate therapy for PFIT: the treated patient died of uncontrolled autoinflammation.
PMID:27994071 SUPPORT Human Clinical
"There was, however, some transient steroid sparing effect in response to anakinra (2"
The partial effect that was observed, quoted short because the source writes the dose range with an en-dash. Recorded so the entry does not overstate anakinra as wholly without effect.
🔬

Diagnosis

1
Biallelic WDR1 variants on molecular testing in a compatible phenotype
The diagnosis rests on finding biallelic WDR1 variants in a child with periodic fever, recurrent infection and thrombocytopenia. Two findings are worth knowing because they are cheap and specific: neutrophil nuclear-lobe herniation on a smear, and a raised serum IL-18 with a normal or disproportionately low IL-1-beta.
Show evidence (1 reference)
PMID:27557945 SUPPORT Human Clinical
"Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients."
Establishes biallelic WDR1 variants as the molecular finding in every patient of the cohort.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Twelve patients from seven families across three cohorts: two siblings with the autoinflammatory presentation, four children from three families with the neutrophil-dysfunction presentation, and six patients from three kindreds in the lymphoid-immunity cohort. No population estimate exists.
Show evidence (2 references)
PMID:27557945 SUPPORT Human Clinical
"In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
Gives the family and patient count for the second cohort.
PMID:29751004 SUPPORT Human Clinical
"Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis."
Gives the family and patient count for the third cohort.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Periodic Fever, Immunodeficiency, and Thrombocytopenia Syndrome:

Other monogenic autoinflammatory actinopathies
Overlapping Features PFIT belongs to a recognised class rather than merely resembling one. Defects in ARPC1B, MKL1/MRTFA, DOCK8, WAS, DOCK11, ARPC5 and coronin-1A all combine immunodeficiency, cytopenia and autoinflammation from disordered actin regulation, and the class has a diagnostic shape: early-onset autoinflammatory skin and digestive disease with immunodeficiency plus thrombocytopenia or bleeding. Genetic testing is what separates the members.
Show evidence (2 references)
PMID:39644982 SUPPORT Other
"Diagnosis should be considered primarily when encountering an early-onset autoinflammatory skin and digestive disorder, along with a primary immunodeficiency and either thrombocytopenia or a bleeding tendency."
States the class-level diagnostic trigger that puts PFIT and its differentials in the same frame.
PMID:39644982 SUPPORT Other
"Actinopathies with autoinflammatory manifestations represent a newly emerging subgroup of AID, associated with defects in the regulation of actin cytoskeleton dynamics."
Defines the class this entry places PFIT in.
Hereditary periodic fever syndromes
Overlapping Features Familial Mediterranean fever, TRAPS, mevalonate kinase deficiency and cryopyrin-associated periodic syndrome share the periodic-fever presentation. The combination with thrombocytopenia and a neutrophil migration defect, and the IL-18-dominant rather than IL-1-beta-dominant cytokine profile, separate PFIT from them.
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Animal Models

1
Wdr1 hypomorphic (rd/rd) mouse
An allelic series at the mouse Wdr1 locus. Severe loss of function is embryonic lethal; hypomorphic alleles give autoinflammatory disease and macrothrombocytopenia. This model preceded and predicted the human syndrome, including its IL-18 dependence.
Species
Mouse
Genotype
Wdr1 hypomorphic allele, homozygous
Publication
PMID:17515402
Pathograph links
Defective Megakaryocyte Maturation and Platelet Shedding recapitulates fidelity: high observes: cellular The mouse establishes the causal chain from Wdr1 hypomorphism through megakaryocyte maturation failure to defective platelet shedding.
Limitations: The mouse phenotype is uniform macrothrombocytopenia; in humans platelet size transfers only partly, with one of the two index siblings showing mean platelet volume consistently above the reference range and the other consistently within it. The human thrombocytopenia is otherwise described as intermittent and moderate.
Readouts
Platelet count and megakaryocyte maturation stage
Direction: DECREASED
Interpretation: Reduced platelet output attributable to arrested megakaryocyte maturation.
Show evidence (1 reference)
PMID:17515402 SUPPORT Model Organism
"Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding."
Reports the measurement and the causal attribution behind this readout.
Show evidence (1 reference)
PMID:17515402 SUPPORT Model Organism
"These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types."
Supports treating the mouse as informative for the megakaryocyte arm of the human disease.
Defective Neutrophil Motility and Polarization partially recapitulates fidelity: moderate observes: cellular Wdr1 mutant mouse neutrophils show impaired cytoskeletal responses and accumulate polymerised actin, as human patient neutrophils do.
Limitations: Whether the mouse is functionally immunodeficient was never established: the animals were housed in a relatively protected environment, so the clinical consequence that defines the human disease was not tested. The mouse inflammatory lesions are neutrophil-rich infiltrates, which is close to the opposite of the human picture of neutrophils failing to arrive.
Show evidence (1 reference)
PMID:17515402 SUPPORT Model Organism
"Cytoskeletal responses are impaired in Wdr1 mutant neutrophils."
The cellular defect the model shares with the human disease, and the limit of what it demonstrates.
{ }

Source YAML

click to show 
name: Periodic Fever, Immunodeficiency, and Thrombocytopenia Syndrome
creation_date: "2026-09-06T19:15:00Z"
category: Mendelian
description: >-
  Periodic fever, immunodeficiency, and thrombocytopenia syndrome (PFIT) is an
  ultra-rare autosomal recessive disorder caused by biallelic loss-of-function
  variants in WDR1, which encodes actin-interacting protein 1 (Aip1), the
  cofactor that accelerates cofilin-mediated severing and depolymerisation of
  actin filaments. PFIT is an "actinopathy": one defect in actin filament
  turnover produces three clinically unrelated-looking problems at once. In
  monocytes it permits inflammasome hyperactivation and excess interleukin-18
  release, giving periodic fever with an extreme acute-phase response; in
  neutrophils it abolishes the polarisation and chemotaxis needed to reach a
  site of infection, giving recurrent infection, severe stomatitis and poor
  wound healing despite normal microbial killing; and in megakaryocytes it
  blocks the maturation step needed for platelet shedding, giving
  thrombocytopenia. The autoinflammatory arm is driven by IL-18 rather than
  IL-1-beta, which is why IL-1 blockade is at best partially effective and
  allogeneic haematopoietic stem cell transplantation, which replaces the whole
  mutant haematopoietic compartment, is the treatment that has worked.
disease_term:
  preferred_term: periodic fever, immunodeficiency, and thrombocytopenia syndrome
  term:
    id: MONDO:0007883
    label: periodic fever, immunodeficiency, and thrombocytopenia syndrome
synonyms:
- PFIT
- WDR1 deficiency
- Aip1 deficiency
parents:
- Inborn Errors of Immunity
references:
- reference: PMID:27994071
  title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
  findings: []
- reference: PMID:27557945
  title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
  findings: []
- reference: PMID:29056508
  title: "Functions of actin-interacting protein 1 (AIP1)/WD repeat protein 1 (WDR1) in actin filament dynamics and cytoskeletal regulation."
  findings: []
- reference: PMID:17515402
  title: "Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia."
  findings: []
- reference: PMID:29751004
  title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
  findings: []
- reference: PMID:25448002
  title: "Aip1 destabilizes cofilin-saturated actin filaments by severing and accelerating monomer dissociation from ends."
  findings: []
- reference: PMID:39644982
  title: "Current landscape of monogenic autoinflammatory actinopathies: A literature review."
  findings: []
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive. Affected individuals carry biallelic WDR1 variants;
    heterozygous relatives are clinically normal.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive."
    explanation: >-
      States the inheritance mode and the segregation observation it rests on.
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia."
    explanation: >-
      The index family is a consanguineous kindred with a homozygous variant in
      two affected siblings, consistent with recessive inheritance.
pathophysiology:
- name: Biallelic WDR1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic WDR1 variants reduce the function of actin-interacting protein 1
    (Aip1). The index PFIT family carries a homozygous missense substitution
    affecting both transcripts; the neutrophil-dysfunction families carry
    biallelic variants affecting distinct antiparallel beta-strands of the
    protein.
  genetic_context:
    gene:
      preferred_term: WDR1
      term:
        id: hgnc:12754
        label: WDR1
    allele_type: missense
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, homozygous missense L153F/L293F mutation in the actin regulatory gene WDR1 causes a new AID in humans, with periodic fevers, immunodeficiency, and intermittent thrombocytopenia (PFIT)."
    explanation: >-
      Names the causal gene, the zygosity and the substitution, and asserts
      causation for the syndrome this entry describes.
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients."
    explanation: >-
      Independent confirmation of biallelic WDR1 variants in a separate cohort
      of four children from three families.
  downstream:
  - target: Impaired Cofilin-Mediated Actin Filament Disassembly
    description: >-
      Aip1 is the accelerator of cofilin-mediated filament severing, so reduced
      Aip1 function slows actin filament turnover.
- name: Impaired Cofilin-Mediated Actin Filament Disassembly
  biological_scale: MOLECULAR
  description: >-
    Aip1/WDR1 preferentially disassembles cofilin-decorated actin filaments.
    With Aip1 function reduced, filaments that cofilin has already decorated are
    not cleared, and polymerised actin accumulates. Patient neutrophils carry
    roughly four times the normal F-actin content.
  biological_processes:
  - preferred_term: actin filament depolymerization
    term:
      id: GO:0030042
      label: actin filament depolymerization
    modifier: DECREASED
  evidence:
  - reference: PMID:29056508
    reference_title: "Functions of actin-interacting protein 1 (AIP1)/WD repeat protein 1 (WDR1) in actin filament dynamics and cytoskeletal regulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AIP1 preferentially promotes disassembly of ADF/cofilin-decorated actin filaments but exhibits minimal effects on bare actin filaments."
    explanation: >-
      States the specific biochemical activity that is lost, and that it is
      selective for cofilin-decorated filaments rather than actin generally.
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neutrophil F-actin was elevated fourfold, suggesting an abnormality in F-actin regulation."
    explanation: >-
      Quantifies the accumulation of polymerised actin in patient cells, the
      direct cellular readout of failed depolymerisation.
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found impaired actin dynamics in patient immune cells."
    explanation: >-
      Confirms the same actin-dynamics defect in the independent PFIT family.
  - reference: PMID:25448002
    reference_title: "Aip1 destabilizes cofilin-saturated actin filaments by severing and accelerating monomer dissociation from ends."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results indicate that Aip1 is a cofilin-dependent actin depolymerization factor and not a barbed-end-capping factor as was previously thought."
    explanation: >-
      Corrects what the lost activity actually is. Aip1 depolymerises rather
      than caps, which matters because a capping defect and a depolymerisation
      defect predict opposite changes in F-actin, and patient cells show F-actin
      accumulation.
  - reference: PMID:25448002
    reference_title: "Aip1 destabilizes cofilin-saturated actin filaments by severing and accelerating monomer dissociation from ends."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified Aip1 as a critical factor responsible for the severing and destabilization of actin filaments even in the presence of high amounts of cofilin."
    explanation: >-
      Explains why cofilin alone cannot compensate: at the cofilin
      concentrations found in lymphoid cells, severing needs Aip1.
  downstream:
  - target: Defective Immunological Synapse Formation in Lymphocytes
    description: >-
      B-cell and T-cell immunological synapses depend on Aip1-driven actin
      turnover.
  - target: Pyrin Sequestration by Mutant WDR1 Aggregates
    description: >-
      Mutant WDR1 protein aggregates, and the aggregates appear to trap pyrin.
    causal_link_type: DIRECT
  - target: Defective Neutrophil Motility and Polarization
    description: >-
      Neutrophil chemotaxis and polarisation depend on continuous actin
      turnover at the leading edge.
  - target: Defective Megakaryocyte Maturation and Platelet Shedding
    description: >-
      Megakaryocyte maturation and proplatelet shedding require cofilin/Aip1
      actin dynamics.
- name: Pyrin Sequestration by Mutant WDR1 Aggregates
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In HEK293T cells co-transfected with pyrin and mutant WDR1, the mutant
    protein forms aggregates that accumulate pyrin. The proposal is that this
    concentrates pyrin and so nucleates inflammasome assembly. This is an
    overexpression experiment in a heterologous cell line and the authors
    themselves state it only as a possibility, so the node is marked
    PROVISIONAL rather than asserted.
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly."
    explanation: >-
      The only direct observation behind this node, and the reason it is
      PROVISIONAL: "appeared to" and "could potentially" are the authors' own
      hedges, and the experiment is transfected HEK293T cells rather than
      patient monocytes.
  downstream:
  - target: Inflammasome Hyperactivation in Monocytes
    description: >-
      Concentrating pyrin is proposed to lower the threshold for inflammasome
      assembly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Inflammasome Hyperactivation in Monocytes
  biological_scale: CELLULAR
  description: >-
    Patient monocytes show increased caspase-1 cleavage, the biochemical
    signature of inflammasome activation.
  cell_types:
  - preferred_term: Monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: inflammasome-mediated signaling pathway
    term:
      id: GO:0141084
      label: inflammasome-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity."
    explanation: >-
      Measured in patient cells rather than a model system, which is why this
      node is asserted while the pyrin-sequestration node above is provisional.
  downstream:
  - target: Excess Interleukin-18 Production
    description: >-
      Activated caspase-1 matures pro-IL-18.
- name: Excess Interleukin-18 Production
  biological_scale: ORGANISM
  description: >-
    The autoinflammatory arm of PFIT runs through IL-18, not IL-1-beta. Serum
    IL-18 is high without a matching rise in IL-18-binding protein, so free
    bioactive IL-18 is increased, and patient cells secrete more IL-18 but not
    more IL-1-beta in culture. This is the mechanistic reason IL-1 blockade is
    only partially effective.
  biological_processes:
  - preferred_term: positive regulation of interleukin-18 production
    term:
      id: GO:0032741
      label: positive regulation of interleukin-18 production
    modifier: INCREASED
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture."
    explanation: >-
      Establishes both halves of the claim: IL-18 is elevated and unbuffered by
      its binding protein, and IL-1-beta is not elevated.
  downstream:
  - target: Recurrent fever
    description: >-
      Systemic IL-18-driven autoinflammation manifests as periodic febrile
      episodes with an extreme acute-phase response.
  - target: Increased circulating interleukin 18 concentration
    description: >-
      The directly measured serum correlate of this node.
- name: Defective Neutrophil Motility and Polarization
  biological_scale: CELLULAR
  description: >-
    Patient neutrophils cannot polarise, spread or move directionally, yet kill
    staphylococci normally once contact is made and mount an increased
    oxidative burst. The defect is therefore in getting to the infection, not
    in dealing with it, which is the distinctive shape of this immunodeficiency.
    Neutrophil nuclear lobes herniate and cytosolic regions are agranular.

    This node is contested across cohorts, and the REFUTE items below record
    it. The motility defect is the Kuhns cohort's central finding, but the
    founding PFIT family was measured in a Dunn chamber and showed no
    difference in velocity or chemotactic index, with the authors concluding
    that neutrophil dysfunction alone cannot account for the phenotype. The
    node is kept because the defect is real where it was found, not because
    the disagreement is settled.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: DECREASED
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We further assessed neutrophil migratory function from patient IV-4 using a modified Dunn chamber, and found no significant difference in velocity or chemotactic index (Fig. 5, A–C)."
    explanation: >-
      The founding PFIT family, measured directly, showed no migration
      defect. This contradicts the node for that cohort and is why the
      description calls the finding contested rather than settled.
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The neutrophil defects in these patients appeared relatively mild, as respiratory burst and phagocytosis were normal (Table S1)."
    explanation: >-
      The same paper grades the neutrophil abnormalities as mild,
      against the node's claim of a defining motility failure.
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation."
    explanation: >-
      Establishes the selective motility defect with preserved killing, the
      claim this node makes.
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neutrophil spreading on glass and cell polarization were also impaired."
    explanation: >-
      Adds the polarisation and spreading defects named in this node.
  downstream:
  - target: Impaired Innate Host Defense at Barrier Surfaces
    description: >-
      Neutrophils that cannot reach a site of infection cannot clear it.
  - target: Impaired neutrophil chemotaxis
  - target: Abnormal neutrophil morphology
- name: Impaired Innate Host Defense at Barrier Surfaces
  biological_scale: ORGANISM
  description: >-
    Failure of neutrophil recruitment produces recurrent infection and,
    strikingly, severe oral inflammation that can scar to oral stenosis, plus
    impaired wound healing.
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
    explanation: >-
      Lists the clinical consequences this node groups, in the cohort in which
      they were described.
  downstream:
  - target: Recurrent bacterial infections
  - target: Stomatitis
  - target: Poor wound healing
- name: Defective Immunological Synapse Formation in Lymphocytes
  biological_scale: CELLULAR
  description: >-
    The arm of the disease that the founding reports missed. Patient T cells
    accumulate atypical actin structures at the immunological synapse, with
    reduced calcium flux and mildly impaired proliferation on T-cell receptor
    stimulation. The B-cell compartment is affected more severely still:
    peripheral B lymphopenia, few marrow B-cell progenitors, no switched memory
    B cells, reduced clonal diversity, abnormal spreading, and increased
    apoptosis on receptor stimulation. So the immunodeficiency in PFIT is not
    only a neutrophil delivery problem; it has an adaptive component with its
    own mechanism at the same molecular step.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  cellular_components:
  - preferred_term: immunological synapse
    term:
      id: GO:0001772
      label: immunological synapse
  evidence:
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation."
    explanation: >-
      The T-cell half of this node, measured in patient cells.
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation."
    explanation: >-
      The B-cell half, and the observation that it is the more severely
      affected compartment.
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses."
    explanation: >-
      States the mechanism this node asserts: actin turnover at the synapse.
  downstream:
  - target: Decreased total B cell count
  - target: Impaired Innate Host Defense at Barrier Surfaces
    description: >-
      Loss of switched memory B cells and B lymphopenia add an antibody-side
      contribution to the same clinical infection burden.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Defective Megakaryocyte Maturation and Platelet Shedding
  biological_scale: CELLULAR
  description: >-
    Bone marrow from a PFIT patient contained small atypical megakaryocytes
    that had failed to develop a demarcating membrane system, the structure
    from which proplatelets are extended. Thrombocytopenia in PFIT is therefore
    a production defect at the shedding step, not peripheral destruction.
  cell_types:
  - preferred_term: Megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  biological_processes:
  - preferred_term: platelet formation
    term:
      id: GO:0030220
      label: platelet formation
    modifier: DECREASED
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed ultrastructural abnormalities of megakaryocytes in patient IV-4 (Fig"
    explanation: >-
      Records that the megakaryocyte abnormality was observed in patient
      marrow. Quoted short because the sentence continues into a figure
      callout; the morphological detail is in the next item.
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealing occasional small, atypical megakaryocytes, with no nucleus and failure of the development of the demarcating membrane system."
    explanation: >-
      The specific ultrastructural lesion: absent demarcating membrane system,
      which is the structure proplatelet shedding requires.
  - reference: PMID:17515402
    reference_title: "Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding."
    explanation: >-
      The mouse experiment that establishes the causal step the human
      ultrastructure is read against. Indirect because it is a mouse hypomorph,
      and because platelet size transfers only partly: of the two index
      siblings, one had mean platelet volume consistently above the reference
      range and the other consistently within it, so the human phenotype is
      variable rather than uniformly normocytic. The next evidence item records
      that measurement.
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Patient IV-2 had mean MPV consistently greater than the reference range (with the exception of two measurements: mean MPV, 11.77 fl; range, 10.6–13.10), and significantly higher than her sibling both before and after HSCT (P < 0.0001, ANOVA)."
    explanation: >-
      Qualifies how far the mouse macrothrombocytopenia transfers: one of
      the two index siblings did have a raised mean platelet volume.
      Indirect because it bears on the fidelity of the mouse model rather
      than on the shedding mechanism itself.
  downstream:
  - target: Thrombocytopenia
phenotypes:
- category: Inflammatory
  name: Recurrent fever
  description: >-
    Periodic fevers from the first weeks of life, lasting 3 to 7 days and
    recurring every 6 to 12 weeks, with complete normalisation of inflammatory
    markers between episodes.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both had periodic fevers lasting 3"
    explanation: >-
      Documents the periodic fever and its duration. Quoted short because the
      source writes the range with an en-dash inside a long compound sentence;
      the periodicity and acute-phase detail are carried by the laboratory
      phenotypes below.
- category: Laboratory
  name: Increased circulating interleukin 18 concentration
  description: >-
    Raised serum IL-18 without a matching rise in IL-18-binding protein. This
    is the biomarker that identifies the autoinflammatory arm as IL-18-driven.
  phenotype_term:
    preferred_term: Increased circulating interleukin 18 concentration
    term:
      id: HP:0034447
      label: Increased circulating interleukin 18 concentration
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture."
    explanation: >-
      Reports the elevated serum IL-18 measurement directly.
- category: Immunologic
  name: Recurrent respiratory infections
  description: >-
    The presenting infection in the lymphoid cohort, which is six of the
    twelve reported patients. Curated separately from the general
    recurrent bacterial infections phenotype because that term keeps the
    organism class and loses the organ the cohort actually described.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis."
    explanation: >-
      Names respiratory tract infections as a presenting feature in the
      six-patient lymphoid cohort.
- category: Immunologic
  name: Reduced circulating follicular helper T cells
  description: >-
    T-cell development is otherwise normal, which makes this subset loss
    specific rather than part of a global lymphopenia. It also supplies a
    mechanism for the absent switched memory B cells curated below, since
    follicular helper T cells are what drive that switching.

    Deliberately unbound. HPO has obsoleted its whole helper-T-cell-proportion
    branch (HP:0005407, HP:0008165, HP:0500263, HP:0500264, HP:0500267 are all
    obsolete) and has no live follicular-helper term. The live alternatives are
    total-T-cell counts such as HP:0005403 Decreased total T cell count, which
    would contradict the source: it states T-cell development is normal apart
    from this one subset. No term is better than a term that inverts the claim.
  phenotype_term:
    preferred_term: Reduced circulating follicular helper T cells
  evidence:
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset."
    explanation: >-
      Reports normal T-cell development with the follicular helper subset
      as the stated exception.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Intermittent thrombocytopenia, deepening during febrile episodes and during
    inflammatory responses to intercurrent infection.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: RECURRENT
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both developed severe inflammatory responses to (presumed) viral infections, with moderate thrombocytopenia."
    explanation: >-
      Documents thrombocytopenia and its association with inflammatory
      episodes.
- category: Infectious
  name: Recurrent bacterial infections
  description: >-
    Recurrent infection, the immunodeficiency component of the syndrome.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
    explanation: >-
      Recurrent infection is the presenting feature of the four-child cohort.
- category: Oral
  name: Stomatitis
  description: >-
    Severe stomatitis, which in this cohort scarred to oral stenosis. The
    severity of the oral disease relative to the modest neutrophil count is a
    diagnostic clue that the defect is functional rather than numerical.
  phenotype_term:
    preferred_term: Stomatitis
    term:
      id: HP:0010280
      label: Stomatitis
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
    explanation: >-
      Names severe stomatitis with oral stenosis among the presenting features.
- category: Dermatologic
  name: Poor wound healing
  phenotype_term:
    preferred_term: Poor wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
    explanation: >-
      Names impaired wound healing among the presenting features.
- category: Hematologic
  name: Decreased total neutrophil count
  description: >-
    Mild neutropenia. Note this is not the main immunological problem: the
    neutrophils that are present cannot migrate, so the functional deficit far
    exceeds what the count predicts.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    severity: MILD
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
    explanation: >-
      Reports the neutropenia and grades it mild.
- category: Cellular
  name: Abnormal neutrophil morphology
  description: >-
    Herniation of the neutrophil nuclear lobes and agranular regions within the
    cytosol, present in every patient examined and, being visible on a routine
    smear, potentially the cheapest pointer to the diagnosis.
  phenotype_term:
    preferred_term: Abnormal neutrophil morphology
    term:
      id: HP:0011992
      label: Abnormal neutrophil morphology
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients studied had similar distinctive neutrophil herniation of the nuclear lobes and agranular regions within the cytosol."
    explanation: >-
      Describes the morphological abnormality and states it was present in all
      patients studied.
- category: Immunologic
  name: Decreased total B cell count
  description: >-
    Peripheral B lymphopenia with loss of switched memory B cells, in the third
    reported cohort.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation."
    explanation: >-
      Reports the B lymphopenia this phenotype records.
- category: Dermatologic
  name: Skin ulcer
  description: >-
    Skin ulceration, a presenting feature in the third cohort alongside
    respiratory infection and stomatitis.
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis."
    explanation: >-
      Names skin ulceration among the presenting features of the third cohort.
- category: Cellular
  name: Impaired neutrophil chemotaxis
  phenotype_term:
    preferred_term: Impaired neutrophil chemotaxis
    term:
      id: HP:0040238
      label: Impaired neutrophil chemotaxis
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation."
    explanation: >-
      The direct measurement of impaired chemotaxis in patient neutrophils.
genetic:
- name: WDR1
  gene_term:
    preferred_term: WDR1
    term:
      id: hgnc:12754
      label: WDR1
  relationship_type: CAUSATIVE
  notes: >-
    WDR1 encodes actin-interacting protein 1 (Aip1). Reported disease alleles
    are biallelic and hypomorphic rather than null; complete loss of Wdr1
    function is embryonic lethal in mouse, which is the likely reason no
    null-allele human cases are described.
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in WDR1 affect neutrophil morphology, motility, and function, causing a novel primary immunodeficiency."
    explanation: >-
      States the gene-disease relationship for the immunodeficiency arm.
  - reference: PMID:17515402
    reference_title: "Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles."
    explanation: >-
      Supports the notes claim that only hypomorphic alleles are compatible
      with life. Indirect: the lethality is established in mouse, not human.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twelve patients from seven families across three cohorts: two siblings with
    the autoinflammatory presentation, four children from three families with
    the neutrophil-dysfunction presentation, and six patients from three
    kindreds in the lymphoid-immunity cohort. No population estimate exists.
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death."
    explanation: >-
      Gives the family and patient count for the second cohort.
  - reference: PMID:29751004
    reference_title: "Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis."
    explanation: >-
      Gives the family and patient count for the third cohort.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Replacing the mutant haematopoietic compartment addresses all three arms of
    the disease at once, because the neutrophil, monocyte and megakaryocyte
    defects are all cell-intrinsic to bone-marrow-derived cells. One PFIT
    patient transplanted at age 8 remained well and off all medication three
    years later, and transplantation corrected the immunological defect in one
    patient of the neutrophil-dysfunction cohort.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic haematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Defective Neutrophil Motility and Polarization
    description: >-
      Donor-derived neutrophils carry wild-type WDR1 and migrate normally.
  - target: Inflammasome Hyperactivation in Monocytes
    description: >-
      Donor-derived monocytes remove the source of excess IL-18.
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient IV-4 successfully underwent allogeneic hematopoietic stem cell transplantation (HSCT) at age 8, and remains well, off all medication, 3 yr later."
    explanation: >-
      The single reported durable outcome in PFIT, and the basis for treating
      transplantation as definitive rather than supportive.
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given that severe autoinflammation coexists with immunodeficiency and thrombocytopenia in PFIT, for the time being, we suggest that HSCT is the most appropriate treatment."
    explanation: >-
      The authors' explicit treatment recommendation, and their reasoning that
      it is the coexistence of the three arms that makes transplant the answer.
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Allogeneic stem cell transplantation corrected the immunologic defect in 1 patient."
    explanation: >-
      An independent transplant outcome in the second cohort, restricted to the
      immunological arm.
  - reference: PMID:39644982
    reference_title: "Current landscape of monogenic autoinflammatory actinopathies: A literature review."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "In most cases, the severity of the conditions necessitates allogeneic marrow transplantation as a treatment option."
    explanation: >-
      Places transplantation as the usual answer across the actinopathy class.
      Graded INDIRECT because the statement is about autoinflammatory
      actinopathies as a group, not about PFIT specifically.
- name: Interleukin-1 Blockade with Anakinra
  description: >-
    Anakinra produced only a transient steroid-sparing effect and did not
    control the autoinflammatory episodes; the patient treated with it died at
    14 of sterile systemic inflammation and multiorgan failure. This is the
    expected result if the driver is IL-18 rather than IL-1-beta, and the entry
    carries it as a REFUTE item against the IL-1 hypothesis rather than as a
    recommended therapy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  evidence:
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultimately, however, this did not control the episodes of autoinflammation, and this patient died at 14 yr of age from sterile systemic inflammation and multiorgan failure."
    explanation: >-
      Refutes IL-1 blockade as adequate therapy for PFIT: the treated patient
      died of uncontrolled autoinflammation.
  - reference: PMID:27994071
    reference_title: "Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was, however, some transient steroid sparing effect in response to anakinra (2"
    explanation: >-
      The partial effect that was observed, quoted short because the source
      writes the dose range with an en-dash. Recorded so the entry does not
      overstate anakinra as wholly without effect.
animal_models:
- name: Wdr1 hypomorphic (rd/rd) mouse
  species: Mouse
  genotype: Wdr1 hypomorphic allele, homozygous
  publication: PMID:17515402
  description: >-
    An allelic series at the mouse Wdr1 locus. Severe loss of function is
    embryonic lethal; hypomorphic alleles give autoinflammatory disease and
    macrothrombocytopenia. This model preceded and predicted the human
    syndrome, including its IL-18 dependence.
  modeled_mechanisms:
  - target: Defective Megakaryocyte Maturation and Platelet Shedding
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The mouse establishes the causal chain from Wdr1 hypomorphism through
      megakaryocyte maturation failure to defective platelet shedding.
    limitations: >-
      The mouse phenotype is uniform macrothrombocytopenia; in humans platelet
      size transfers only partly, with one of the two index siblings showing
      mean platelet volume consistently above the reference range and the other
      consistently within it. The human thrombocytopenia is otherwise described
      as intermittent and moderate.
    readouts:
    - name: Platelet count and megakaryocyte maturation stage
      target: Defective Megakaryocyte Maturation and Platelet Shedding
      direction: DECREASED
      interpretation: >-
        Reduced platelet output attributable to arrested megakaryocyte
        maturation.
      evidence:
      - reference: PMID:17515402
        reference_title: "Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding."
        explanation: >-
          Reports the measurement and the causal attribution behind this
          readout.
    evidence:
    - reference: PMID:17515402
      reference_title: "Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types."
      explanation: >-
        Supports treating the mouse as informative for the megakaryocyte arm of
        the human disease.
  - target: Defective Neutrophil Motility and Polarization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Wdr1 mutant mouse neutrophils show impaired cytoskeletal responses and
      accumulate polymerised actin, as human patient neutrophils do.
    limitations: >-
      Whether the mouse is functionally immunodeficient was never established:
      the animals were housed in a relatively protected environment, so the
      clinical consequence that defines the human disease was not tested. The
      mouse inflammatory lesions are neutrophil-rich infiltrates, which is
      close to the opposite of the human picture of neutrophils failing to
      arrive.
    evidence:
    - reference: PMID:17515402
      reference_title: "Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cytoskeletal responses are impaired in Wdr1 mutant neutrophils."
      explanation: >-
        The cellular defect the model shares with the human disease, and the
        limit of what it demonstrates.
diagnosis:
- name: Biallelic WDR1 variants on molecular testing in a compatible phenotype
  description: >-
    The diagnosis rests on finding biallelic WDR1 variants in a child with
    periodic fever, recurrent infection and thrombocytopenia. Two findings are
    worth knowing because they are cheap and specific: neutrophil nuclear-lobe
    herniation on a smear, and a raised serum IL-18 with a normal or
    disproportionately low IL-1-beta.
  evidence:
  - reference: PMID:27557945
    reference_title: "Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients."
    explanation: >-
      Establishes biallelic WDR1 variants as the molecular finding in every
      patient of the cohort.
differential_diagnoses:
- name: Other monogenic autoinflammatory actinopathies
  description: >-
    PFIT belongs to a recognised class rather than merely resembling one.
    Defects in ARPC1B, MKL1/MRTFA, DOCK8, WAS, DOCK11, ARPC5 and coronin-1A all
    combine immunodeficiency, cytopenia and autoinflammation from disordered
    actin regulation, and the class has a diagnostic shape: early-onset
    autoinflammatory skin and digestive disease with immunodeficiency plus
    thrombocytopenia or bleeding. Genetic testing is what separates the
    members.
  evidence:
  - reference: PMID:39644982
    reference_title: "Current landscape of monogenic autoinflammatory actinopathies: A literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis should be considered primarily when encountering an early-onset autoinflammatory skin and digestive disorder, along with a primary immunodeficiency and either thrombocytopenia or a bleeding tendency."
    explanation: >-
      States the class-level diagnostic trigger that puts PFIT and its
      differentials in the same frame.
  - reference: PMID:39644982
    reference_title: "Current landscape of monogenic autoinflammatory actinopathies: A literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Actinopathies with autoinflammatory manifestations represent a newly emerging subgroup of AID, associated with defects in the regulation of actin cytoskeleton dynamics."
    explanation: >-
      Defines the class this entry places PFIT in.
- name: Hereditary periodic fever syndromes
  description: >-
    Familial Mediterranean fever, TRAPS, mevalonate kinase deficiency and
    cryopyrin-associated periodic syndrome share the periodic-fever
    presentation. The combination with thrombocytopenia and a neutrophil
    migration defect, and the IL-18-dominant rather than IL-1-beta-dominant
    cytokine profile, separate PFIT from them.
discussions:
- discussion_id: pfit_pyrin_sequestration_evidence
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Pyrin Sequestration by Mutant WDR1 Aggregates
  prompt: >-
    Does mutant WDR1 sequester pyrin in patient monocytes, or is the aggregate
    an artefact of overexpression in HEK293T cells?
  rationale: >-
    The link from impaired actin turnover to inflammasome activation is the
    load-bearing step of the autoinflammatory arm, and it rests on a single
    co-transfection experiment in a heterologous cell line, reported by its
    authors with two hedges in one sentence. Patient monocytes show increased
    caspase-1 cleavage, so something activates the inflammasome; whether it is
    pyrin sequestration by aggregates is untested in a patient-derived cell.
    The node is marked PROVISIONAL for this reason.
  proposed_experiments:
  - experiment_id: pfit_pyrin_localisation_patient_monocytes
    name: Pyrin localisation in patient-derived monocytes
    description: >-
      Image endogenous pyrin and WDR1 in patient monocytes or
      patient-iPSC-derived macrophages at physiological expression, and ask
      whether pyrin co-localises with WDR1 aggregates.
    readouts:
    - name: Pyrin and WDR1 co-localisation
      target: pathophysiology#Pyrin Sequestration by Mutant WDR1 Aggregates
      direction: INCREASED
      interpretation: >-
        Co-localisation at endogenous expression would move the node off
        PROVISIONAL.
- discussion_id: pfit_il18_versus_il1_target
  kind: CONTROVERSY
  attaches_to:
  - pathophysiology#Excess Interleukin-18 Production
  - treatments#Interleukin-1 Blockade with Anakinra
  prompt: >-
    If PFIT autoinflammation is IL-18-driven, why did anakinra have any effect
    at all, and would IL-18 blockade work better?
  rationale: >-
    The cytokine data are unambiguous that IL-18 and not IL-1-beta is raised,
    yet anakinra produced a transient steroid-sparing effect. The authors
    themselves raise the possibility that anakinra partially antagonises IL-18,
    which would reconcile the two observations, but no PFIT patient has been
    treated with a specific IL-18 blocker such as recombinant IL-18-binding
    protein. Until one is, the mechanistic model predicts a therapy that has
    never been tested in this disease.
notes: >-
  On the deep-research report. An openscientist report was generated for this
  disease and reconciled into the entry after the first draft. It passed the
  Named Entity Confusion preflight (WDR1 mentioned 45 times, no rival gene, and
  the OMIM identifier matched MONDO's xref). Its most valuable contribution was
  PMID:29751004, a third cohort establishing a lymphoid arm that neither
  founding report describes; that node and its phenotypes exist because of the
  report. Every PMID taken from it was verified against PubMed before citation.

  One report-cited reference was deliberately not used: PMID:24840128, a
  cardiomyocyte-specific Wdr1 conditional knockout with cardiac hypertrophy and
  QT prolongation. No cardiac phenotype is reported in any human PFIT patient,
  so curating it would import an organ the disease does not involve. It is not
  cited and not committed.

  Three cohorts describe this disease from different ends and have never
  been formally reconciled. PMID:27994071 named PFIT from two siblings whose
  dominant problem was autoinflammation; PMID:27557945 described four children
  whose dominant problem was neutrophil dysfunction and named it a primary
  immunodeficiency, without using the term PFIT; PMID:29751004 described six
  patients whose dominant problem was lymphoid, and framed WDR1 deficiency as
  an adaptive-immunity disorder. This entry curates them as one disease because
  the gene, the biochemical lesion and the cell types are the same, but the
  three papers do not share a phenotype definition, and whether the phenotypic
  weighting reflects allele severity is unknown.

  Not curated, and why. No `datasets:` and no `clinical_trials:` - no verified
  accessions or trial registrations exist for a disease with twelve reported
  patients. No `environmental:` - no exposure is implicated. No `biochemical:`
  reference ranges - serum IL-18 is carried as a phenotype rather than a
  biomarker readout because no reference interval for it is given in either
  source. `directness` is set only where it was actually assessed. No count is
  given: this sentence said "four" and was correct until the previous review
  round added a fifth item, which is the second time a count in prose here has
  gone stale.

  On the OMIM 150550 cross-reference. MONDO:0007883 carries a historical xref
  to OMIM 150550, whose title is "lazy leukocyte syndrome". That looks alarming
  and is not: MONDO's own label for 0007883 is "periodic fever,
  immunodeficiency, and thrombocytopenia syndrome", so the binding is to the
  right concept and 150550 is a retitled MIM number rather than a different
  disease. Recorded here so the next curator does not re-litigate it. No
  `mappings:` block is added, because the entry cites no source that states the
  MIM number and its role, and the deep-research report is a lead rather than a
  citable authority for an identifier.
📚

References & Deep Research

References

7
PMID:27994071
Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1.
No top-level findings curated for this source.
PMID:27557945
Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency.
No top-level findings curated for this source.
PMID:29056508
Functions of actin-interacting protein 1 (AIP1)/WD repeat protein 1 (WDR1) in actin filament dynamics and cytoskeletal regulation.
No top-level findings curated for this source.
PMID:17515402
Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia.
No top-level findings curated for this source.
PMID:29751004
Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity.
No top-level findings curated for this source.
PMID:25448002
Aip1 destabilizes cofilin-saturated actin filaments by severing and accelerating monomer dissociation from ends.
No top-level findings curated for this source.
PMID:39644982
Current landscape of monogenic autoinflammatory actinopathies: A literature review.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

On the deep-research report. An openscientist report was generated for this disease and reconciled into the entry after the first draft. It passed the Named Entity Confusion preflight (WDR1 mentioned 45 times, no rival gene, and the OMIM identifier matched MONDO's xref). Its most valuable contribution was PMID:29751004, a third cohort establishing a lymphoid arm that neither founding report describes; that node and its phenotypes exist because of the report. Every PMID taken from it was verified against PubMed before citation. One report-cited reference was deliberately not used: PMID:24840128, a cardiomyocyte-specific Wdr1 conditional knockout with cardiac hypertrophy and QT prolongation. No cardiac phenotype is reported in any human PFIT patient, so curating it would import an organ the disease does not involve. It is not cited and not committed. Three cohorts describe this disease from different ends and have never been formally reconciled. PMID:27994071 named PFIT from two siblings whose dominant problem was autoinflammation; PMID:27557945 described four children whose dominant problem was neutrophil dysfunction and named it a primary immunodeficiency, without using the term PFIT; PMID:29751004 described six patients whose dominant problem was lymphoid, and framed WDR1 deficiency as an adaptive-immunity disorder. This entry curates them as one disease because the gene, the biochemical lesion and the cell types are the same, but the three papers do not share a phenotype definition, and whether the phenotypic weighting reflects allele severity is unknown. Not curated, and why. No `datasets:` and no `clinical_trials:` - no verified accessions or trial registrations exist for a disease with twelve reported patients. No `environmental:` - no exposure is implicated. No `biochemical:` reference ranges - serum IL-18 is carried as a phenotype rather than a biomarker readout because no reference interval for it is given in either source. `directness` is set only where it was actually assessed. No count is given: this sentence said "four" and was correct until the previous review round added a fifth item, which is the second time a count in prose here has gone stale. On the OMIM 150550 cross-reference. MONDO:0007883 carries a historical xref to OMIM 150550, whose title is "lazy leukocyte syndrome". That looks alarming and is not: MONDO's own label for 0007883 is "periodic fever, immunodeficiency, and thrombocytopenia syndrome", so the binding is to the right concept and 150550 is a retitled MIM number rather than a different disease. Recorded here so the next curator does not re-litigate it. No `mappings:` block is added, because the entry cites no source that states the MIM number and its role, and the deep-research report is a lead rather than a citable authority for an identifier.

Reconcile openscientist deep-research report into PFIT entry · 2026-09-06T19:51:38Z · View source

Reconciled the openscientist deep-research report, which returned after the entry was first written. The report passed the Named Entity Confusion preflight. Its principal contribution was PMID:29751004, a third cohort establishing a lymphoid arm of the disease that neither founding report describes: a new pathophysiology node for defective immunological synapse formation in T and B lymphocytes, two new phenotypes (decreased total B cell count, skin ulcer), and a corrected patient count of twelve across seven families. Also added PMID:25448002 refining what the lost Aip1 activity is (a cofilin-dependent depolymerisation factor, not a barbed-end capper) and PMID:39644982 placing PFIT in the monogenic autoinflammatory actinopathy class. PMID:24840128, a cardiomyocyte-specific Wdr1 conditional knockout the report cited, was deliberately not curated because no human PFIT patient has a cardiac phenotype. Snippet count rose from 37/37 to 48/48 verified.

OpenScientist ▸
Periodic Fever, Immunodeficiency, and Thrombocytopenia Syndrome (PFIT): Comprehensive Disease Report
openscientist-autonomous 7 citations 2026-09-06T19:43:16.511687

Periodic Fever, Immunodeficiency, and Thrombocytopenia Syndrome (PFIT): Comprehensive Disease Report

Disease: Periodic Fever, Immunodeficiency, and Thrombocytopenia Syndrome (PFIT) MONDO: MONDO:0007883 · Category: Mendelian (autosomal recessive) Causal gene: WDR1 (encoding Aip1 / actin-interacting protein 1)

Summary

Periodic Fever, Immunodeficiency, and Thrombocytopenia syndrome (PFIT) is an ultra-rare, autosomal-recessive monogenic autoinflammatory "actinopathy" caused by biallelic hypomorphic missense mutations in WDR1, the gene encoding actin-interacting protein 1 (Aip1). Aip1 is a WD40 β-propeller cofactor that cooperates with cofilin/ADF to accelerate depolymerization and turnover of actin filaments. Because the actin cytoskeleton is indispensable to leukocyte motility, immune-synapse formation, and megakaryocyte/platelet biogenesis, partial loss of Aip1 function produces a distinctive triad of recurrent/periodic fevers (autoinflammation), immunodeficiency, and thrombocytopenia, accompanied by severe stomatitis, oral stenosis, skin ulceration, and impaired wound healing. The condition typically presents in the neonatal period or early childhood and, untreated, can be fatal.

Mechanistically, PFIT is defined by two coupled abnormalities. First, loss of Aip1 elevates neutrophil F-actin roughly four-fold and impairs chemotaxis, spreading, and polarization while paradoxically preserving microbial killing and increasing oxidative burst. Second, the disease drives an IL-18–dominant autoinflammatory state: patients have high serum IL-18 (without a matching rise in IL-1β or IL-18–binding protein) and increased caspase-1 cleavage in monocytes, and mutant WDR1 protein aggregates that sequester pyrin, plausibly precipitating inflammasome assembly. Beyond myeloid cells, WDR1 deficiency causes lymphoid immunodeficiency — aberrant T-cell activation at the immunologic synapse and severe B-cell abnormalities (B lymphopenia, loss of switched memory B cells) — and macrothrombocytopenia from defective megakaryocyte maturation.

WDR1 is among the most loss-of-function–intolerant genes in the human genome (gnomAD pLI ≈ 1.0), which explains why every reported human patient carries hypomorphic missense alleles rather than complete-null variants: in mice, severe Wdr1 loss of function is embryonic-lethal, whereas hypomorphic alleles are viable and reproduce the human phenotype (macrothrombocytopenia plus neutrophil-driven autoinflammation). The mechanism is deeply evolutionarily conserved from yeast (AIP1), C. elegans (unc-78), and plants to mouse Wdr1. Allogeneic hematopoietic stem cell transplantation (HSCT) is the definitive, corrective treatment, having reversed the immunologic defect in transplanted patients; diagnosis is genetic (WES/WGS or targeted autoinflammatory/immunodeficiency panels). This report consolidates eight confirmed findings across three primary human cohorts (total ~12 patients) and multiple mechanistic and model-organism studies.

Key Findings

Finding 1 — PFIT is caused by biallelic (autosomal recessive) missense mutations in WDR1 (encoding Aip1)

PFIT was defined independently by two 2016–2017 index reports. Kuhns et al. (2016) identified biallelic WDR1 mutations affecting distinct antiparallel β-strands of Aip1 in four children across three families; heterozygous relatives were clinically normal, establishing autosomal-recessive inheritance. Standing et al. (2017) reported a homozygous missense WDR1 mutation in two siblings with the periodic-fever/immunodeficiency/thrombocytopenia triad, coining the PFIT acronym. WDR1 encodes actin-interacting protein 1 (Aip1), a cofactor that accelerates cofilin-mediated actin filament depolymerization.

"We report a homozygous missense mutation in WDR1 in two siblings causing periodic fevers with immunodeficiency and thrombocytopenia." — PMID: 27994071

"Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients… Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive." — PMID: 27557945

Gene identifiers: WDR1 — HGNC:12754, NCBI Gene 9948, Ensembl ENSG00000071127, UniProt O75083 (Aip1), gene OMIM *604734, cytoband 4p16.1 (GRCh38 chr4:~10.07–10.12 Mb, minus strand).

Finding 2 — Loss of Aip1 elevates F-actin and produces distinctive neutrophil morphologic and motility defects

In patient neutrophils, F-actin was elevated ~4-fold, and chemotaxis and chemokinesis were markedly impaired. Cells showed a distinctive morphology — herniation of nuclear lobes and agranular cytosolic regions — with impaired spreading on glass and defective polarization. Notably, staphylococcal killing was preserved and oxidative burst was paradoxically increased at baseline and on stimulation, indicating a specific defect in actin-dependent motility rather than a global neutrophil failure. Pfajfer et al. (2018) additionally documented defective adhesion and motility of neutrophils and monocytes. The biochemical basis is that Aip1 destabilizes cofilin-saturated actin filaments by severing them and accelerating monomer dissociation from both barbed and pointed ends; loss of this activity impairs filament turnover and lets F-actin accumulate.

"Neutrophil F-actin was elevated fourfold, suggesting an abnormality in F-actin regulation." — PMID: 27557945

"Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation." — PMID: 27557945

"Aip1 also augments the monomer dissociation rate at both the barbed and pointed ends of actin." — PMID: 25448002

Finding 3 — PFIT autoinflammation is IL-18–dominant and driven by increased inflammasome/caspase-1 activity linked to pyrin

Standing et al. (2017) found PFIT patients had high serum IL-18 without a corresponding rise in IL-18–binding protein or IL-1β; patient cells secreted more IL-18 but not IL-1β in culture. Increased caspase-1 cleavage in patient monocytes indicated heightened inflammasome activity. In HEK293T co-transfection experiments, mutant WDR1 protein formed aggregates that accumulated pyrin, potentially precipitating inflammasome assembly. This extends the Wdr1-mutant mouse model, in which autoinflammatory disease is bone-marrow–derived, nonlymphoid, and characterized by massive neutrophil infiltration.

"Patients had high serum levels of IL-18, without a corresponding increase in IL-18-binding protein or IL-1β, and their cells also secreted more IL-18 but not IL-1β in culture." — PMID: 27994071

"We found increased caspase-1 cleavage within patient monocytes indicative of increased inflammasome activity." — PMID: 27994071

"Mutant protein formed aggregates that appeared to accumulate pyrin; this could potentially precipitate inflammasome assembly." — PMID: 27994071

"Autoinflammatory disease, which is bone marrow-derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions." — PMID: 17515402

Finding 4 — WDR1 deficiency also causes lymphoid immunodeficiency and macrothrombocytopenia

Pfajfer et al. (2018) identified novel homozygous/compound-heterozygous WDR1 missense mutations in 6 patients from 3 kindreds presenting with respiratory tract infections, skin ulceration, and stomatitis. Beyond myeloid defects, WDR1 deficiency caused aberrant T-cell activation — atypical actin accumulation at the immunologic synapse, reduced calcium flux, mildly impaired proliferation, and selective loss of follicular helper T cells — and severe B-cell abnormalities: peripheral B-cell lymphopenia, paucity of bone-marrow B-cell progenitors, and lack of switched memory B cells. Thrombocytopenia parallels the macrothrombocytopenia of hypomorphic Wdr1 mice, which arises from megakaryocyte maturation defects causing failure of normal platelet shedding.

"we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis." — PMID: 29751004

"WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells." — PMID: 29751004

"peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation." — PMID: 29751004

"Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding." — PMID: 17515402

Finding 5 — PFIT belongs to the autoinflammatory "actinopathies"; onset is neonatal/early-childhood, and allogeneic HSCT is definitive

Kuhns et al. (2016) reported that allogeneic stem cell transplantation corrected the immunologic defect in one patient, whereas untreated patients had severe outcomes including oral stenosis and death. Reviews of autoinflammatory actinopathies (Mertz et al. 2024) classify WDR1 deficiency within this emerging autoinflammatory-disease subgroup, which typically manifests in the neonatal period and combines primary immunodeficiency, cytopenia (especially thrombocytopenia), and autoinflammation affecting skin and digestive system — often requiring allogeneic marrow transplantation.

"Allogeneic stem cell transplantation corrected the immunologic defect in 1 patient." — PMID: 27557945

"These diseases typically manifest in the neonatal period and variably combine a primary immunodeficiency of varying severity, cytopenia (particularly thrombocytopenia), autoinflammatory manifestations primarily affecting the skin and digestive system." — PMID: 39644982

"In most cases, the severity of the conditions necessitates allogeneic marrow transplantation as a treatment." — PMID: 39644982

Finding 6 — WDR1 is extremely loss-of-function-intolerant, so human PFIT arises only from hypomorphic biallelic missense variants

gnomAD constraint metrics place WDR1 among the most LoF-intolerant genes: pLI = 0.9999, LOEUF (oe_lof upper) = 0.42, observed/expected LoF = 0.29, lof_z = 5.09. Consistent with this, all reported human PFIT patients carry biallelic missense (hypomorphic) variants — Kuhns 2016 (distinct antiparallel β-strands of Aip1), Standing 2017 (homozygous missense), Pfajfer 2018 (homozygous and compound-heterozygous missense). This mirrors the Wdr1 mouse allelic series, in which severe loss of function is embryonic-lethal but hypomorphic alleles are viable and produce autoinflammation plus macrothrombocytopenia.

"Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients." — PMID: 27557945

"While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles." — PMID: 17515402

Finding 7 — Wdr1/Aip1 function and disease are evolutionarily conserved; mouse models recapitulate F-actin accumulation and tissue pathology

Two complementary mouse models establish causality and conserved mechanism. (1) Hypomorphic Wdr1 mice (Kile et al. 2007) develop macrothrombocytopenia (megakaryocyte maturation defect) plus bone-marrow–derived, nonlymphoid autoinflammatory disease with massive neutrophil infiltration; severe LoF is embryonic-lethal. (2) A cardiomyocyte-specific Wdr1 conditional knockout (Yuan et al. 2014) died by postnatal day 24 with cardiac hypertrophy, impaired left-ventricular contraction, prolonged QT, and progressive F-actin accumulation within myofibrils, with ectopic cofilin colocalizing at the aggregates. Aip1 orthologs are deeply conserved: S. cerevisiae AIP1, C. elegans unc-78, plant AIP1 (rice/Arabidopsis), and mouse Wdr1 (NCBI Gene 22388), all promoting cofilin/ADF-mediated actin disassembly.

"Actin filament (F-actin) accumulations began at P10 and became prominent at P12 in the myocardium of cKO mice… Ectopic cofilin colocalized with F-actin aggregates." — PMID: 24840128

"These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types." — PMID: 17515402

Finding 8 — PFIT clinical phenotype spectrum and suggested HPO annotations

Across the three reported cohorts (Kuhns 2016 n=4; Standing 2017 n=2; Pfajfer 2018 n=6), the recurrent core features are: recurrent/periodic fevers, immunodeficiency with recurrent bacterial and respiratory infections, thrombocytopenia/bleeding tendency (including macrothrombocytopenia), mild neutropenia, severe stomatitis/recurrent oral ulceration progressing to oral stenosis, skin ulceration, and impaired wound healing. Laboratory hallmarks include markedly elevated serum IL-18 (with normal/low IL-1β and IL-18BP), elevated neutrophil F-actin (4-fold), distinctive neutrophil nuclear herniation with agranular cytosolic regions, B lymphopenia, and lack of switched memory B cells.

"we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death." — PMID: 27557945

Phenotype Suggested HPO term Frequency / notes
Recurrent/periodic fever (autoinflammation) HP:0001954 (recurrent fever) Core; episodic flares
Recurrent respiratory infections HP:0002205 Common in Pfajfer cohort
Recurrent bacterial infections HP:0002718 Core immunodeficiency feature
Thrombocytopenia HP:0001873 Core
Macrothrombocytopenia (large platelets) HP:0040314 Parallels mouse model
Neutropenia (mild) HP:0001875 Variable
Recurrent oral ulceration / stomatitis HP:0010280 (oral ulcer) Severe; can progress
Oral stenosis HP:0011099 (functional/anatomic stenosis) Severe untreated cases
Skin ulceration HP:0200042 Pfajfer cohort
Poor/impaired wound healing HP:0001058 Core
Elevated serum IL-18 (laboratory biomarker) Diagnostic hallmark

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic hypomorphic missense mutation in WDR1 (4p16.1) leads to a partially functional Aip1 β-propeller protein (complete-null alleles are embryonic-lethal, so only hypomorphs survive).
  2. Reduced Aip1 activity results in failure to sever and disassemble cofilin/ADF-bound actin filaments (Aip1 normally accelerates monomer dissociation from both filament ends).
  3. Impaired filament turnover leads to pathological accumulation of F-actin (~4-fold in neutrophils) and aberrant actin structures in hematopoietic and other cells.
  4. Elevated/dysregulated F-actin branches into three effector arms:
  5. Arm A — Myeloid/innate: impaired neutrophil chemotaxis, spreading, and polarization (motility defect) with preserved killing and increased oxidative burst → recurrent infections + tissue neutrophil infiltration.
  6. Arm B — Autoinflammation: mutant WDR1 aggregates sequester pyrin, and cytoskeletal dysregulation acts as a homeostasis-altering signal → inflammasome/caspase-1 activation → IL-18–dominant cytokine release (without IL-1β) → periodic fevers, cutaneous-digestive inflammation.
  7. Arm C — Lymphoid + platelets: defective immune-synapse actin dynamics → T-cell activation defects + B-cell developmental failure (immunodeficiency); megakaryocyte maturation failure → defective platelet shedding → macrothrombocytopenia/bleeding.
  8. The combined arms result in the clinical triad — periodic fever + immunodeficiency + thrombocytopenia — plus stomatitis, oral stenosis, skin ulceration, and poor wound healing; untreated disease can be fatal.
  9. Because the defect is intrinsic to bone-marrow–derived cells, allogeneic HSCT replaces the defective hematopoietic compartment and corrects the disease (definitive treatment).

(Step 4B's pyrin/inflammasome link is mechanistically supported by co-transfection aggregation data and elevated caspase-1 cleavage but the precise molecular trigger connecting F-actin dysregulation to inflammasome assembly remains partly inferred.)

 WDR1 missense (hypomorphic, biallelic)
│
▼
 Reduced Aip1 activity ──► cofilin-bound filaments not disassembled
│
▼
 F-actin accumulation (~4× in neutrophils)
│
  ┌─────┼─────────────────────────┐
  ▼     ▼                         ▼
Neutrophil   Inflammasome/pyrin   Lymphoid + megakaryocyte
motility     → caspase-1          synapse/maturation defects
defect       → IL-18↑ (IL-1β−)    │
  │             │                 ├─ T/B-cell immunodeficiency
  ▼             ▼                 └─ macrothrombocytopenia
Recurrent    Periodic fever,          (bleeding)
infections   skin/digestive
     autoinflammation
│
▼
   PFIT clinical triad → (untreated) death │ (HSCT) correction

Upstream vs downstream

  • Upstream (initiating): WDR1 mutation → Aip1 hypofunction → defective cofilin-mediated actin disassembly (molecular lesion).
  • Central node: F-actin accumulation / disrupted actin turnover.
  • Downstream (effector): neutrophil/lymphocyte dysfunction, inflammasome-driven IL-18, megakaryocyte failure → the clinical phenotype.

Cell types and processes (suggested ontology terms)

  • Cells (CL): neutrophil (CL:0000775), monocyte (CL:0000576), T cell (CL:0000084), B cell (CL:0000236), megakaryocyte (CL:0000556), platelet (CL:0000233).
  • Biological processes (GO): actin filament depolymerization (GO:0030042), regulation of actin cytoskeleton organization (GO:0032956), neutrophil chemotaxis (GO:0030593), inflammasome complex assembly (GO:0044546), interleukin-18 production (GO:0032620), megakaryocyte differentiation (GO:0030219), immunological synapse formation (GO:0001771).
  • Cellular components (GO CC): cortical actin cytoskeleton (GO:0030864), lamellipodium (GO:0030027), actin filament (GO:0005884).
  • Anatomy (UBERON): bone marrow (UBERON:0002371), blood (UBERON:0000178), oral mucosa (UBERON:0003729), skin (UBERON:0002097).
  • Chemical entities (CHEBI): interleukin-18 (protein), reactive oxygen species (CHEBI:26523).

Report by Template Section

1. Disease Information

PFIT is an ultra-rare Mendelian autoinflammatory immunodeficiency defined by the triad of periodic fever, immunodeficiency, and thrombocytopenia, caused by WDR1 mutations. Identifiers: MONDO:0007883; gene OMIM *604734 (WDR1). MONDO:0007883 is historically cross-referenced to OMIM 150550 ("lazy leukocyte syndrome"), an older descriptive label for a neutrophil-motility disorder — a mapping caveat worth flagging for curators, who should reconcile it against the specific WDR1-PFIT phenotype entry. Synonyms: WDR1 deficiency; Aip1 deficiency; autoinflammatory PFIT; a member of the "autoinflammatory actinopathies." Information is derived from aggregated disease-level resources plus small primary case series (≈12 patients across 3 kindreds/cohorts), not EHR-scale data.

2. Etiology

Causal factor: monogenic — biallelic hypomorphic missense mutations in WDR1. Genetic risk: requires two pathogenic alleles (AR); consanguinity increases risk (homozygous cases reported). No environmental cause; infections are downstream consequences of immunodeficiency rather than causes. Protective factors: none established. Gene–environment interaction: infectious exposures likely precipitate flares and morbidity in an immunodeficient host, but no formal GxE data exist.

3. Phenotypes

See Finding 8 table. Onset is neonatal/early childhood; severity is variable but often severe; course is chronic with episodic autoinflammatory flares. Quality-of-life impact is substantial (recurrent infections, painful stomatitis/oral stenosis limiting feeding, bleeding tendency); formal QoL instruments (EQ-5D/SF-36) have not been reported for this ultra-rare disease.

4. Genetic / Molecular Information

Causal gene: WDR1 (HGNC:12754; NCBI Gene 9948; Ensembl ENSG00000071127; UniProt O75083; 4p16.1). Variant class: missense (hypomorphic) — pathogenic/likely pathogenic per ACMG in reported families; affecting the Aip1 β-propeller (distinct antiparallel β-strands). Functional consequence: partial loss of function (impaired cofilin-dependent actin disassembly). Constraint: pLI ≈ 1.0, LOEUF 0.42 — strong LoF intolerance, so null alleles are not observed in surviving patients. Origin: germline. Modifier genes / epigenetics / chromosomal abnormalities: none established.

5. Environmental Information

No toxic, occupational, or lifestyle etiologic factors. Infectious agents (e.g., Staphylococcus, respiratory pathogens) act as complicating/triggering factors in the immunodeficient host, not as primary causes.

6. Mechanism / Pathophysiology

See the ordered causal chain and diagram above. Core pathway: cofilin/ADF–Aip1 actin-disassembly axis → F-actin dysregulation → branching myeloid, inflammasome (IL-18/pyrin/caspase-1), and lymphoid/megakaryocyte effector arms. Molecular profiling to date is limited to targeted cytokine (IL-18) and cell-biological (F-actin, synapse) assays plus HEK293T co-transfection; no large-scale transcriptomic/proteomic/metabolomic PFIT datasets are published.

7. Anatomical Structures Affected

Primary: bone marrow / hematopoietic system (neutrophils, monocytes, T and B lymphocytes, megakaryocytes/platelets). Secondary/target tissues: oral mucosa (stomatitis, oral stenosis), skin (ulceration, poor healing), respiratory tract (infections). Involvement is systemic/bilateral (hematologic). Subcellular: cortical actin cytoskeleton, lamellipodium; F-actin aggregates.

8. Temporal Development

Onset: neonatal/early childhood. Pattern: chronic disease with episodic (periodic) autoinflammatory fever flares superimposed on persistent immunodeficiency and thrombocytopenia. Progression: can be severe/progressive if untreated (oral stenosis, fatal outcomes). Remission: treatment-induced (HSCT corrective); no reliable spontaneous remission. Critical window: early diagnosis enables transplantation before irreversible complications.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: appears high/complete in biallelic carriers; heterozygotes are unaffected. Expressivity: variable (severity and organ emphasis differ across families). Consanguinity: contributory (homozygous cases). Epidemiology: ultra-rare — only ~12 reported patients across 3 kindreds/cohorts; true prevalence/incidence unknown. No founder effect established for WDR1 PFIT; no strong sex bias reported.

10. Diagnostics

Genetic diagnosis is definitive: WES/WGS or targeted autoinflammatory/immunodeficiency gene panels identifying biallelic WDR1 missense variants. Supportive labs/biomarkers: markedly elevated serum IL-18 (with normal/low IL-1β and IL-18BP), thrombocytopenia with large platelets on smear, mild neutropenia, elevated inflammatory markers, 4-fold elevated neutrophil F-actin, distinctive neutrophil nuclear herniation/agranular cytosol, B lymphopenia and absent switched memory B cells on immunophenotyping. Differential diagnosis: other autoinflammatory actinopathies (e.g., ARPC1B deficiency, MKL1, ACTB/Baraitser-Winter), other periodic fever syndromes (FMF, HIDS), and other inherited macrothrombocytopenias/immunodeficiencies. Screening: cascade genetic testing of at-risk relatives; carrier testing in families.

11. Outcome / Prognosis

Untreated: poor — recurrent infections, bleeding, severe stomatitis/oral stenosis, and reported death. With HSCT: immunologic defect corrected; substantially improved prognosis. Prognostic factors include age at diagnosis, severity of infections/bleeding, and access to transplant.

12. Treatment

Definitive: allogeneic hematopoietic stem cell transplantation (HSCT) — corrective, replaces the defective bone-marrow compartment (NCIT: Allogeneic Hematopoietic Stem Cell Transplantation, C15393). Supportive/bridging: antimicrobial prophylaxis and treatment of infections; management of bleeding/thrombocytopenia; targeting the IL-18/inflammasome autoinflammatory axis is mechanistically rational (IL-18/IL-1 pathway modulation, anti-inflammatory agents) but not established as curative. Wound and oral care for stomatitis/ulceration. Pharmacogenomics: not applicable/established.

13. Prevention

No primary prevention (monogenic). Genetic counseling for AR recurrence risk (25% per pregnancy for carrier couples), carrier and prenatal/preimplantation testing in known families, and cascade screening. Tertiary prevention centers on early transplant and infection prophylaxis to avert complications.

14. Other Species / Natural Disease

Aip1/Wdr1 is deeply conserved: mouse Wdr1 (NCBI Gene 22388), S. cerevisiae AIP1, C. elegans unc-78, plant AIP1 (rice OsAIP1, Arabidopsis). No naturally occurring companion-animal PFIT disease is catalogued; relevance is via engineered models. Not zoonotic.

15. Model Organisms

Mouse (Mus musculus) is the principal model. Hypomorphic Wdr1 mice (Kile 2007) recapitulate macrothrombocytopenia and neutrophil-driven autoinflammation; severe LoF is embryonic-lethal (allelic-series dose dependence mirroring human missense-only genotypes). Cardiomyocyte-specific Wdr1 cKO (Yuan 2014) demonstrates in-vivo F-actin accumulation and tissue pathology. In vitro: HEK293T co-transfection shows mutant WDR1 aggregation and pyrin accumulation; patient-derived neutrophils/T/B cells provide cellular assays. Invertebrate/yeast orthologs (unc-78, AIP1) support mechanistic conservation. Limitations: cardiomyocyte cKO models tissue-specific actin pathology rather than the hematologic/autoinflammatory human disease; small human cohorts limit genotype–phenotype resolution.

Evidence Base

PMID Title (abbrev.) Role / contribution Evidence type
27994071 Autoinflammatory PFIT caused by WDR1 mutation Index report; defines PFIT triad; IL-18 dominance; pyrin/caspase-1 Human clinical
27557945 Cytoskeletal abnormalities & neutrophil dysfunction in WDR1 deficiency 4-patient cohort; 4× F-actin; AR inheritance; HSCT corrective Human clinical
29751004 WDR1 mutations lead to aberrant lymphoid immunity 6-patient cohort; T-synapse defect; B-cell failure; mucocutaneous phenotype Human clinical
17515402 Aip1/Wdr1 mutations cause autoinflammation & macrothrombocytopenia Mouse allelic series; LoF lethality vs hypomorph viability Model organism
24840128 Cardiomyocyte-specific Wdr1 knockout In-vivo F-actin accumulation; ectopic cofilin colocalization Model organism
25448002 Aip1 destabilizes cofilin-saturated filaments Biochemical mechanism of Aip1 disassembly activity In vitro
39644982 Monogenic autoinflammatory actinopathies review Classification; neonatal onset; HSCT as mainstay Review
37596178 Actinopathy-associated autoinflammatory diseases review Diagnostic approach; cutaneous-digestive autoinflammation Review
33558442 Cytoskeletal proteins in immune diseases Context: WDR1 among actin regulators in immunopathology Review
32846417 Actinopathies as a PID category Framework for immunologic actinopathies Review
14742433 · 14680631 · 16421248 AIP1/cofilin biochemistry Mechanistic basis of Aip1-cofilin cooperative disassembly In vitro / yeast
23134061 Rice OsAIP1 promotes actin turnover Evolutionary conservation of Aip1 function Plant model

Consistency: All three human cohorts converge on biallelic WDR1 missense variants, actin dysregulation, and the PFIT triad, with independent replication of AR inheritance and HSCT correction. Mouse and biochemical studies provide congruent mechanistic support. No published study in the reviewed set contradicts the core model.

Limitations and Knowledge Gaps

  • Very small n (~12 patients): prevalence, incidence, penetrance, and full expressivity are imprecise; genotype–phenotype correlation is limited.
  • Inflammasome trigger partly inferred: the exact molecular link from F-actin dysregulation to pyrin/inflammasome activation rests on co-transfection aggregation data and caspase-1 cleavage — direct in-vivo mechanistic proof in patient tissue is incomplete.
  • No large-scale omics: no published PFIT transcriptomic/proteomic/single-cell datasets to define cell-type-resolved mechanisms.
  • Therapeutic evidence beyond HSCT is anecdotal: targeted IL-18/inflammasome blockade is rational but not validated in trials.
  • Identifier ambiguity: MONDO:0007883's historical cross-reference to OMIM 150550 ("lazy leukocyte syndrome") should be verified against the specific WDR1-PFIT OMIM phenotype entry for curation accuracy.

Proposed Follow-up Experiments / Actions

  1. Establish an international PFIT/WDR1 registry to capture natural history, penetrance, genotype–phenotype correlations, and HSCT outcomes.
  2. Patient-derived single-cell multi-omics (scRNA-seq/CITE-seq of bone marrow and blood) to resolve cell-type-specific actin/inflammasome dysregulation and IL-18 sources.
  3. Mechanistic dissection of the F-actin → pyrin/inflammasome link using patient monocytes and CRISPR-engineered WDR1-hypomorph cell lines/organoids; test whether restoring actin turnover normalizes IL-18.
  4. Preclinical trials of IL-18/IL-1 pathway blockade (as a bridge to or adjunct with HSCT) in hypomorphic Wdr1 mice and patient cells.
  5. Structure–function studies mapping reported β-propeller missense variants onto Aip1 structure to predict residual activity and severity (variant-interpretation aid).
  6. Curate ontology annotations (HPO frequencies, GO/CL/UBERON/CHEBI terms above) into the disease knowledge base and reconcile MONDO/OMIM cross-references.

Report compiled from 8 confirmed findings and 18 reviewed papers across 5 investigation iterations. Evidence types are labeled human clinical, model organism, in vitro, or review throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 21
Quoted claims found in source 19
Quoted claims not found in source 2
References weighed for topical relevance 14
On topic 6
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:27557945 (abstract only): "Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients… Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive."
  • closest text in source: "Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients"
  • PMID:24840128 (abstract only): "Actin filament (F-actin) accumulations began at P10 and became prominent at P12 in the myocardium of cKO mice… Ectopic cofilin colocalized with F-actin aggregates."
  • closest text in source: "Actin filament (F-actin) accumulations began at P10 and became prominent at P12 in the myocardium of cKO mice"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 33
Resolved 32
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 10
Terms named correctly 4
Terms named as a different term 3
Terms whose name is worth a second look 3

Terms the report names something else

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:

  • HP:0040314 (1 mention) - the report calls it "Macrothrombocytopenia (large platelets)"; HP calls it Blind vagina
  • HP:0010280 (1 mention) - the report calls it "oral ulcer"; HP calls it Stomatitis
  • HP:0011099 (1 mention) - the report calls it "functional/anatomic stenosis"; HP calls it Spastic hemiparesis

Terms whose name is worth a second look

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:0001875 (1 mention) - the report calls it "Neutropenia (mild)"; HP calls it Decreased total neutrophil count, and lists "Neutropenia" among its other names
  • HP:0200042 (1 mention) - the report calls it "Skin ulceration"; HP calls it Skin ulcer
  • HP:0001058 (1 mention) - the report calls it "Poor/impaired wound healing"; HP calls it Poor wound healing