Pelger-Huet-like Anomaly and Episodic Fever with Abdominal Pain

Mendelian MONDO:0009842 Pathograph 28 Show in embeddings browser autoinflammatory syndrome primary immunodeficiency disease

An autosomal recessive combined autoinflammatory and immunodeficiency syndrome caused by biallelic missense variants in CEBPE, the gene encoding the late myeloid transcription factor C/EBP-epsilon. The clinical picture, described in a Finnish kindred from the 1970s onward and long labelled an atypical Pelger-Huet anomaly, combines recurrent multi-day attacks of aseptic fever, abdominal pain and systemic inflammation with a neutrophil defect: hyposegmented nuclei, impaired chemotaxis, abscesses, purulent paronychia, mucosal ulceration and a mild bleeding diathesis. The molecular basis was resolved in 2019 as a homozygous p.Arg219His substitution in the basic-leucine-zipper DNA-binding domain of C/EBP-epsilon, which the authors named CAIN (C/EBP-epsilon-associated autoinflammation and immune impairment of neutrophils). The mechanism is neomorphic rather than simply loss- or gain-of-dosage: the mutant factor loses association with more than a hundred protein partners, many of them transcriptional repressors, and consequently occupies roughly three times as many chromatin sites as wild type without any change in its recognition motif. The resulting genome-wide transcriptional dysregulation includes constitutive expression of caspase-5 in resting macrophages, which primes the noncanonical caspase-4/5 inflammasome so that intracellular bacterial LPS provokes an exaggerated IL-1-beta and IL-18 response. The disorder is therefore the first reported human monogenic noncanonical inflammasomopathy. The MONDO label preserves the 1970s clinical description; the same concept (OMIM 260570) also carries the synonym "immunodeficiency 108 with autoinflammation", and the recent literature refers to it that way.

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1
Inheritance
10
Pathophys.
1
Histopath.
18
Phenotypes
4
Gaps
28
Pathograph
1
Genes
2
Medical Actions
6
References
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive HP:0000007
Disease requires the homozygous state. Heterozygous carriers are clinically unaffected but are not molecularly normal: their granulocytes show an intermediate increase in C/EBP-epsilon chromatin occupancy, which the authors read as evidence of post-transcriptional compensation rather than of a dominant effect.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31201888 SUPPORT Human Clinical
"We report an autosomal recessive GOF PID, C/EBPε-associated autoinflammation and immune impairment of neutrophils (CAIN), in a family with a genetically uncharacterized autoinflammatory syndrome."
States the inheritance pattern and names the entity in the family in which it was characterized.
PMID:31201888 SUPPORT INDIRECT In Vitro
"Analysis of heterozygous relatives without reported clinical manifestations of disease showed intermediate cellular changes."
Supports recessiveness at the clinical level while showing that the heterozygous state is not molecularly silent. INDIRECT because it is a cellular measurement offered in support of an inheritance claim.
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Discussions and Knowledge Gaps

4
Is the depressed delta-aminolevulinic acid synthase activity found in this kindred in 1987 a consequence of the CEBPE p.Arg219His allele, and does heme depletion contribute to the abdominal attacks?
KNOWLEDGE GAP gap_cain_heme_synthesis_hypothesis
Attached to
phenotypes#Abdominal pain pathophysiology#Genome-Wide Transcriptional Dysregulation in Granulocytes pathophysiology#Hyperinflammatory Response to Bacterial Stimuli
Before the gene was known, granulocyte delta-aminolevulinic acid synthase activity was measured in this kindred and found depressed in all three symptomatic members while normal in the asymptomatic Pelger-Huet carriers studied alongside them. The investigators proposed that the abdominal attacks were caused by heme depletion, drawing an explicit analogy to porphyria. The 2019 study that identified CEBPE p.Arg219His accounts for the attacks through noncanonical inflammasome priming and does not address the heme finding, so the two mechanisms are neither reconciled nor mutually excluded. Whether heme biosynthesis genes are among the 464 dysregulated transcripts would be the cheapest first test, and it is answerable from data that already exist.
What compensates for the substantially increased C/EBP-epsilon chromatin occupancy seen in clinically unaffected heterozygous carriers?
KNOWLEDGE GAP gap_cain_heterozygote_compensation
Attached to
pathophysiology#Increased C/EBP-epsilon Chromatin Occupancy inheritance#Autosomal recessive
Heterozygous carriers occupy an intermediate position on every molecular measure — 4686 chromatin binding sites against 3391 in controls and 10322 in patients — yet have no reported clinical manifestations. The authors read this as post-transcriptional compensation of unknown kind, report that DNA methylation analysis in the patients found nothing that would explain either the symptoms or their mildness, and propose histone methylation and open chromatin binding as the next thing to test in a knock-in animal model. This matters beyond this disease: it is a worked case of a transcription-factor allele whose genomic effect is far larger than its phenotypic one.
What causes the mild bleeding diathesis, given that platelet granule morphology is normal?
KNOWLEDGE GAP gap_cain_bleeding_mechanism
Attached to
pathophysiology#Mild Bleeding Diathesis of Unresolved Mechanism phenotypes#Epistaxis
Every affected member of the index kindred bleeds mildly, and C/EBP-epsilon is known to control platelet granule formation, so a platelet granule defect was the obvious candidate. It was looked for and not found: granule and overall platelet structure were morphologically normal. Platelet function testing, granule secretion assays and von Willebrand studies are not reported in any cited source. The `Mild Bleeding Diathesis of Unresolved Mechanism` node is curated HYPOTHETICAL for this reason.
Does blocking IL-1-beta or IL-18 control the inflammatory attacks, as the mechanism predicts?
KNOWLEDGE GAP gap_cain_targeted_cytokine_blockade
Attached to
pathophysiology#Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming treatments#Baricitinib
The mechanism identified in 2019 is an exaggerated IL-1-beta and IL-18 response through the noncanonical caspase-4/5 inflammasome, and the authors say in as many words that anti-IL-1-beta and anti-IL-18 look like likely treatment modalities but remain untested. The only reported durable treatment response in this disease is to a JAK inhibitor, in one patient carrying a different allele, so the prediction that follows most directly from the mechanism has not been tried in anyone.
Proposed experiments
Targeted IL-1-beta or IL-18 blockade in a molecularly confirmed patient
exp_cain_il1_il18_blockade
Trial an IL-1-beta antagonist, and separately an IL-18 antagonist, in a patient with a confirmed biallelic CEBPE DNA-binding-domain variant, measuring attack frequency and duration alongside serum IL-1-beta, IL-18 and C-reactive protein, and repeating the intracellular-LPS macrophage assay before and during treatment.
Would support
pathophysiology#Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
Would refute
pathophysiology#Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
Supporting outcome
  • Attack frequency falls and the ex vivo macrophage response to intracellular LPS normalizes under blockade of either cytokine.
Refuting outcome
  • Attacks continue unchanged under adequate cytokine blockade, which would place the clinical attacks downstream of something other than the noncanonical inflammasome output.
⚙

Pathophysiology

10
CEBPE p.Arg219His Substitution in the DNA-Binding Domain
A homozygous c.656G>A change in CEBPE exon 2 substitutes histidine for arginine at residue 219, within the highly conserved carboxy-terminal DNA-binding region of the basic leucine zipper shared by all four C/EBP-epsilon isoforms. The variant cosegregated with disease in the index kindred and was the only homozygous rare variant shared by all three genotyped patients.
CEBPE hgnc:1836 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CEBPE (hgnc:1836). hgnc:1836 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context CEBPE hgnc:1836 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CEBPE (hgnc:1836). hgnc:1836 is a gene from the HUGO Gene Nomenclature Committee. allele_type: MISSENSE variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: NEOMORPHIC
Curated NEOMORPHIC on the authors' own analysis: the substitution was predicted to abolish DNA binding, but in patients' granulocytes it instead produced a large increase in chromatin occupancy with an unchanged recognition motif, alongside a loss-of-function effect on protein-protein interactions. The paper describes the resulting entity as the first human monogenic neomorphic inflammasomopathy.
DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
Downstream
Loss of C/EBP-epsilon Association with Transcriptional Repressors The substitution is proposed to change protein conformation rather than DNA recognition, stripping the factor of most of its partner interactions.
Mild Bleeding Diathesis of Unresolved Mechanism C/EBP-epsilon controls platelet granule formation, so a bleeding tendency in these patients is plausibly a direct consequence of the same allele; the platelet studies that were done did not find the expected lesion, so the edge is curated with unknown intermediates.
Preserved Neutrophil Granule Content Unlike the specific-granule-deficiency alleles of the same gene, this substitution leaves granule content intact — the observation that separates the two CEBPE disorders.
Show evidence (2 references)
PMID:31201888 SUPPORT DIRECT Human Clinical
"Only one of these variants was homozygous in all 3 patients (ENSG00000092067:ENST00000206513: exon2:c.G656A;p.Arg219His) in the CEPBE gene."
Identifies the causal allele from whole-exome sequencing of the index kindred. (The source spells the gene "CEPBE" at this point; the quote is reproduced verbatim.)
PMID:31201888 SUPPORT DIRECT Human Clinical
"It resided in the highly conserved basic zipper region’s carboxyl terminal DNA-binding domain shared by all 4 C/EBPε isoforms"
Locates the substitution in the DNA-binding domain, which is what makes a chromatin-occupancy mechanism the one to test.
Loss of C/EBP-epsilon Association with Transcriptional Repressors
Of 144 C/EBP-epsilon interaction partners identified, 108 were significantly altered by the substitution and 106 of those were decreased. A large share of the lost partners are transcriptional repressors, including several SWI/SNF chromatin-remodelling subunits, which is the proposed reason the mutant factor is no longer restrained on chromatin.
association with transcriptional repressors, including SWI/SNF subunits GO:0001221 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased association with transcriptional repressors, including SWI/SNF subunits, annotated with transcription coregulator binding (GO:0001221). GO:0001221 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Increased C/EBP-epsilon Chromatin Occupancy Without its repressor partners the mutant factor binds far more sites, while recognizing the same DNA motif as wild type.
Show evidence (1 reference)
PMID:31201888 SUPPORT DIRECT In Vitro
"Importantly, many of the diminished interactors were transcriptional repressors, suggesting widely dysregulated C/EBPε-driven transcription"
Identifies transcriptional repressors as the class of partner lost, which is the step that connects the interaction defect to the transcriptional one.
Increased C/EBP-epsilon Chromatin Occupancy
Chromatin immunoprecipitation sequencing of patient granulocytes found about three times as many C/EBP-epsilon binding sites as in controls, with heterozygous carriers intermediate — a dose-dependent occupancy gradient across the three genotypes. De novo motif analysis found essentially the same consensus sequence in mutant and wild type.
granulocyte CL:0000094 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte (CL:0000094). CL:0000094 is a cell type from the Cell Ontology.
chromatin binding GO:0003682 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased chromatin binding (GO:0003682). GO:0003682 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Genome-Wide Transcriptional Dysregulation in Granulocytes Excess occupancy at unchanged motifs translates into a large, interferon-weighted shift in the granulocyte transcriptome.
Show evidence (1 reference)
PMID:31201888 SUPPORT DIRECT In Vitro
"Peak calling and overlap analysis from biological replicates revealed 3391 C/EBPε-binding sites in control subjects, 4686 in Arg219His heterozygote carriers, and 10322 in homozygous patients"
Directly quantifies the occupancy increase and shows it tracks allele dosage.
Genome-Wide Transcriptional Dysregulation in Granulocytes
464 genes are differentially transcribed in unstimulated patient granulocytes, 198 of them interferon-related, with NLRP3 up more than eightfold. Interferon stimulation widens rather than normalizes the difference, and NLRP12 — a suppressor of neutrophil migration — rises 13.6-fold after type I interferon.
granulocyte CL:0000094 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte (CL:0000094). CL:0000094 is a cell type from the Cell Ontology.
regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ↕ DYSREGULATED response to type I interferon GO:0034340 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to type I interferon (GO:0034340). GO:0034340 is a biological process from the Gene Ontology. ⚠ ABNORMAL response to type II interferon GO:0034341 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to type II interferon (GO:0034341). GO:0034341 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming Human caspase-5 expression is normally interferon-dependent; the transcriptional shift makes it constitutive, removing the priming step that would otherwise gate noncanonical inflammasome activation.
Impaired Neutrophil Chemotaxis with Reduced CD66b The same transcriptional programme raises NLRP12, a suppressor of neutrophil migration, while surface CD66b falls.
Neutrophil Nuclear Hyposegmentation Hyposegmented nuclei in a fifth of patient neutrophils, the finding that gave the disorder its Pelger-Huet-like name, in a factor that governs late myeloid differentiation.
Show evidence (5 references)
PMID:31201888 SUPPORT DIRECT In Vitro
"This identified 464 significantly differentially transcribed (fold change [FC] ≥ 2 or ≤ 0.5, false discovery rate [FDR] ≤ 0.05) genes, 198 of which, including NLRP3 (FC = 8.25), were interferon related"
The primary transcriptomic result, in patients' own granulocytes.
PMID:31201888 SUPPORT DIRECT In Vitro
"In response to IFN-α2b stimulation, 534 genes were differentially transcribed (FC ≥ 2 or ≤ 0.5, FDR ≤ 0.05) between patients and control subjects"
Quantifies the type I interferon arm specifically, which is the larger of the two stimulated responses and the basis for the `response to type I interferon` annotation.
PMID:31201888 SUPPORT DIRECT In Vitro
"These included a significant 13.6-fold increase in NLRP12 expression in patients."
Gives the magnitude of the NLRP12 rise after type I interferon stimulation, the specific result named in this node's description.
+ 2 more references
Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
Resting patient macrophages express caspase-5 without interferon priming, and peripheral blood mononuclear cells show both increased pro-caspase-5 and more processed caspase-5. The canonical NLRP3 pathway is untouched: whole-blood canonical activation and monocyte caspase-1 activity are normal, and priming control cells with interferon abolishes the difference — so the defect is specifically that the noncanonical arm is pre-primed.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
non-canonical inflammasome complex assembly GO:0160075 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased non-canonical inflammasome complex assembly (GO:0160075). GO:0160075 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hyperinflammatory Response to Bacterial Stimuli Because the priming step is already satisfied, an ordinary encounter with intracellular bacterial LPS produces a disproportionate cytokine response.
Show evidence (2 references)
PMID:31201888 SUPPORT DIRECT In Vitro
"Notably, we found increased baseline expression of caspase-5 in patients’ macrophages and increased IL-1β and IL-18 secretion on stimulation of the noncanonical caspase-4/5 inflammasome with intracellular LPS."
The central mechanistic finding: constitutive caspase-5 plus an exaggerated noncanonical response in the same cells.
PMID:31201888 SUPPORT DIRECT In Vitro
"In cultured macrophages secretion of both IL-1β and constitutively expressed IL-18 was similar after canonical activation (Fig 5, C) but was markedly enhanced after noncanonical caspase-4/5–mediated NLRP3 activation in patients compared with control subjects"
Separates the affected pathway from the unaffected one, which is what makes this a noncanonical rather than a classical inflammasomopathy.
Hyperinflammatory Response to Bacterial Stimuli
Clinically, attacks of aseptic fever, abdominal pain and systemic inflammation lasting four to five days, accompanied by an acute-phase response. Attacks became more prominent at puberty and subsided after menopause in the affected women of the index kindred.
Downstream
Recurrent fever Aseptic fever is one of the two cardinal attack symptoms.
Abdominal pain Abdominal pain is the other cardinal attack symptom and names the disorder.
Elevated circulating C-reactive protein concentration Attacks are accompanied by an acute-phase response; the later independent case also had elevated CRP with normal procalcitonin.
Pyoderma gangrenosum A neutrophilic dermatosis reported occasionally during attacks in the index kindred.
Intra-abdominal granuloma Granulomas listed among the occasional accompaniments of the attacks. Typed with unknown intermediates because no cited source establishes whether they arise from the exaggerated inflammasome response or from defective neutrophil clearance, and the entry does not pick between them.
Increased total leukocyte count The authors' own conclusion is that the raised white cell count reflected infection and the inflammatory response rather than leukaemia, which is what places it downstream of the inflammatory response rather than beside it. Typed with unknown intermediates because the source states the attribution as a conclusion, not a demonstrated mechanism.
Show evidence (1 reference)
PMID:31201888 SUPPORT DIRECT Human Clinical
"Patients experienced recurrent attacks of abdominal pain, aseptic fever, and systemic inflammation lasting 4 to 5 days."
Describes the attack phenotype, including its duration and its aseptic character.
Impaired Neutrophil Chemotaxis with Reduced CD66b
The oldest measured abnormality in this kindred: patient polymorphonuclear cells migrate slowly both spontaneously and toward a chemoattractant, a defect the 1979 investigators localized to intrinsic locomotor capacity rather than to cell deformability or receptor responsiveness. The 2019 study supplies a candidate molecular basis in reduced surface CD66b together with strongly increased NLRP12 transcription.
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
Downstream
Impaired neutrophil chemotaxis The chemotaxis defect is itself a recorded laboratory phenotype.
Recurrent abscess formation Nailbed, tongue, submandibular and gluteal abscesses in the index kindred.
Paronychia Frequent episodes of purulent paronychia, sometimes with lymphangitis.
Recurrent aphthous stomatitis Buccal ulceration reported during attacks.
Recurrent upper respiratory tract infections Purulent upper respiratory tract infections reported in the kindred.
Poor wound healing Delayed wound healing recorded in the symptomatic members in 1987.
Osteomyelitis Deep, culture-positive bone infection in the independently reported case, read here as the severe end of the same failure of neutrophil recruitment that produces the superficial abscesses.
Show evidence (4 references)
PMID:477034 SUPPORT DIRECT In Vitro
"The spontaneous migration of the PMNs of the three sisters was significantly slower both under agarose and in a membrane filter than that of the PMNs of the asymptomatic patients with P-H anomaly."
Measures the motility defect in the symptomatic members against asymptomatic Pelger-Huet controls, so the comparison isolates the syndrome rather than the nuclear anomaly.
PMID:477034 SUPPORT DIRECT In Vitro
"Our results suggests that the impaired chemotaxis was due to a defect in the intrinsic locomotor capacity of PMNs rather than in their deformability or their responsiveness to the chemotactic stimulus."
Localizes the defect to the cell's own motile machinery, excluding two alternative explanations.
PMID:31201888 SUPPORT DIRECT In Vitro
"Patients’ granulocytes displayed impaired expression of CD66b compared with those from age- and sex-matched control subjects"
Supplies a measured surface-molecule abnormality in the same cells decades after the functional defect was described.
+ 1 more reference
Neutrophil Nuclear Hyposegmentation
About one in five patient neutrophils has a hyposegmented nucleus on Wright-stained smears. This is the feature that led to the disorder being called an atypical Pelger-Huet anomaly for four decades, and it remains the most accessible diagnostic clue.
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.
Downstream
Hyposegmentation of neutrophil nuclei The morphological finding as recorded on the blood film.
Show evidence (1 reference)
PMID:31201888 SUPPORT DIRECT Human Clinical
"20% of patients’ neutrophils were hyposegmented"
Quantifies the nuclear abnormality in the molecularly confirmed patients.
Preserved Neutrophil Granule Content
Electron microscopy and Wright staining show normal azurophilic, specific and tertiary granules in normal numbers, and granule-resident CD66a and CD11b reach the surface normally. This is the discriminator against neutrophil-specific granule deficiency, the other CEBPE disorder, in which granule content is the thing that is lost.
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.
Show evidence (2 references)
PMID:31201888 SUPPORT DIRECT In Vitro
"electron microscopy showed that patients’ neutrophils contained normal-sized azurophilic specific and tertiary granules in normal numbers"
Direct ultrastructural evidence that granule content is intact.
PMID:31201888 SUPPORT DIRECT In Vitro
"On flow cytometry, CD66a and CD11b expression was unaffected, which is consistent with a non-SGD disease"
Independent flow-cytometric confirmation, and the authors' own reading of it as excluding specific granule deficiency.
Mild Bleeding Diathesis of Unresolved Mechanism
Mechanism confidence: Hypothetical
Every affected member of the index kindred had a mild bleeding tendency with frequent nosebleeds and easy bruising after needle sticks and procedures. Because C/EBP-epsilon is known to control platelet granule formation, the investigators looked for a platelet granule defect and did not find one: granule and overall platelet structure were morphologically normal, with only dilated open canalicular systems and slight activation noted.
Downstream
Epistaxis Frequent nosebleeds are the reported expression of the bleeding tendency.
Bruising susceptibility The tendency to hematomas after needle sticks and procedures is the other reported expression of the same bleeding tendency.
Show evidence (2 references)
PMID:31201888 SUPPORT DIRECT Human Clinical
"All affected members further had mild bleeding diathesis with frequent nosebleeds and a tendency toward hematomas after needle sticks and procedures."
Establishes the bleeding tendency as a constant clinical feature of the kindred.
PMID:31201888 REFUTE In Vitro
"No morphologic aberrancies were found in a granule and overall platelets structure."
Refutes the platelet-granule explanation for the bleeding tendency, which is why the node is curated as mechanistically unresolved.
✶

Histopathology

1
Marrow monocytoid predominance with dim cytoplasmic MPO and absent AML markers
In the independently reported case the bone marrow aspirate was 90 percent abnormal monocytes/promonocytes expressing CD13, CD14, CD33, CD36, CD38, CD58 and CD64 with dim cytoplasmic myeloperoxidase, while CD34, CD117 and HLA-DR were absent. Those three absences, with a negative leukaemia panel and a normal karyotype, are what separate the picture from acute myeloid leukaemia. The authors read the cells as arrested immature granulocytes rather than true monocytes, which is what C/EBP-epsilon's role in late myeloid differentiation would predict.
Show evidence (2 references)
PMID:41026272 SUPPORT Human Clinical
"The bone marrow contained 90% abnormal monocytes/promonocytes"
Quantifies the monocytoid predominance in the marrow aspirate.
PMID:41026272 SUPPORT Human Clinical
"AML-related markers, such as CD34, CD117, and HLA-DR, were absent."
Records the immunophenotypic absences that argue against acute myeloid leukaemia despite the monocytoid morphology.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Pelger-Huet-like Anomaly and Episodic Fever with Abdominal Pain Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Blood 7
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:477034 SUPPORT In Vitro
"Chemotactic and chemokinetic locomotion of the PMNs of the symptomatic sisters was also slow."
Reports the chemotactic and chemokinetic defect specifically in the symptomatic members of the kindred.
Hyposegmentation of neutrophil nuclei HP:0011447 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyposegmentation of neutrophil nuclei (HP:0011447). HP:0011447 is a phenotype from the Human Phenotype Ontology.
Numerator/denominator here is per cell, not per patient: 20 percent of 200 consecutive leukocytes scored on Wright-stained smears from the genotyped patients.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"20% of patients’ neutrophils were hyposegmented"
Quantifies the proportion of hyposegmented neutrophils.
Epistaxis HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"All affected members further had mild bleeding diathesis with frequent nosebleeds and a tendency toward hematomas after needle sticks and procedures."
Reports frequent nosebleeds in every affected member of the kindred.
Bruising susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
No frequency band is given. The sentence says all affected members, but the denominator is the four sisters of a single kindred, and this entry does not put frequency bands on a four-patient series.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"All affected members further had mild bleeding diathesis with frequent nosebleeds and a tendency toward hematomas after needle sticks and procedures."
Reports the tendency toward hematomas after needle sticks and procedures in every affected member of the kindred.
Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased total leukocyte count (HP:0001974). HP:0001974 is a phenotype from the Human Phenotype Ontology.
Single reported patient, so no frequency band. The recorded count was 52800 per microliter against a stated reference range of 5000-13000; the cited source presents those figures in a table which the reference cache flattens into a run of digits, so the quoted evidence here is the surrounding prose rather than the table row.
Show evidence (2 references)
PMID:41026272 SUPPORT Human Clinical
"her white blood cell count was observed to be significantly elevated, prompting further investigations for potential hematologic malignancy."
Records the leukocytosis and the diagnostic consequence that makes it worth curating separately.
PMID:41026272 SUPPORT Human Clinical
"Elevated CRP levels, normal procalcitonin levels, and persistent leukocytosis suggested an immune-mediated process rather than active infection."
Records that the leukocytosis persisted and was read as immune-mediated, which is what separates it from a simple infective response.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Deliberately not wired into the pathograph. No cited source proposes a mechanism for the anaemia - it is a single reported value in a complete blood count, and attaching it downstream of the hyperinflammatory node would assert an anaemia of inflammation that nothing here states. Single patient, so no frequency band. The cited source presents the value in a table which the reference cache flattens, so the quoted row reads as run-together figures.
Show evidence (1 reference)
PMID:41026272 SUPPORT Human Clinical
"Complete Blood Count (CBC):Serial no.ParameterValueNormal Range1.Hb gm/dl6.911.0-15.5"
The complete blood count row giving a haemoglobin of 6.9 g/dL against a reference range of 11.0-15.5.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Deliberately not wired into the pathograph, for the same reason as the anaemia: no cited source gives it a mechanism. It is worth recording that this is a separate observation from the index kindred's bleeding tendency, which was investigated and found to have morphologically normal platelets - the two are not connected by any cited source, and this entry does not connect them. Single patient, so no frequency band.
Show evidence (1 reference)
PMID:41026272 SUPPORT Human Clinical
"2.Total leukocyte counts/microliter528005000-130003.Platelet counts/microliter119000150000-4100004.Peripheral smear: large monocytoid cells with cytoplasmic granules."
The complete blood count row giving a platelet count of 119000 per microliter against a reference range of 150000-410000.
Head and Neck 2
Recurrent aphthous stomatitis HP:0011107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent aphthous stomatitis (HP:0011107). HP:0011107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"These were accompanied by an acute-phase response and occasionally by nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal granulomas; pyoderma gangrenosum; and buccal ulcerations."
Lists buccal ulceration among the attack accompaniments.
Recurrent upper respiratory tract infections HP:0002788 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent upper respiratory tract infections (HP:0002788). HP:0002788 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"Furthermore, they experienced frequent episodes of purulent paronychia complicated by lymphangitis, superficial skin, and mucosal and purulent upper respiratory tract infections."
Reports purulent upper respiratory tract infection in the index kindred.
Immune 3
Intra-abdominal granuloma HP:0032252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intra-abdominal granuloma, annotated with Granuloma (HP:0032252). HP:0032252 is a phenotype from the Human Phenotype Ontology.
Bound to the general HPO term because HPO has no abdominal-site granuloma term: `HP:0034841` gastrointestinal granulomatosis would assert gut-wall disease that the source does not localize, and `HP:0011955` hepatic granulomatosis names an organ the source does not name. The site is carried in `preferred_term` instead. Reported as an occasional accompaniment of attacks in one kindred, so no `frequency` band is asserted.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"These were accompanied by an acute-phase response and occasionally by nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal granulomas; pyoderma gangrenosum; and buccal ulcerations."
Lists intra-abdominal granulomas among the occasional accompaniments of the inflammatory attacks.
Recurrent abscess formation HP:0002722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent abscess formation (HP:0002722). HP:0002722 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31201888 SUPPORT Human Clinical
"These were accompanied by an acute-phase response and occasionally by nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal granulomas; pyoderma gangrenosum; and buccal ulcerations."
Enumerates the abscess sites in the index kindred.
PMID:41026272 SUPPORT Human Clinical
"Cultures from the humeral abscess grew methicillin-resistant Staphylococcus aureus (MRSA), suggesting the need for targeted antibiotic therapy."
Documents a culture-positive deep abscess in the independent case, establishing that the infectious susceptibility is not confined to the index kindred.
Osteomyelitis HP:0002754 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteomyelitis (HP:0002754). HP:0002754 is a phenotype from the Human Phenotype Ontology.
Reported in a single patient — the eight-year-old homozygous for a different CEBPE allele — so no `frequency` band is asserted. Split out from `Recurrent abscess formation` because deep bone infection carries different clinical weight from the nailbed and gluteal abscesses of the index kindred, and because the bony lesions were the imaging finding initially read as chloromas.
Show evidence (1 reference)
PMID:41026272 SUPPORT Human Clinical
"An 8-year-old girl, the first child of non-consanguineous parents, presented with a two-month history of intermittent fever, osteomyelitis of the right proximal humerus, and multiple bony lesions."
Reports the humeral osteomyelitis and the accompanying bony lesions.
Integument 3
Pyoderma gangrenosum HP:0025452 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pyoderma gangrenosum (HP:0025452). HP:0025452 is a phenotype from the Human Phenotype Ontology.
Reported as an occasional accompaniment of attacks rather than a constant feature, so no `frequency` band is asserted.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"These were accompanied by an acute-phase response and occasionally by nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal granulomas; pyoderma gangrenosum; and buccal ulcerations."
Lists pyoderma gangrenosum among the occasional attack accompaniments.
Paronychia HP:0001818 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paronychia (HP:0001818), qualified as temporality recurrent. HP:0001818 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"Furthermore, they experienced frequent episodes of purulent paronychia complicated by lymphangitis, superficial skin, and mucosal and purulent upper respiratory tract infections."
Reports recurrent purulent paronychia in the index kindred.
Poor wound healing HP:0001058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed wound healing, annotated with Poor wound healing (HP:0001058). HP:0001058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3678479 SUPPORT Human Clinical
"3 of these patients from the same kindred had a syndrome of recurrent attacks of fever and abdominal pains, a tendency to skin infections, delayed wound healing and impaired neutrophil motility."
Names delayed wound healing as part of the syndrome in the kindred.
Metabolism 2
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
No `frequency` band: reported in the affected members of one Finnish kindred and in one unrelated child, which is a denominator of four at most.
Show evidence (3 references)
PMID:31201888 SUPPORT Human Clinical
"Patients experienced recurrent attacks of abdominal pain, aseptic fever, and systemic inflammation lasting 4 to 5 days."
Reports recurrent aseptic fever and its duration in the index kindred.
DOI:10.1182/blood.V43.6.871.871 SUPPORT Human Clinical
"In a family four sisters have suffered, the oldest two for nearly 20 yr, from recurring attacks of abdominal pain and fever of unknown etiology."
The founding 1974 description, which records the attacks in four sisters and their duration of nearly two decades in the eldest two.
PMID:41026272 SUPPORT Human Clinical
"An 8-year-old girl, the first child of non-consanguineous parents, presented with a two-month history of intermittent fever, osteomyelitis of the right proximal humerus, and multiple bony lesions."
Independent case with a different homozygous CEBPE allele presenting with intermittent fever.
Elevated circulating C-reactive protein concentration HP:0011227 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating C-reactive protein concentration (HP:0011227). HP:0011227 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31201888 SUPPORT Human Clinical
"These were accompanied by an acute-phase response and occasionally by nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal granulomas; pyoderma gangrenosum; and buccal ulcerations."
Records the acute-phase response accompanying attacks.
PMID:41026272 SUPPORT Human Clinical
"Persistent high-grade fever, negative blood cultures, and increased inflammatory cytokines (IL-6 and TNF-α) further supported the diagnosis of an autoinflammatory condition."
The inflammatory-marker profile in the independent case that established the autoinflammatory diagnosis.
Constitutional 1
Abdominal pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027), qualified as temporality recurrent. HP:0002027 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
No `frequency` band: the denominator is the affected members of one kindred.
Show evidence (3 references)
PMID:31201888 SUPPORT Human Clinical
"Patients experienced recurrent attacks of abdominal pain, aseptic fever, and systemic inflammation lasting 4 to 5 days."
Reports the recurrent abdominal attacks in the molecularly confirmed kindred.
DOI:10.1182/blood.V43.6.871.871 SUPPORT Human Clinical
"In a family four sisters have suffered, the oldest two for nearly 20 yr, from recurring attacks of abdominal pain and fever of unknown etiology."
The 1974 report that names the syndrome, describing the abdominal attacks in the four affected sisters of the index kindred.
PMID:3678479 SUPPORT Human Clinical
"3 of these patients from the same kindred had a syndrome of recurrent attacks of fever and abdominal pains, a tendency to skin infections, delayed wound healing and impaired neutrophil motility."
The 1987 clinical description of the same kindred, which the 2019 study cites as a prior report of this family.
🧬

Genetic Associations

1
CEBPE (Biallelic missense variants; the characterized allele lies in the DNA-binding domain)
Gene: CEBPE hgnc:1836 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CEBPE (hgnc:1836). hgnc:1836 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:31201888 SUPPORT Human Clinical
"The novel homozygous CEBPE 14:23586886 C>T mutation cosegregated perfectly with the disease phenotype"
Cosegregation in the index kindred is the genetic argument that the allele is causal.
PMID:41026272 SUPPORT Human Clinical
"A homozygous missense variant in exon 2 of the CEBPE gene (chr14:g.23117702G > A; depth: 223x) that results in the amino acid substitution of tryptophan for arginine at codon 211 (p.Arg211Trp; ENST00000206513.6) was detected."
A second, independent homozygous CEBPE allele in the same exon, in a patient diagnosed under the same OMIM entity.
💊

Medical Actions

2
Baricitinib
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: baricitinib CHEBI:95341 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses baricitinib (CHEBI:95341). CHEBI:95341 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A JAK inhibitor, given in the independently reported case after the autoinflammatory diagnosis was made, with sustained clinical improvement and normalization of cytokine levels over months. This is a single-patient result, and it is the only reported treatment for this disease that produced a durable response.
Mechanism Target:
Hyperinflammatory Response to Bacterial Stimuli — JAK inhibition targets the cytokine signalling downstream of the dysregulated inflammasome and interferon programme.
Show evidence (1 reference)
PMID:41026272 SUPPORT Human Clinical
"Treatment with the JAK inhibitor baricitinib resulted in significant clinical improvement, with normalization of cytokine levels over the following months."
Reports both the clinical and the biochemical response, which is what connects the drug to the inflammatory mechanism rather than to the infections.
Show evidence (1 reference)
PMID:41026272 SUPPORT Human Clinical
"Treatment with the JAK inhibitor baricitinib resulted in significant clinical improvement, with normalization of cytokine levels over the following months."
The single reported treatment response in this disease.
Prednisolone
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: prednisolone CHEBI:8378 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisolone (CHEBI:8378). CHEBI:8378 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Prednisolone gave temporary symptomatic relief in the independently reported case but fever recurred on tapering, so it did not control the disease.
Show evidence (1 reference)
PMID:41026272 SUPPORT Human Clinical
"A trial of corticosteroids (prednisolone) yielded temporary symptom relief, but fever recurred upon tapering."
Records a partial, non-durable response — curated because a treatment that does not hold is clinically informative.
🔬

Diagnosis

1
Recognition of the Autoinflammatory Syndrome Behind an AML-like Picture
The one published diagnostic pitfall for this disease is mistaking it for acute myeloid leukaemia. In the independently reported case, marked leukocytosis with 90 percent abnormal monocyte-like marrow cells and PET-CT lesions read as chloromas led to AML-directed chemotherapy before a negative leukaemia panel, a persisting inflammatory profile with negative cultures, and clinical exome sequencing redirected the diagnosis. The mechanistic reading offered is that the apparently abnormal monocytes were arrested immature granulocytes, consistent with C/EBP-epsilon's role in late myeloid differentiation.
Show evidence (2 references)
PMID:41026272 SUPPORT Human Clinical
"An 8-year-old patient initially suspected of having AML was found to harbor a homozygous CEBPE mutation."
States the diagnostic confusion and its resolution.
PMID:41026272 SUPPORT Human Clinical
"her white blood cell count was observed to be significantly elevated, prompting further investigations for potential hematologic malignancy"
Identifies the specific finding — marked leukocytosis — that triggered the malignancy work-up.
📊

Prevalence

1
Reported cases worldwide
Cases In Literature Ultra Rare
Three surviving members of one Finnish kindred were genotyped in the study that identified CEBPE p.Arg219His, and one unrelated 8-year-old girl has since been reported with a different homozygous CEBPE allele. The kindred had been followed clinically since the 1970s, so the number of individuals ever affected in it is larger than the number genotyped; no cited source states that total, and none is asserted here.
Show evidence (1 reference)
PMID:31201888 SUPPORT Human Clinical
"we analyzed DNA from 3 surviving members (II.2, II.7, and II.13) of the index family by performing whole-exome sequencing"
Gives the number of individuals genotyped in the index kindred.
{ }

Source YAML

click to show 
name: Pelger-Huet-like Anomaly and Episodic Fever with Abdominal Pain
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
description: >-
  An autosomal recessive combined autoinflammatory and immunodeficiency syndrome
  caused by biallelic missense variants in CEBPE, the gene encoding the late
  myeloid transcription factor C/EBP-epsilon. The clinical picture, described in
  a Finnish kindred from the 1970s onward and long labelled an atypical
  Pelger-Huet anomaly, combines recurrent multi-day attacks of aseptic fever,
  abdominal pain and systemic inflammation with a neutrophil defect: hyposegmented
  nuclei, impaired chemotaxis, abscesses, purulent paronychia, mucosal ulceration
  and a mild bleeding diathesis. The molecular basis was resolved in 2019 as a
  homozygous p.Arg219His substitution in the basic-leucine-zipper DNA-binding
  domain of C/EBP-epsilon, which the authors named CAIN (C/EBP-epsilon-associated
  autoinflammation and immune impairment of neutrophils). The mechanism is
  neomorphic rather than simply loss- or gain-of-dosage: the mutant factor loses
  association with more than a hundred protein partners, many of them
  transcriptional repressors, and consequently occupies roughly three times as
  many chromatin sites as wild type without any change in its recognition motif.
  The resulting genome-wide transcriptional dysregulation includes constitutive
  expression of caspase-5 in resting macrophages, which primes the noncanonical
  caspase-4/5 inflammasome so that intracellular bacterial LPS provokes an
  exaggerated IL-1-beta and IL-18 response. The disorder is therefore the first
  reported human monogenic noncanonical inflammasomopathy. The MONDO label
  preserves the 1970s clinical description; the same concept (OMIM 260570) also
  carries the synonym "immunodeficiency 108 with autoinflammation", and the
  recent literature refers to it that way.
disease_term:
  preferred_term: Pelger-Huet-like anomaly and episodic fever with abdominal pain
  term:
    id: MONDO:0009842
    label: Pelger-Huet-like anomaly and episodic fever with abdominal pain
parents:
- autoinflammatory syndrome
- primary immunodeficiency disease
synonyms:
- immunodeficiency 108 with autoinflammation
- CAIN
- C/EBP-epsilon-associated autoinflammation and immune impairment of neutrophils
- CEBPE-related immunodeficiency with autoinflammation
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      A systemic autoinflammatory disease with a neutrophil functional defect;
      Harrison's covers immune-mediated and inflammatory disorders here, and the
      same assignment is used for Familial Mediterranean Fever, the entity the
      1974 report compared this kindred with.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A monogenic autosomal recessive disorder whose manifestations span
      haematology, immunology, dermatology and the gut rather than sitting in one
      organ-system chapter.
notes: >-
  Six points a reader of this entry should have.

  First, **CEBPE causes two different diseases and they are not the same
  entry.** The gene's other, longer-known disorder is neutrophil-specific granule
  deficiency (SGD), and its allele p.Val218Ala sits one residue away from the
  allele curated here. The 2019 study tested both side by
  side and found that most C/EBP-epsilon protein interactions changed by Arg219His
  were unchanged by Val218Ala, and that the Arg219His patients' neutrophils had
  normal granule content and normal CD66a and CD11b surface expression, which the
  authors call "consistent with a non-SGD disease". `Specific_Granule_Deficiency_1`
  is a separate stub and should stay one. Classic Pelger-Huet anomaly (LBR) is a
  third, unrelated concept — the shared feature is only the hyposegmented nucleus,
  which is why a KB text search for "Pelger" hits `Greenberg_Dysplasia` and the
  `Chondrodysplasia_Punctata` grouping.

  Second, **MONDO's placement under `hereditary disorder of connective tissue`
  is not supported by anything in the cited literature.** MONDO:0009842 has two
  parents: `autoinflammatory syndrome`, which the 2019 characterization confirms,
  and `hereditary disorder of connective tissue`, for which no cited source
  reports connective-tissue involvement of any kind. The entry's `parents` are set
  to autoinflammatory syndrome and primary immunodeficiency, following the source
  paper, which describes the disorder as simultaneously a primary immunodeficiency
  and a systemic autoinflammatory disease. The connective-tissue parent looks like
  an ontology artifact of the Pelger-Huet label rather than a claim about this
  disease, and is worth raising upstream.

  Third, **the pre-2019 literature is curated as evidence, not discarded as
  history.** The neutrophil-motility defect (PMID:477034) and the clinical
  syndrome (PMID:3678479) were measured in the index kindred decades before the
  gene was known, and the 2019 paper cites all three early reports as prior
  descriptions of the same family. The 1987 study additionally found depressed
  delta-aminolevulinic acid synthase activity in the symptomatic members and
  proposed heme depletion as the cause of the abdominal attacks. That hypothesis
  has neither been confirmed nor refuted against the CEBPE mechanism, and is
  recorded as a knowledge gap rather than silently dropped. The 1974 report that
  names the syndrome is cited through its DOI rather than its PMID: PubMed's
  record (PMID:4831644) carries no abstract and no retrievable full text, but the
  publisher's record reached through `DOI:10.1182/blood.V43.6.871.871` carries
  the abstract, so the founding clinical description of the four affected sisters
  is quotable after all. Both identifiers are listed in `references` because they
  are the same paper.

  Fourth, **searching this disease by its MONDO label finds the 1970s
  literature and misses the answer.** The molecular characterization is published
  under a different name — the paper's title says "gain-of-function CEBPE
  mutation", the entity it names is CAIN, and OMIM's current title is
  "immunodeficiency 108 with autoinflammation". A Falcon/Edison deep-research run
  against this entry's name produced a report that never mentions CEBPE and
  concludes that "no independent modern cohort, causal gene, pathogenic variant,
  validated mechanism, treatment trial, or prevalence estimate was found" — a
  false negative about a disease that was solved in 2019 and has a published
  treatment response. The report was discarded rather than mined; the route that
  works is the MONDO xrefs (OMIM:260570) and the PMID behind the phenotype
  annotations, which is what this entry was built from. Note that
  `just preflight-dr` returns SKIP rather than FAIL here, because MONDO records
  no causal gene for this term and the automated gene-identity check has nothing
  to discriminate on. The failure is reproducible rather than anecdotal, because
  the provider response is cached: re-running `just research-disorder falcon
  Pelger-Huet-like_Anomaly_And_Episodic_Fever_With_Abdominal_Pain` returns the
  same report in under a second. In it, CEBPE, C/EBP, baricitinib and OMIM 260570
  each occur zero times, while LBR occurs 40 times and NBAS 35, and `preflight-dr`
  reports the report's OMIM anchors as 169400 and 614800 rather than this
  disease's 260570. The report is deliberately not committed under `research/`:
  files there are indexed and mined as curation inputs, and this one states that
  no causal gene, validated mechanism or treatment exists for a disease that was
  solved in 2019 and has a published treatment response.

  Fifth, **the phenotype records carry no `frequency` bands.** The molecularly
  confirmed population is three surviving members of one Finnish kindred plus one
  unrelated child with a different homozygous CEBPE allele, so any percentage
  would be a denominator of three or four rather than a disease frequency. Counts
  are stated in each record's `notes` instead.


  Sixth, **`classifications` carries only the Harrison's assignment.** The IUIS
  slot is left empty on purpose: this disease is simultaneously an IUIS phagocyte
  defect and an autoinflammatory disorder — the source paper's own framing is
  that it is both a primary immunodeficiency and a systemic autoinflammatory
  disease — and `iuis_category` is single-valued, so recording either value alone
  would assert a resolution the literature does not make. `MechanisticNosologyEnum`
  likewise has no value for an inflammasomopathy, so `mechanistic_category` is
  omitted rather than approximated.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires the homozygous state. Heterozygous carriers are clinically
    unaffected but are not molecularly normal: their granulocytes show an
    intermediate increase in C/EBP-epsilon chromatin occupancy, which the authors
    read as evidence of post-transcriptional compensation rather than of a
    dominant effect.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report an autosomal recessive GOF PID, C/EBPε-associated autoinflammation
      and immune impairment of neutrophils (CAIN), in a family with a genetically
      uncharacterized autoinflammatory syndrome.
    explanation: >-
      States the inheritance pattern and names the entity in the family in which
      it was characterized.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of heterozygous relatives without reported clinical manifestations
      of disease showed intermediate cellular changes.
    explanation: >-
      Supports recessiveness at the clinical level while showing that the
      heterozygous state is not molecularly silent. INDIRECT because it is a
      cellular measurement offered in support of an inheritance claim.
pathophysiology:
- name: CEBPE p.Arg219His Substitution in the DNA-Binding Domain
  biological_scale: MOLECULAR
  description: >-
    A homozygous c.656G>A change in CEBPE exon 2 substitutes histidine for
    arginine at residue 219, within the highly conserved carboxy-terminal
    DNA-binding region of the basic leucine zipper shared by all four
    C/EBP-epsilon isoforms. The variant cosegregated with disease in the index
    kindred and was the only homozygous rare variant shared by all three
    genotyped patients.
  genes:
  - preferred_term: CEBPE
    term:
      id: hgnc:1836
      label: CEBPE
  genetic_context:
    gene:
      preferred_term: CEBPE
      term:
        id: hgnc:1836
        label: CEBPE
    allele_type: MISSENSE
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: NEOMORPHIC
    description: >-
      Curated NEOMORPHIC on the authors' own analysis: the substitution was
      predicted to abolish DNA binding, but in patients' granulocytes it instead
      produced a large increase in chromatin occupancy with an unchanged
      recognition motif, alongside a loss-of-function effect on protein-protein
      interactions. The paper describes the resulting entity as the first human
      monogenic neomorphic inflammasomopathy.
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only one of these variants was homozygous in all 3 patients
      (ENSG00000092067:ENST00000206513: exon2:c.G656A;p.Arg219His) in the CEPBE
      gene.
    explanation: >-
      Identifies the causal allele from whole-exome sequencing of the index
      kindred. (The source spells the gene "CEPBE" at this point; the quote is
      reproduced verbatim.)
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It resided in the highly conserved basic zipper region’s carboxyl terminal
      DNA-binding domain shared by all 4 C/EBPε isoforms
    explanation: >-
      Locates the substitution in the DNA-binding domain, which is what makes a
      chromatin-occupancy mechanism the one to test.
  downstream:
  - target: Loss of C/EBP-epsilon Association with Transcriptional Repressors
    description: >-
      The substitution is proposed to change protein conformation rather than DNA
      recognition, stripping the factor of most of its partner interactions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Based on quantitative interaction analysis, 108 PPIs were significantly
        (P < .05) altered; 106 showed decreased and 2 showed increased
        interaction with mutant compared with WT C/EBPε
      explanation: >-
        Quantifies the interaction loss caused by the mutant protein relative to
        wild type in a matched expression system.
  - target: Mild Bleeding Diathesis of Unresolved Mechanism
    description: >-
      C/EBP-epsilon controls platelet granule formation, so a bleeding tendency
      in these patients is plausibly a direct consequence of the same allele; the
      platelet studies that were done did not find the expected lesion, so the
      edge is curated with unknown intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        C/EBPε is known to control platelet granule formation.
      explanation: >-
        Establishes the biological rationale for connecting the allele to a
        bleeding tendency. INDIRECT because it is background about the wild-type
        factor, not a measurement in these patients.
  - target: Preserved Neutrophil Granule Content
    description: >-
      Unlike the specific-granule-deficiency alleles of the same gene, this
      substitution leaves granule content intact — the observation that separates
      the two CEBPE disorders.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        On flow cytometry, CD66a and CD11b expression was unaffected, which is
        consistent with a non-SGD disease
      explanation: >-
        Granule-resident adhesion molecules are present at normal surface levels,
        which the authors read as excluding specific granule deficiency.
- name: Loss of C/EBP-epsilon Association with Transcriptional Repressors
  biological_scale: MOLECULAR
  description: >-
    Of 144 C/EBP-epsilon interaction partners identified, 108 were significantly
    altered by the substitution and 106 of those were decreased. A large share of
    the lost partners are transcriptional repressors, including several SWI/SNF
    chromatin-remodelling subunits, which is the proposed reason the mutant
    factor is no longer restrained on chromatin.
  molecular_functions:
  - preferred_term: association with transcriptional repressors, including SWI/SNF subunits
    term:
      id: GO:0001221
      label: transcription coregulator binding
    modifier: DECREASED
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, many of the diminished interactors were transcriptional
      repressors, suggesting widely dysregulated C/EBPε-driven transcription
    explanation: >-
      Identifies transcriptional repressors as the class of partner lost, which
      is the step that connects the interaction defect to the transcriptional
      one.
  downstream:
  - target: Increased C/EBP-epsilon Chromatin Occupancy
    description: >-
      Without its repressor partners the mutant factor binds far more sites,
      while recognizing the same DNA motif as wild type.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This suggests that the increased C/EBPε chromatin occupancy was caused by
        mechanisms other than the altered DNA-binding motifs usually seen in
        neomorphisms.
      explanation: >-
        The authors' explicit attribution of the occupancy increase to something
        other than a changed recognition sequence, which is what points back to
        the lost repressors.
- name: Increased C/EBP-epsilon Chromatin Occupancy
  biological_scale: MOLECULAR
  description: >-
    Chromatin immunoprecipitation sequencing of patient granulocytes found about
    three times as many C/EBP-epsilon binding sites as in controls, with
    heterozygous carriers intermediate — a dose-dependent occupancy gradient
    across the three genotypes. De novo motif analysis found essentially the same
    consensus sequence in mutant and wild type.
  cell_types:
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  molecular_functions:
  - preferred_term: chromatin binding
    term:
      id: GO:0003682
      label: chromatin binding
    modifier: INCREASED
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Peak calling and overlap analysis from biological replicates revealed 3391
      C/EBPε-binding sites in control subjects, 4686 in Arg219His heterozygote
      carriers, and 10322 in homozygous patients
    explanation: >-
      Directly quantifies the occupancy increase and shows it tracks allele
      dosage.
  downstream:
  - target: Genome-Wide Transcriptional Dysregulation in Granulocytes
    description: >-
      Excess occupancy at unchanged motifs translates into a large,
      interferon-weighted shift in the granulocyte transcriptome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This identified 464 significantly differentially transcribed (fold change
        [FC] ≥ 2 or ≤ 0.5, false discovery rate [FDR] ≤ 0.05) genes, 198 of
        which, including NLRP3 (FC = 8.25), were interferon related
      explanation: >-
        Quantifies the transcriptional consequence measured in the same patients'
        granulocytes, and names NLRP3 as one of the upregulated genes.
- name: Genome-Wide Transcriptional Dysregulation in Granulocytes
  biological_scale: CELLULAR
  description: >-
    464 genes are differentially transcribed in unstimulated patient
    granulocytes, 198 of them interferon-related, with NLRP3 up more than
    eightfold. Interferon stimulation widens rather than normalizes the
    difference, and NLRP12 — a suppressor of neutrophil migration — rises
    13.6-fold after type I interferon.
  cell_types:
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DYSREGULATED
  - preferred_term: response to type I interferon
    term:
      id: GO:0034340
      label: response to type I interferon
    modifier: ABNORMAL
  - preferred_term: response to type II interferon
    term:
      id: GO:0034341
      label: response to type II interferon
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      This identified 464 significantly differentially transcribed (fold change
      [FC] ≥ 2 or ≤ 0.5, false discovery rate [FDR] ≤ 0.05) genes, 198 of which,
      including NLRP3 (FC = 8.25), were interferon related
    explanation: >-
      The primary transcriptomic result, in patients' own granulocytes.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      In response to IFN-α2b stimulation, 534 genes were differentially
      transcribed (FC ≥ 2 or ≤ 0.5, FDR ≤ 0.05) between patients and control
      subjects
    explanation: >-
      Quantifies the type I interferon arm specifically, which is the larger of
      the two stimulated responses and the basis for the
      `response to type I interferon` annotation.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      These included a significant 13.6-fold increase in NLRP12 expression in
      patients.
    explanation: >-
      Gives the magnitude of the NLRP12 rise after type I interferon stimulation,
      the specific result named in this node's description.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      In response to IFN-γ stimulation, 427 genes were differentially expressed
    explanation: >-
      The type II interferon arm, which is what `GO:0034341` on this node is bound
      to; it previously carried no quote of its own.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      a significant 3.8-fold increase in NLRP12 expression after IFN-γ stimulation.
    explanation: >-
      The NLRP12 response to type II interferon, quantified so it can be compared
      with the 13.6-fold type I result quoted above.
  downstream:
  - target: Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
    description: >-
      Human caspase-5 expression is normally interferon-dependent; the
      transcriptional shift makes it constitutive, removing the priming step that
      would otherwise gate noncanonical inflammasome activation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Notably, we found increased baseline expression of caspase-5 in patients’
        macrophages and increased IL-1β and IL-18 secretion on stimulation of the
        noncanonical caspase-4/5 inflammasome with intracellular LPS.
      explanation: >-
        Connects the transcriptional change to a measured protein-level and
        functional consequence in patients' macrophages.
  - target: Impaired Neutrophil Chemotaxis with Reduced CD66b
    description: >-
      The same transcriptional programme raises NLRP12, a suppressor of
      neutrophil migration, while surface CD66b falls.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The aberrantly low CD66b expression likely contributes, with increased
        transcription of NLRP12, to the impaired chemotaxis previously reported.
      explanation: >-
        The authors' own two-factor account of the chemotaxis defect. The edge is
        typed with unknown intermediates because the sentence is a proposed
        contribution rather than a demonstrated causal chain.
  - target: Neutrophil Nuclear Hyposegmentation
    description: >-
      Hyposegmented nuclei in a fifth of patient neutrophils, the finding that
      gave the disorder its Pelger-Huet-like name, in a factor that governs late
      myeloid differentiation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        20% of patients’ neutrophils were hyposegmented
      explanation: >-
        Quantifies the nuclear abnormality on Wright-stained smears. The edge is
        typed with unknown intermediates because no cited source identifies which
        of the dysregulated genes produces it.
- name: Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
  biological_scale: CELLULAR
  description: >-
    Resting patient macrophages express caspase-5 without interferon priming, and
    peripheral blood mononuclear cells show both increased pro-caspase-5 and more
    processed caspase-5. The canonical NLRP3 pathway is untouched: whole-blood
    canonical activation and monocyte caspase-1 activity are normal, and priming
    control cells with interferon abolishes the difference — so the defect is
    specifically that the noncanonical arm is pre-primed.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: non-canonical inflammasome complex assembly
    term:
      id: GO:0160075
      label: non-canonical inflammasome complex assembly
    modifier: INCREASED
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Notably, we found increased baseline expression of caspase-5 in patients’
      macrophages and increased IL-1β and IL-18 secretion on stimulation of the
      noncanonical caspase-4/5 inflammasome with intracellular LPS.
    explanation: >-
      The central mechanistic finding: constitutive caspase-5 plus an exaggerated
      noncanonical response in the same cells.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      In cultured macrophages secretion of both IL-1β and constitutively
      expressed IL-18 was similar after canonical activation (Fig 5, C) but was
      markedly enhanced after noncanonical caspase-4/5–mediated NLRP3 activation
      in patients compared with control subjects
    explanation: >-
      Separates the affected pathway from the unaffected one, which is what makes
      this a noncanonical rather than a classical inflammasomopathy.
  downstream:
  - target: Hyperinflammatory Response to Bacterial Stimuli
    description: >-
      Because the priming step is already satisfied, an ordinary encounter with
      intracellular bacterial LPS produces a disproportionate cytokine response.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This sensitized the patients’ macrophages to respond pronouncedly to
        intracellular LPS - clinically causing hyperinflammation after bacterial
        stimuli.
      explanation: >-
        The authors' explicit statement linking the cellular sensitization to the
        clinical inflammatory attacks.
- name: Hyperinflammatory Response to Bacterial Stimuli
  biological_scale: ORGANISM
  description: >-
    Clinically, attacks of aseptic fever, abdominal pain and systemic
    inflammation lasting four to five days, accompanied by an acute-phase
    response. Attacks became more prominent at puberty and subsided after
    menopause in the affected women of the index kindred.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients experienced recurrent attacks of abdominal pain, aseptic fever,
      and systemic inflammation lasting 4 to 5 days.
    explanation: >-
      Describes the attack phenotype, including its duration and its aseptic
      character.
  downstream:
  - target: Recurrent fever
    description: Aseptic fever is one of the two cardinal attack symptoms.
    causal_link_type: DIRECT
  - target: Abdominal pain
    description: Abdominal pain is the other cardinal attack symptom and names the disorder.
    causal_link_type: DIRECT
  - target: Elevated circulating C-reactive protein concentration
    description: >-
      Attacks are accompanied by an acute-phase response; the later independent
      case also had elevated CRP with normal procalcitonin.
    causal_link_type: DIRECT
  - target: Pyoderma gangrenosum
    description: >-
      A neutrophilic dermatosis reported occasionally during attacks in the index
      kindred.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intra-abdominal granuloma
    description: >-
      Granulomas listed among the occasional accompaniments of the attacks. Typed
      with unknown intermediates because no cited source establishes whether they
      arise from the exaggerated inflammasome response or from defective
      neutrophil clearance, and the entry does not pick between them.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31201888
      reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These were accompanied by an acute-phase response and occasionally by
        nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal
        granulomas; pyoderma gangrenosum; and buccal ulcerations.
      explanation: >-
        Places the granulomas among the accompaniments of the attacks, which is
        what puts them downstream of the attack node.
  - target: Increased total leukocyte count
    description: >-
      The authors' own conclusion is that the raised white cell count reflected
      infection and the inflammatory response rather than leukaemia, which is what
      places it downstream of the inflammatory response rather than beside it.
      Typed with unknown intermediates because the source states the attribution as
      a conclusion, not a demonstrated mechanism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41026272
      reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the leukocytosis in this patient was likely due to infection and the
        inflammatory response rather than acute leukemia, with the abnormal cells
        being immature granulocytes rather than promonocytes, as initially
        suspected.
      explanation: >-
        States the authors' attribution of the leukocytosis to the inflammatory
        response, with their own hedge preserved.
- name: Impaired Neutrophil Chemotaxis with Reduced CD66b
  biological_scale: CELLULAR
  description: >-
    The oldest measured abnormality in this kindred: patient polymorphonuclear
    cells migrate slowly both spontaneously and toward a chemoattractant, a defect
    the 1979 investigators localized to intrinsic locomotor capacity rather than
    to cell deformability or receptor responsiveness. The 2019 study supplies a
    candidate molecular basis in reduced surface CD66b together with strongly
    increased NLRP12 transcription.
  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:477034
    reference_title: "Impaired neutrophil chemotaxis in Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The spontaneous migration of the PMNs of the three sisters was
      significantly slower both under agarose and in a membrane filter than that
      of the PMNs of the asymptomatic patients with P-H anomaly.
    explanation: >-
      Measures the motility defect in the symptomatic members against
      asymptomatic Pelger-Huet controls, so the comparison isolates the syndrome
      rather than the nuclear anomaly.
  - reference: PMID:477034
    reference_title: "Impaired neutrophil chemotaxis in Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Our results suggests that the impaired chemotaxis was due to a defect in
      the intrinsic locomotor capacity of PMNs rather than in their deformability
      or their responsiveness to the chemotactic stimulus.
    explanation: >-
      Localizes the defect to the cell's own motile machinery, excluding two
      alternative explanations.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Patients’ granulocytes displayed impaired expression of CD66b compared with
      those from age- and sex-matched control subjects
    explanation: >-
      Supplies a measured surface-molecule abnormality in the same cells decades
      after the functional defect was described.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Taken together, these data suggest a deficiency in specific granule function.
    explanation: >-
      The authors' own summary of the CD66b result. Graded INDIRECT because it is
      their interpretive conclusion rather than a measurement, and it is recorded
      here rather than on `Preserved Neutrophil Granule Content` because it
      concerns granule function, which that node does not claim.
  downstream:
  - target: Impaired neutrophil chemotaxis
    description: The chemotaxis defect is itself a recorded laboratory phenotype.
    causal_link_type: DIRECT
  - target: Recurrent abscess formation
    description: >-
      Nailbed, tongue, submandibular and gluteal abscesses in the index kindred.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Paronychia
    description: Frequent episodes of purulent paronychia, sometimes with lymphangitis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Recurrent aphthous stomatitis
    description: Buccal ulceration reported during attacks.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Recurrent upper respiratory tract infections
    description: Purulent upper respiratory tract infections reported in the kindred.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Poor wound healing
    description: Delayed wound healing recorded in the symptomatic members in 1987.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Osteomyelitis
    description: >-
      Deep, culture-positive bone infection in the independently reported case,
      read here as the severe end of the same failure of neutrophil recruitment
      that produces the superficial abscesses.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Neutrophil Nuclear Hyposegmentation
  biological_scale: CELLULAR
  description: >-
    About one in five patient neutrophils has a hyposegmented nucleus on
    Wright-stained smears. This is the feature that led to the disorder being
    called an atypical Pelger-Huet anomaly for four decades, and it remains the
    most accessible diagnostic clue.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      20% of patients’ neutrophils were hyposegmented
    explanation: >-
      Quantifies the nuclear abnormality in the molecularly confirmed patients.
  downstream:
  - target: Hyposegmentation of neutrophil nuclei
    description: The morphological finding as recorded on the blood film.
    causal_link_type: DIRECT
- name: Preserved Neutrophil Granule Content
  biological_scale: CELLULAR
  description: >-
    Electron microscopy and Wright staining show normal azurophilic, specific and
    tertiary granules in normal numbers, and granule-resident CD66a and CD11b
    reach the surface normally. This is the discriminator against
    neutrophil-specific granule deficiency, the other CEBPE disorder, in which
    granule content is the thing that is lost.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  notes: >-
    Deliberately carries no `downstream` edge: a preserved structure cannot cause
    a consequence. The node exists because the negative result is what
    distinguishes this disease from specific granule deficiency, and losing it
    would make the two entries look interchangeable. The node claims preserved
    granule *content*, not preserved granule *function*: the same authors conclude
    from the reduced CD66b that these data suggest a deficiency in specific granule
    function. That conclusion is curated on
    `Impaired Neutrophil Chemotaxis with Reduced CD66b`, and the two are not in
    conflict - granule structure and cargo are intact while a granule-resident
    adhesion molecule reaches the surface at reduced levels.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      electron microscopy showed that patients’ neutrophils contained
      normal-sized azurophilic specific and tertiary granules in normal numbers
    explanation: >-
      Direct ultrastructural evidence that granule content is intact.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      On flow cytometry, CD66a and CD11b expression was unaffected, which is
      consistent with a non-SGD disease
    explanation: >-
      Independent flow-cytometric confirmation, and the authors' own reading of
      it as excluding specific granule deficiency.
- name: Mild Bleeding Diathesis of Unresolved Mechanism
  biological_scale: ORGANISM
  description: >-
    Every affected member of the index kindred had a mild bleeding tendency with
    frequent nosebleeds and easy bruising after needle sticks and procedures.
    Because C/EBP-epsilon is known to control platelet granule formation, the
    investigators looked for a platelet granule defect and did not find one:
    granule and overall platelet structure were morphologically normal, with only
    dilated open canalicular systems and slight activation noted.
  mechanism_confidence: HYPOTHETICAL
  notes: >-
    Curated HYPOTHETICAL because the clinical observation is firm and the
    mechanism is not. The obvious candidate — a platelet granule defect, by
    analogy with the factor's known role — was tested and not confirmed.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected members further had mild bleeding diathesis with frequent
      nosebleeds and a tendency toward hematomas after needle sticks and
      procedures.
    explanation: >-
      Establishes the bleeding tendency as a constant clinical feature of the
      kindred.
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      No morphologic aberrancies were found in a granule and overall platelets
      structure.
    explanation: >-
      Refutes the platelet-granule explanation for the bleeding tendency, which
      is why the node is curated as mechanistically unresolved.
  downstream:
  - target: Epistaxis
    description: Frequent nosebleeds are the reported expression of the bleeding tendency.
    causal_link_type: DIRECT
  - target: Bruising susceptibility
    description: >-
      The tendency to hematomas after needle sticks and procedures is the other
      reported expression of the same bleeding tendency.
    causal_link_type: DIRECT
phenotypes:
- name: Recurrent fever
  category: Constitutional
  description: >-
    Aseptic fever in attacks lasting four to five days, recurring over decades;
    intermittent fever was also the presenting complaint in the independently
    reported case.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  notes: >-
    No `frequency` band: reported in the affected members of one Finnish kindred
    and in one unrelated child, which is a denominator of four at most.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients experienced recurrent attacks of abdominal pain, aseptic fever,
      and systemic inflammation lasting 4 to 5 days.
    explanation: Reports recurrent aseptic fever and its duration in the index kindred.
  - reference: DOI:10.1182/blood.V43.6.871.871
    reference_title: Recurrent Attacks of Abdominal Pain and Fever With Familial Segmentation
      Arrest of Granulocytes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a family four sisters have suffered, the oldest two for nearly 20 yr,
      from recurring attacks of abdominal pain and fever of unknown etiology.
    explanation: >-
      The founding 1974 description, which records the attacks in four sisters and
      their duration of nearly two decades in the eldest two.
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An 8-year-old girl, the first child of non-consanguineous parents,
      presented with a two-month history of intermittent fever, osteomyelitis of
      the right proximal humerus, and multiple bony lesions.
    explanation: >-
      Independent case with a different homozygous CEBPE allele presenting with
      intermittent fever.
- name: Abdominal pain
  category: Gastrointestinal
  description: >-
    Recurrent attacks of abdominal pain, the feature that names the disorder and
    the one that prompted the 1987 heme-synthesis investigation.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
    temporality: RECURRENT
  notes: >-
    No `frequency` band: the denominator is the affected members of one kindred.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients experienced recurrent attacks of abdominal pain, aseptic fever,
      and systemic inflammation lasting 4 to 5 days.
    explanation: Reports the recurrent abdominal attacks in the molecularly confirmed kindred.
  - reference: DOI:10.1182/blood.V43.6.871.871
    reference_title: Recurrent Attacks of Abdominal Pain and Fever With Familial Segmentation
      Arrest of Granulocytes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a family four sisters have suffered, the oldest two for nearly 20 yr,
      from recurring attacks of abdominal pain and fever of unknown etiology.
    explanation: >-
      The 1974 report that names the syndrome, describing the abdominal attacks in
      the four affected sisters of the index kindred.
  - reference: PMID:3678479
    reference_title: "Impaired heme synthesis in a family with Pelger-Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 of these patients from the same kindred had a syndrome of recurrent
      attacks of fever and abdominal pains, a tendency to skin infections,
      delayed wound healing and impaired neutrophil motility.
    explanation: >-
      The 1987 clinical description of the same kindred, which the 2019 study
      cites as a prior report of this family.
- name: Elevated circulating C-reactive protein concentration
  category: Laboratory
  description: >-
    An acute-phase response accompanies the attacks; in the independently
    reported case CRP was elevated with normal procalcitonin, which is what
    redirected the diagnosis from infection to autoinflammation.
  phenotype_term:
    preferred_term: Elevated circulating C-reactive protein concentration
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These were accompanied by an acute-phase response and occasionally by
      nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal
      granulomas; pyoderma gangrenosum; and buccal ulcerations.
    explanation: Records the acute-phase response accompanying attacks.
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistent high-grade fever, negative blood cultures, and increased
      inflammatory cytokines (IL-6 and TNF-α) further supported the diagnosis of
      an autoinflammatory condition.
    explanation: >-
      The inflammatory-marker profile in the independent case that established
      the autoinflammatory diagnosis.
- name: Pyoderma gangrenosum
  category: Dermatological
  description: A neutrophilic dermatosis reported occasionally in the index kindred.
  phenotype_term:
    preferred_term: Pyoderma gangrenosum
    term:
      id: HP:0025452
      label: Pyoderma gangrenosum
  notes: >-
    Reported as an occasional accompaniment of attacks rather than a constant
    feature, so no `frequency` band is asserted.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These were accompanied by an acute-phase response and occasionally by
      nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal
      granulomas; pyoderma gangrenosum; and buccal ulcerations.
    explanation: Lists pyoderma gangrenosum among the occasional attack accompaniments.
- name: Intra-abdominal granuloma
  category: Gastrointestinal
  description: >-
    Granulomas inside the abdomen, reported among the findings that occasionally
    accompanied the inflammatory attacks in the index kindred. In a disorder that
    also carries a neutrophil functional defect this is the feature that raises
    chronic granulomatous disease as a differential; no cited source reports the
    NADPH-oxidase testing that would settle it, and the entry does not claim a
    respiratory-burst defect.
  phenotype_term:
    preferred_term: Intra-abdominal granuloma
    term:
      id: HP:0032252
      label: Granuloma
  notes: >-
    Bound to the general HPO term because HPO has no abdominal-site granuloma
    term: `HP:0034841` gastrointestinal granulomatosis would assert gut-wall
    disease that the source does not localize, and `HP:0011955` hepatic
    granulomatosis names an organ the source does not name. The site is carried
    in `preferred_term` instead. Reported as an occasional accompaniment of
    attacks in one kindred, so no `frequency` band is asserted.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These were accompanied by an acute-phase response and occasionally by
      nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal
      granulomas; pyoderma gangrenosum; and buccal ulcerations.
    explanation: >-
      Lists intra-abdominal granulomas among the occasional accompaniments of the
      inflammatory attacks.
- name: Impaired neutrophil chemotaxis
  category: Immunological
  description: >-
    Slow spontaneous, chemotactic and chemokinetic locomotion of patient
    polymorphonuclear cells, measured against asymptomatic carriers of the
    Pelger-Huet nuclear anomaly rather than against unrelated controls.
  phenotype_term:
    preferred_term: Impaired neutrophil chemotaxis
    term:
      id: HP:0040238
      label: Impaired neutrophil chemotaxis
  evidence:
  - reference: PMID:477034
    reference_title: "Impaired neutrophil chemotaxis in Pelger-Huët anomaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Chemotactic and chemokinetic locomotion of the PMNs of the symptomatic
      sisters was also slow.
    explanation: >-
      Reports the chemotactic and chemokinetic defect specifically in the
      symptomatic members of the kindred.
- name: Hyposegmentation of neutrophil nuclei
  category: Hematological
  description: >-
    Hyposegmented neutrophil nuclei in about 20 percent of cells, the finding that
    made the syndrome look like an atypical Pelger-Huet anomaly for forty years.
  phenotype_term:
    preferred_term: Hyposegmentation of neutrophil nuclei
    term:
      id: HP:0011447
      label: Hyposegmentation of neutrophil nuclei
  notes: >-
    Numerator/denominator here is per cell, not per patient: 20 percent of 200
    consecutive leukocytes scored on Wright-stained smears from the genotyped
    patients.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      20% of patients’ neutrophils were hyposegmented
    explanation: Quantifies the proportion of hyposegmented neutrophils.
- name: Recurrent abscess formation
  category: Immunological
  description: >-
    Nailbed, tongue, submandibular and gluteal abscesses in the index kindred,
    and in the independently reported case a humeral osteomyelitis with multiple
    bony abscesses that grew methicillin-resistant Staphylococcus aureus.
  phenotype_term:
    preferred_term: Recurrent abscess formation
    term:
      id: HP:0002722
      label: Recurrent abscess formation
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These were accompanied by an acute-phase response and occasionally by
      nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal
      granulomas; pyoderma gangrenosum; and buccal ulcerations.
    explanation: Enumerates the abscess sites in the index kindred.
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cultures from the humeral abscess grew methicillin-resistant Staphylococcus
      aureus (MRSA), suggesting the need for targeted antibiotic therapy.
    explanation: >-
      Documents a culture-positive deep abscess in the independent case,
      establishing that the infectious susceptibility is not confined to the
      index kindred.
- name: Osteomyelitis
  category: Musculoskeletal
  description: >-
    Osteomyelitis of the right proximal humerus with further bony lesions was the
    presenting feature of the independently reported case, and the humeral
    abscess grew methicillin-resistant Staphylococcus aureus. Not reported in the
    index kindred, whose infections were superficial.
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
  notes: >-
    Reported in a single patient — the eight-year-old homozygous for a different
    CEBPE allele — so no `frequency` band is asserted. Split out from
    `Recurrent abscess formation` because deep bone infection carries different
    clinical weight from the nailbed and gluteal abscesses of the index kindred,
    and because the bony lesions were the imaging finding initially read as
    chloromas.
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An 8-year-old girl, the first child of non-consanguineous parents,
      presented with a two-month history of intermittent fever, osteomyelitis of
      the right proximal humerus, and multiple bony lesions.
    explanation: Reports the humeral osteomyelitis and the accompanying bony lesions.
- name: Paronychia
  category: Dermatological
  description: >-
    Frequent episodes of purulent paronychia, at times complicated by
    lymphangitis.
  phenotype_term:
    preferred_term: Paronychia
    term:
      id: HP:0001818
      label: Paronychia
    temporality: RECURRENT
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, they experienced frequent episodes of purulent paronychia
      complicated by lymphangitis, superficial skin, and mucosal and purulent
      upper respiratory tract infections.
    explanation: Reports recurrent purulent paronychia in the index kindred.
- name: Recurrent aphthous stomatitis
  category: Mucosal
  description: Buccal ulceration accompanying inflammatory attacks.
  phenotype_term:
    preferred_term: Recurrent aphthous stomatitis
    term:
      id: HP:0011107
      label: Recurrent aphthous stomatitis
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These were accompanied by an acute-phase response and occasionally by
      nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal
      granulomas; pyoderma gangrenosum; and buccal ulcerations.
    explanation: Lists buccal ulceration among the attack accompaniments.
- name: Recurrent upper respiratory tract infections
  category: Immunological
  description: Purulent upper respiratory tract infections alongside skin and mucosal infection.
  phenotype_term:
    preferred_term: Recurrent upper respiratory tract infections
    term:
      id: HP:0002788
      label: Recurrent upper respiratory tract infections
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, they experienced frequent episodes of purulent paronychia
      complicated by lymphangitis, superficial skin, and mucosal and purulent
      upper respiratory tract infections.
    explanation: Reports purulent upper respiratory tract infection in the index kindred.
- name: Poor wound healing
  category: Immunological
  description: Delayed wound healing recorded in the symptomatic members of the kindred.
  phenotype_term:
    preferred_term: Delayed wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:3678479
    reference_title: "Impaired heme synthesis in a family with Pelger-Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      3 of these patients from the same kindred had a syndrome of recurrent
      attacks of fever and abdominal pains, a tendency to skin infections,
      delayed wound healing and impaired neutrophil motility.
    explanation: Names delayed wound healing as part of the syndrome in the kindred.
- name: Epistaxis
  category: Hematological
  description: >-
    Frequent nosebleeds, the commonest expression of the mild bleeding diathesis
    present in all affected members.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected members further had mild bleeding diathesis with frequent
      nosebleeds and a tendency toward hematomas after needle sticks and
      procedures.
    explanation: Reports frequent nosebleeds in every affected member of the kindred.
- name: Bruising susceptibility
  category: Hematological
  description: >-
    A tendency to form hematomas after needle sticks and procedures, reported in
    every affected member of the index kindred alongside the nosebleeds. It is the
    second half of the same bleeding tendency, and like the nosebleeds it is a
    clinical observation whose mechanism the investigators looked for and did not
    find.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  notes: >-
    No frequency band is given. The sentence says all affected members, but the
    denominator is the four sisters of a single kindred, and this entry does not
    put frequency bands on a four-patient series.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected members further had mild bleeding diathesis with frequent
      nosebleeds and a tendency toward hematomas after needle sticks and
      procedures.
    explanation: >-
      Reports the tendency toward hematomas after needle sticks and procedures in
      every affected member of the kindred.
- name: Increased total leukocyte count
  category: Hematological
  description: >-
    A markedly raised white cell count in the independently reported paediatric
    case. This is the finding that started the disease down the wrong diagnostic
    path - it is what prompted the search for a haematologic malignancy, and it
    persisted through antimicrobial treatment, which is part of what redirected the
    workup toward an autoinflammatory cause. The authors' final reading is that the
    leukocytosis reflected infection and the inflammatory response rather than
    leukaemia.
  phenotype_term:
    preferred_term: Increased total leukocyte count
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  notes: >-
    Single reported patient, so no frequency band. The recorded count was 52800 per
    microliter against a stated reference range of 5000-13000; the cited source
    presents those figures in a table which the reference cache flattens into a run
    of digits, so the quoted evidence here is the surrounding prose rather than the
    table row.
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      her white blood cell count was observed to be significantly elevated,
      prompting further investigations for potential hematologic malignancy.
    explanation: >-
      Records the leukocytosis and the diagnostic consequence that makes it worth
      curating separately.
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated CRP levels, normal procalcitonin levels, and persistent leukocytosis
      suggested an immune-mediated process rather than active infection.
    explanation: >-
      Records that the leukocytosis persisted and was read as immune-mediated,
      which is what separates it from a simple infective response.
- name: Anemia
  category: Hematological
  description: >-
    A haemoglobin of 6.9 g/dL against a stated reference range of 11.0-15.5 in the
    independently reported paediatric case, present at the time of the initial
    presentation with fever and osteomyelitis.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  notes: >-
    Deliberately not wired into the pathograph. No cited source proposes a
    mechanism for the anaemia - it is a single reported value in a complete blood
    count, and attaching it downstream of the hyperinflammatory node would assert
    an anaemia of inflammation that nothing here states. Single patient, so no
    frequency band. The cited source presents the value in a table which the
    reference cache flattens, so the quoted row reads as run-together figures.
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete Blood Count (CBC):Serial no.ParameterValueNormal Range1.Hb
      gm/dl6.911.0-15.5
    explanation: >-
      The complete blood count row giving a haemoglobin of 6.9 g/dL against a
      reference range of 11.0-15.5.
- name: Thrombocytopenia
  category: Hematological
  description: >-
    A platelet count of 119000 per microliter against a stated reference range of
    150000-410000 in the independently reported paediatric case - a mild reduction,
    recorded at the same presentation as the anaemia and the leukocytosis.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  notes: >-
    Deliberately not wired into the pathograph, for the same reason as the anaemia:
    no cited source gives it a mechanism. It is worth recording that this is a
    separate observation from the index kindred's bleeding tendency, which was
    investigated and found to have morphologically normal platelets - the two are
    not connected by any cited source, and this entry does not connect them. Single
    patient, so no frequency band.
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2.Total leukocyte counts/microliter528005000-130003.Platelet
      counts/microliter119000150000-4100004.Peripheral smear: large monocytoid
      cells with cytoplasmic granules.
    explanation: >-
      The complete blood count row giving a platelet count of 119000 per microliter
      against a reference range of 150000-410000.
histopathology:
- name: Marrow monocytoid predominance with dim cytoplasmic MPO and absent AML markers
  description: >-
    In the independently reported case the bone marrow aspirate was 90 percent
    abnormal monocytes/promonocytes expressing CD13, CD14, CD33, CD36, CD38, CD58
    and CD64 with dim cytoplasmic myeloperoxidase, while CD34, CD117 and HLA-DR
    were absent. Those three absences, with a negative leukaemia panel and a
    normal karyotype, are what separate the picture from acute myeloid leukaemia.
    The authors read the cells as arrested immature granulocytes rather than true
    monocytes, which is what C/EBP-epsilon's role in late myeloid differentiation
    would predict.
  context: Single reported patient, homozygous CEBPE, sampled during an inflammatory episode.
  notes: >-
    No `finding_term` is bound. NCIT's morphologic-finding branch has no term for
    a marrow monocytoid predominance of this kind, and binding a leukaemia
    morphology term would assert the diagnosis this finding was used to exclude.
    Recorded here rather than as a phenotype because it is a marrow-aspirate
    observation.
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The bone marrow contained 90% abnormal monocytes/promonocytes
    explanation: Quantifies the monocytoid predominance in the marrow aspirate.
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AML-related markers, such as CD34, CD117, and HLA-DR, were absent.
    explanation: >-
      Records the immunophenotypic absences that argue against acute myeloid
      leukaemia despite the monocytoid morphology.
genetic:
- name: CEBPE
  gene_term:
    preferred_term: CEBPE
    term:
      id: hgnc:1836
      label: CEBPE
  relationship_type: CAUSATIVE
  association: Biallelic missense variants; the characterized allele lies in the DNA-binding domain
  variant_origin: GERMLINE
  notes: >-
    Two homozygous missense alleles have been reported in this disease:
    p.Arg219His in the Finnish index kindred and p.Arg211Trp in an unrelated
    child. Both lie in exon 2. Only p.Arg219His is placed in a protein domain by
    its source, which locates it in the basic zipper region's carboxyl-terminal
    DNA-binding domain; the report of p.Arg211Trp localizes that allele to exon 2
    and does not assign it to the DNA-binding domain, so `association` is worded to
    cover only the characterized allele. That second report also frames
    p.Arg211Trp as suggesting an autosomal recessive variant of specific granule
    deficiency, which sits in tension with this entry's position that SGD is a
    separate entity; the competing framing is recorded here so a future curator
    does not have to rediscover it. Zygosity, allele type and functional-impact
    classification for the characterized allele are curated on the
    `CEBPE p.Arg219His Substitution in the DNA-Binding Domain` pathophysiology
    node, which carries the `genetic_context` block. The gene's other disease,
    neutrophil-specific granule deficiency, involves loss-of-function alleles and
    is a separate entity; see this entry's top-level `notes`.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The novel homozygous CEBPE 14:23586886 C>T mutation cosegregated perfectly
      with the disease phenotype
    explanation: >-
      Cosegregation in the index kindred is the genetic argument that the allele
      is causal.
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous missense variant in exon 2 of the CEBPE gene (chr14:g.23117702G
      > A; depth: 223x) that results in the amino acid substitution of tryptophan
      for arginine at codon 211 (p.Arg211Trp; ENST00000206513.6) was detected.
    explanation: >-
      A second, independent homozygous CEBPE allele in the same exon, in a patient
      diagnosed under the same OMIM entity.
prevalence:
- population: Reported cases worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three surviving members of one Finnish kindred were genotyped in the study
    that identified CEBPE p.Arg219His, and one unrelated 8-year-old girl has since
    been reported with a different homozygous CEBPE allele. The kindred had been
    followed clinically since the 1970s, so the number of individuals ever
    affected in it is larger than the number genotyped; no cited source states
    that total, and none is asserted here.
  evidence:
  - reference: PMID:31201888
    reference_title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we analyzed DNA from 3 surviving members (II.2, II.7, and II.13) of the
      index family by performing whole-exome sequencing
    explanation: Gives the number of individuals genotyped in the index kindred.
diagnosis:
- name: Recognition of the Autoinflammatory Syndrome Behind an AML-like Picture
  description: >-
    The one published diagnostic pitfall for this disease is mistaking it for
    acute myeloid leukaemia. In the independently reported case, marked
    leukocytosis with 90 percent abnormal monocyte-like marrow cells and
    PET-CT lesions read as chloromas led to AML-directed chemotherapy before a
    negative leukaemia panel, a persisting inflammatory profile with negative
    cultures, and clinical exome sequencing redirected the diagnosis. The
    mechanistic reading offered is that the apparently abnormal monocytes were
    arrested immature granulocytes, consistent with C/EBP-epsilon's role in late
    myeloid differentiation.
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An 8-year-old patient initially suspected of having AML was found to harbor
      a homozygous CEBPE mutation.
    explanation: States the diagnostic confusion and its resolution.
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      her white blood cell count was observed to be significantly elevated,
      prompting further investigations for potential hematologic malignancy
    explanation: >-
      Identifies the specific finding — marked leukocytosis — that triggered the
      malignancy work-up.
treatments:
- name: Baricitinib
  description: >-
    A JAK inhibitor, given in the independently reported case after the
    autoinflammatory diagnosis was made, with sustained clinical improvement and
    normalization of cytokine levels over months. This is a single-patient
    result, and it is the only reported treatment for this disease that produced
    a durable response.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baricitinib
      term:
        id: CHEBI:95341
        label: baricitinib
  target_mechanisms:
  - target: Hyperinflammatory Response to Bacterial Stimuli
    description: >-
      JAK inhibition targets the cytokine signalling downstream of the
      dysregulated inflammasome and interferon programme.
    evidence:
    - reference: PMID:41026272
      reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment with the JAK inhibitor baricitinib resulted in significant
        clinical improvement, with normalization of cytokine levels over the
        following months.
      explanation: >-
        Reports both the clinical and the biochemical response, which is what
        connects the drug to the inflammatory mechanism rather than to the
        infections.
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with the JAK inhibitor baricitinib resulted in significant
      clinical improvement, with normalization of cytokine levels over the
      following months.
    explanation: The single reported treatment response in this disease.
- name: Prednisolone
  description: >-
    Prednisolone gave temporary symptomatic relief in the independently reported
    case but fever recurred on tapering, so it did not control the disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  evidence:
  - reference: PMID:41026272
    reference_title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A trial of corticosteroids (prednisolone) yielded temporary symptom relief,
      but fever recurred upon tapering.
    explanation: >-
      Records a partial, non-durable response — curated because a treatment that
      does not hold is clinically informative.
discussions:
- discussion_id: gap_cain_heme_synthesis_hypothesis
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the depressed delta-aminolevulinic acid synthase activity found in this
    kindred in 1987 a consequence of the CEBPE p.Arg219His allele, and does heme
    depletion contribute to the abdominal attacks?
  rationale: >-
    Before the gene was known, granulocyte delta-aminolevulinic acid synthase
    activity was measured in this kindred and found depressed in all three
    symptomatic members while normal in the asymptomatic Pelger-Huet carriers
    studied alongside them. The investigators proposed that the abdominal attacks
    were caused by heme depletion, drawing an explicit analogy to porphyria. The
    2019 study that identified CEBPE p.Arg219His accounts for the attacks through
    noncanonical inflammasome priming and does not address the heme finding, so
    the two mechanisms are neither reconciled nor mutually excluded. Whether heme
    biosynthesis genes are among the 464 dysregulated transcripts would be the
    cheapest first test, and it is answerable from data that already exist.
  attaches_to:
  - phenotypes#Abdominal pain
  - pathophysiology#Genome-Wide Transcriptional Dysregulation in Granulocytes
  - pathophysiology#Hyperinflammatory Response to Bacterial Stimuli
- discussion_id: gap_cain_heterozygote_compensation
  kind: KNOWLEDGE_GAP
  prompt: >-
    What compensates for the substantially increased C/EBP-epsilon chromatin
    occupancy seen in clinically unaffected heterozygous carriers?
  rationale: >-
    Heterozygous carriers occupy an intermediate position on every molecular
    measure — 4686 chromatin binding sites against 3391 in controls and 10322 in
    patients — yet have no reported clinical manifestations. The authors read this
    as post-transcriptional compensation of unknown kind, report that DNA
    methylation analysis in the patients found nothing that would explain either
    the symptoms or their mildness, and propose histone methylation and open
    chromatin binding as the next thing to test in a knock-in animal model. This
    matters beyond this disease: it is a worked case of a transcription-factor
    allele whose genomic effect is far larger than its phenotypic one.
  attaches_to:
  - pathophysiology#Increased C/EBP-epsilon Chromatin Occupancy
  - inheritance#Autosomal recessive
- discussion_id: gap_cain_bleeding_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    What causes the mild bleeding diathesis, given that platelet granule
    morphology is normal?
  rationale: >-
    Every affected member of the index kindred bleeds mildly, and C/EBP-epsilon is
    known to control platelet granule formation, so a platelet granule defect was
    the obvious candidate. It was looked for and not found: granule and overall
    platelet structure were morphologically normal. Platelet function testing,
    granule secretion assays and von Willebrand studies are not reported in any
    cited source. The `Mild Bleeding Diathesis of Unresolved Mechanism` node is
    curated HYPOTHETICAL for this reason.
  attaches_to:
  - pathophysiology#Mild Bleeding Diathesis of Unresolved Mechanism
  - phenotypes#Epistaxis
- discussion_id: gap_cain_targeted_cytokine_blockade
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does blocking IL-1-beta or IL-18 control the inflammatory attacks, as the
    mechanism predicts?
  rationale: >-
    The mechanism identified in 2019 is an exaggerated IL-1-beta and IL-18
    response through the noncanonical caspase-4/5 inflammasome, and the authors
    say in as many words that anti-IL-1-beta and anti-IL-18 look like likely
    treatment modalities but remain untested. The only reported durable treatment
    response in this disease is to a JAK inhibitor, in one patient carrying a
    different allele, so the prediction that follows most directly from the
    mechanism has not been tried in anyone.
  attaches_to:
  - pathophysiology#Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
  - treatments#Baricitinib
  proposed_experiments:
  - experiment_id: exp_cain_il1_il18_blockade
    name: Targeted IL-1-beta or IL-18 blockade in a molecularly confirmed patient
    description: >-
      Trial an IL-1-beta antagonist, and separately an IL-18 antagonist, in a
      patient with a confirmed biallelic CEBPE DNA-binding-domain variant,
      measuring attack frequency and duration alongside serum IL-1-beta, IL-18 and
      C-reactive protein, and repeating the intracellular-LPS macrophage assay
      before and during treatment.
    would_support:
    - pathophysiology#Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
    supporting_outcome:
    - >-
      Attack frequency falls and the ex vivo macrophage response to intracellular
      LPS normalizes under blockade of either cytokine.
    would_refute:
    - pathophysiology#Constitutive Caspase-5 Expression and Noncanonical Inflammasome Priming
    refuting_outcome:
    - >-
      Attacks continue unchanged under adequate cytokine blockade, which would
      place the clinical attacks downstream of something other than the
      noncanonical inflammasome output.
references:
- reference: PMID:4831644
  title: "Recurrent attacks of abdominal pain and fever with familial segmentation arrest of granulocytes."
- reference: DOI:10.1182/blood.V43.6.871.871
  title: Recurrent Attacks of Abdominal Pain and Fever With Familial Segmentation
    Arrest of Granulocytes
- reference: PMID:477034
  title: "Impaired neutrophil chemotaxis in Pelger-Huët anomaly."
- reference: PMID:3678479
  title: "Impaired heme synthesis in a family with Pelger-Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro."
- reference: PMID:31201888
  title: "Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy."
- reference: PMID:41026272
  title: "To the Editor, \"CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease\"."
📚

References & Deep Research

References

6
PMID:4831644
Recurrent attacks of abdominal pain and fever with familial segmentation arrest of granulocytes.
No top-level findings curated for this source.
DOI:10.1182/blood.V43.6.871.871
Recurrent Attacks of Abdominal Pain and Fever With Familial Segmentation Arrest of Granulocytes
No top-level findings curated for this source.
PMID:477034
Impaired neutrophil chemotaxis in Pelger-Huët anomaly.
No top-level findings curated for this source.
PMID:3678479
Impaired heme synthesis in a family with Pelger-Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro.
No top-level findings curated for this source.
PMID:31201888
Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy.
No top-level findings curated for this source.
PMID:41026272
To the Editor, "CEBPE-Related Immunodeficiency Mimicking Acute Myeloid Leukemia: A Diagnostic Pitfall in Pediatric Autoinflammatory Disease".
No top-level findings curated for this source.