Nonimmune Chronic Idiopathic Neutropenia of Adults

Complex MONDO:0011922 Pathograph 8 Show in embeddings browser Chronic neutropenia Acquired bone marrow failure syndrome

Persistent unexplained neutropenia in adults, with no antineutrophil antibodies and no other cause found. It is a diagnosis of exclusion, which raises the fair question of whether it has a conserved enough mechanism to be a disease entry at all. It does, and the reason is a single sustained research programme: the granulopoietic defect has been localised to one cell compartment and attributed to one mediator class, repeatedly, in cohorts of 30 to 130 patients. The mechanism is an inhibitory bone-marrow microenvironment rather than a circulating autoantibody. Activated, oligoclonal marrow T lymphocytes and marrow stromal cells produce myelosuppressive cytokines - TNF-alpha, TGF-beta1, IL-1beta, IL-6 - whose serum levels correlate inversely with the neutrophil count. The target is specific: committed CD34+/CD33+ granulocyte progenitors show accelerated apoptosis and Fas overexpression, while the CD34+/CD33-, CD34-/CD33+ and mature neutrophil compartments do not. That compartment specificity is the strongest single piece of evidence that this is one disease and not a label for several. Three things about this entry are deliberately awkward and are recorded rather than smoothed over. The "nonimmune" in the name means "not antibody-mediated", not "not immune": the mechanism is T-cell driven, so the term is a historical contrast with autoimmune neutropenia rather than a description. The nosological boundary with autoimmune neutropenia is genuinely unsettled, and the most recent natural-history cohort frames the whole entity as immune. And the gene OMIM attaches to this concept, GFI1, comes from patients with a congenital phenotype; it does not explain the adult acquired disease, and the entry says so instead of implying a Mendelian basis it does not have. No pathophysiology node declares conforms_to. kb/modules/myelosuppression was read and rejected: that module begins with a cytotoxic insult to proliferating progenitors and ends in multilineage cytopenias, whereas this disease has no exogenous insult and is lineage-restricted. Forcing the conformance would assert both a cause and a breadth the disease does not have.

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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Deep Research
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Discussions and Knowledge Gaps

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Is nonimmune chronic idiopathic neutropenia of adults separable from autoimmune neutropenia, and does the "nonimmune" qualifier still describe anything?
KNOWLEDGE GAP nonimmune_boundary_with_autoimmune_neutropenia
Attached to
disease#Nonimmune Chronic Idiopathic Neutropenia of Adults pathophysiology#Activation and Oligoclonal Expansion of Marrow T Lymphocytes
The qualifier means "not antibody-mediated" and was coined to contrast with autoimmune neutropenia, but the mechanism curated here is T-cell driven, so the disease is immune in every sense except the serological one. Meanwhile the two are hard to separate in practice: the antineutrophil antibody assay is of uncertain value in both children and adults, the 2017 review calls them very similar and overlapping conditions, and the 2024 prospective cohort enrols CIN and autoimmune neutropenia together and describes the whole group as an immune attack on neutrophils. This entry is built on the cohorts that kept the distinction, and a reader should know that the most recent natural-history data do not. Whether MONDO should keep a separate nonimmune term is a real question, not a curation quibble. Two numbers sharpen this, and both are quotable from references already in this entry. In the 2024 prospective cohort 56 per cent of patients carried anti-neutrophil autoantibodies at baseline and 31 per cent had an autoimmune comorbidity; in the earlier review 44 per cent of the registry patients had some evidence of thyroid disease. A majority-seropositive cohort is not what the word "nonimmune" leads a reader to expect, and the figures belong in the gap rather than only in the reviewer's head.
Show evidence (2 references)
PMID:39300133 SUPPORT Human Clinical
"At baseline, 56% had anti-neutrophil autoantibodies and 31% had autoimmune comorbidities."
The serological and clinical autoimmune burden in the cohort that enrols CIN and autoimmune neutropenia together. Cited here to state the gap, not to reclassify the disease: the cohort's composition is exactly what makes the boundary question open.
PMID:27841775 SUPPORT Human Clinical
"Among these patients, 95 (44%) had some evidence of thyroid disease."
An independent autoimmune association in the registry population, reported by the review this entry's diagnostic section is built on.
Does GFI1 belong on this disease at all?
KNOWLEDGE GAP gfi1_relevance_to_the_adult_entity
Attached to
genetic#GFI1
OMIM attaches GFI1 to this concept and the curation stub inherited that association, but the primary report describes a congenital phenotype ascertained as ELANE-negative severe congenital neutropenia, with immunodeficient lymphocytes and circulating immature myeloid cells, acting by derepression of ELANE. None of that is the acquired adult disease whose mechanism the rest of this entry describes, and no GFI1 variant has been reported in a patient meeting the acquired-CIN definition. The gene is recorded with relationship_type SUSCEPTIBILITY and a note saying this, rather than being silently dropped or silently promoted to CAUSATIVE. Resolving it probably requires someone to decide whether the MONDO concept is the OMIM concept. A 2025 exome study of 25 non-remitting-neutropenia and adult-CIN patients is the first direct evidence on the question, and it points away from GFI1. The variants it retrieved sit in immune-regulation and autoimmunity genes, not in the myeloid differentiation programme GFI1 belongs to, and the paediatric and adult groups shared no genes with each other. That is the genetic shape this entry's pathophysiology predicts, since the lesion it models is a T-cell-and-cytokine marrow microenvironment rather than a granulocyte differentiation block. It is 25 subjects with no replication cohort, so it is cited as a directional result rather than as a gene list, and no gene from it is added to the genetic section.
Show evidence (2 references)
PMID:40725177 SUPPORT Human Clinical
"SPINK5, RELA and CARD11 were retrieved and seem to be consistent with the clinical picture characterized by neutropenia associated to immune dysregulation."
The genes retrieved, and the authors' own reading of what they mean.
PMID:40725177 SUPPORT Human Clinical
"the products of expression by the variants involved belong to the autoimmunity and immune regulation pathways (i.e., SPINK5, PTPN22 and PSMB9)"
The pathway-level result from the enrichment and burden tests, which is the part that bears on whether GFI1 belongs here: the signal is in immune regulation, not in myeloid differentiation.
Is the age-inappropriate telomere shortening a consequence of chronic proliferative stress, or a predisposing defect?
KNOWLEDGE GAP telomere_shortening_cause_or_consequence
Attached to
pathophysiology#Granulocyte Replicative Senescence
The entry models it as downstream, because that is the reading the authors favour and because the shortening correlates with neutrophil count. But the data are cross-sectional and a correlation is compatible with either direction. The observation that the difference from controls is most prominent in patients under 50 is the one that would need explaining under the consequence model, since those patients have had the disease for less time. Telomerase activity was detected less often in patients than controls, which would fit a primary defect. No longitudinal data exist.
Are the somatic myeloid-gene mutations found in a fifth of patients a consequence of a chronically inflamed marrow niche, an incidental age-related finding, or a competing diagnosis?
KNOWLEDGE GAP clonal_hematopoiesis_overlay
Attached to
diagnosis#Bone marrow examination
A prospective cohort found somatic myeloid-gene mutations in 19 per cent of tested patients, associated with age. Clonal haematopoiesis at that frequency in an older cohort may be entirely incidental; it may equally be selection within a cytokine-rich marrow; or it may mean some of these patients have an unrecognised clonal cytopenia rather than this disease. The same cohort saw no malignant evolution in three years, which constrains but does not settle it. This entry does not model clonal haematopoiesis as part of the mechanism for that reason.
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Pathophysiology

6
Low-Grade Chronic Inflammatory State in the Bone Marrow
The upstream end of the chain, and the least resolved part of it. What initiates the process is unknown; what is observed is a persistent low-grade inflammatory reaction in the marrow, with raised circulating inflammatory cytokines and chemokines and features of chronic antigenic stimulation.
cytokine production GO:0001816 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cytokine production (GO:0001816). GO:0001816 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Activation and Oligoclonal Expansion of Marrow T Lymphocytes The antigen driving the T-cell response has not been identified, so what connects the inflammatory state to the clonal expansion is unknown.
Show evidence (1 reference)
PMID:11553265 SUPPORT Human Clinical
"All these findings are suggestive of the existence of an unrecognized low-grade chronic inflammatory process which may be involved in the pathogenesis of the disorder."
The synthesis this node represents, stated with the authors' own hedge ("may be involved") preserved.
Activation and Oligoclonal Expansion of Marrow T Lymphocytes
Activated T lymphocytes with myelosuppressive properties are present in both blood and marrow. Sequencing the T-cell receptor beta repertoire of CD8+ cells in 34 patients found marked skewing and oligoclonality, with clonotypes shared between unrelated patients - which is the finding that makes antigen selection, rather than bystander activation, the favoured reading.
CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
Downstream
Myelosuppressive Cytokine Production
Show evidence (2 references)
PMID:21047210 SUPPORT Human Clinical
"Chronic idiopathic neutropenia (CIN) is a granulopoiesis disorder associated with an inhibitory bone marrow (BM) microenvironment consisting of activated T-lymphocytes and pro-inflammatory mediators."
States the two components of the inhibitory microenvironment this node and the next represent.
PMID:28535087 SUPPORT Human Clinical
"Remarkable repertoire skewing and oligoclonality were observed, along with shared clonotypes between different patients, alluding to antigen selection."
The clonality data. Shared clonotypes across unrelated patients is the specific observation that points at a common antigen.
Myelosuppressive Cytokine Production
Two sources, not one. Activated T cells supply part of it, and marrow mesenchymal stromal cells supply TGF-beta1 - a distinction that matters because the stromal contribution is cell-intrinsic and persists in culture. Serum IL-1beta, TNF-alpha, IL-6, TGF-beta1 and soluble TNF receptor p55 are all raised, and each correlates inversely with the neutrophil count.
bone marrow stromal cell CL:0010001 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves bone marrow stromal cell, annotated with stromal cell of bone marrow (CL:0010001). CL:0010001 is a cell type from the Cell Ontology.
negative regulation of myeloid cell differentiation GO:0045638 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of myeloid cell differentiation (GO:0045638). GO:0045638 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Fas-Mediated Apoptosis of Committed Granulocyte Progenitors
Show evidence (3 references)
PMID:11074551 SUPPORT Human Clinical
"We found that serum interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor-beta(1) (TGF-beta(1)), and soluble tumor necrosis factor receptor p55 (sTNF-RI) were all significantly increased in CINA patients compared to controls."
The cytokine profile, in 132 patients against 34 controls.
PMID:11074551 SUPPORT Human Clinical
"Individual cytokine values inversely correlated with the number of circulating neutrophils."
A dose-response relationship between mediator level and the phenotype, which is what raises this from association to plausible mechanism.
PMID:21047210 SUPPORT In Vitro
"transforming growth factor (TGF)-β1 levels were significantly elevated in patients, particularly in those displaying the -509C/T TGF-β1 polymorphism."
Identifies the stromal cell as a second, independent source of TGF-beta1, measured in cultured mesenchymal stem cell supernatants rather than serum. Note the same study found TNF-alpha, IL-1beta and IL-6 NOT elevated in those supernatants, so the stromal contribution is specific to TGF-beta1.
Fas-Mediated Apoptosis of Committed Granulocyte Progenitors
The most specific finding in the disease, and the reason it holds together as an entity. Patients have a low percentage of CD34+/CD33+ cells with accelerated apoptosis and Fas overexpression in that compartment - and crucially no such excess in the CD34+/CD33- , CD34-/CD33+ or mature neutrophil fractions. The lesion is at the committed granulocyte progenitor and nowhere else along the lineage.
granulocyte monocyte progenitor cell CL:0000557 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte monocyte progenitor cell (CL:0000557). CL:0000557 is a cell type from the Cell Ontology.
Fas-mediated extrinsic apoptotic signaling GO:0097191 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Fas-mediated extrinsic apoptotic signaling, annotated with extrinsic apoptotic signaling pathway (GO:0097191). GO:0097191 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Impaired Granulocytopoiesis
Show evidence (2 references)
PMID:12517813 SUPPORT Human Clinical
"A low percentage of CD34(+)/CD33(+) cells in patients was associated with accelerated apoptosis and Fas overexpression within this cell compartment compared with controls."
The apoptosis and the death receptor, in the compartment this node names.
PMID:12517813 SUPPORT Human Clinical
"suggesting that the underlying cellular defect in CIN probably concerns the committed granulocyte progenitors"
The compartment specificity, which is what distinguishes this from a general marrow failure. Quoted with the authors' hedge intact.
Impaired Granulocytopoiesis
Functional confirmation that the apoptosis has consequences: defective granulocyte colony-forming unit growth from both marrow mononuclear cells and purified CD34+ cells, and low colony recovery in long-term marrow cultures.
granulocyte differentiation GO:0030851 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased granulocyte differentiation (GO:0030851). GO:0030851 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Decreased total neutrophil count
Granulocyte Replicative Senescence Read as a consequence of sustained proliferative stress on a depleted progenitor pool. The direction of causation is inferred from the correlation with neutrophil count, not demonstrated.
Show evidence (1 reference)
PMID:12517813 SUPPORT Human Clinical
"We found that patients with CIN displayed a low percentage of CD34(+)/CD33(+) cells, defective granulocyte colony-forming unit (CFU-G) growth potential of BM mononuclear or purified CD34(+) cells, and low CFU-G recovery in long-term BM cultures (LTBMCs), compared with controls (n = 46)."
Three independent readouts of the same functional deficit, against 46 controls.
Granulocyte Replicative Senescence
Telomeres are shorter than age predicts in both mononuclear cells and granulocytes, and telomerase activity is detectable less often than in controls. Telomere length correlates with the absolute neutrophil count. This is curated as a downstream consequence rather than a cause, but that reading is an interpretation and the alternative is recorded as a knowledge gap.
replicative senescence GO:0090399 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased replicative senescence (GO:0090399). GO:0090399 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:22133767 SUPPORT Human Clinical
"The mean relative telomere values of peripheral blood mononuclear cells and granulocytes were significantly lower in patients compared to controls, and significantly lower than expected on the basis of the age-adjusted healthy control distribution."
Age-adjusted shortening, which is what makes this a disease finding rather than an age effect.
PMID:22133767 SUPPORT Human Clinical
"A significant correlation was observed between individual relative telomere values and absolute neutrophil counts."
The correlation with disease severity. It is a correlation, which is exactly why the upstream edge is marked indirect.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Nonimmune Chronic Idiopathic Neutropenia of Adults 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

7
Blood 2
Decreased total neutrophil count VERY_FREQUENT HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total neutrophil count (HP:0001875), qualified as temporality chronic. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:27841775 SUPPORT Human Clinical
"Neutropenia lasting for at least for 3 months and not attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause is called chronic idiopathic neutropenia (CIN)."
The definition of the entity, which is also the definition of this phenotype.
PMID:39300133 SUPPORT Human Clinical
"Median absolute neutrophil count (ANC) at diagnosis was 0.8 × 109/L (interquartile range, IQR, 0.5–1.14), with moderate neutropenia (< 1 × 109/L) in 39% and severe (< 0.5 × 109/L) in 24%."
The severity distribution, which is what grounds the 0.5 x 10^9/L threshold the treatment section turns on: about a quarter of patients sit below it. Quoted with the source's thin spaces and en dash intact.
Decreased circulating total T cell count FREQUENT Decreased total T cell count HP:0005403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is lymphopenia with selective loss of primed/memory T cells, annotated with Decreased total T cell count (HP:0005403). HP:0005403 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11553265 SUPPORT Human Clinical
"lymphopenia due to selective loss of primed/memory T-cells and NK cells"
Records the lymphoid abnormality. Worth having because it argues the disorder is not purely granulocytic even though the progenitor lesion is.
PMID:40725177 SUPPORT Human Clinical
"no severe infections, presence of rheumathological signs, leukopenia in almost all patients and lymphocytopenia in one-third of the cohort"
An independent cohort two decades later, with a proportion this time - lymphocytopenia in one third - and the same clinical picture of leukopenia without severe infection. Quoted with the source's own misspelling of "rheumatological".
Cardiovascular 1
Splenomegaly FREQUENT HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11553265 SUPPORT Human Clinical
"increased splenic volume on ultrasonography in 48.1% of patients"
A measured prevalence in the cohort, which is what sets the frequency band.
PMID:39300133 REFUTE DIRECT Human Clinical
"A minority of patients showed splenomegaly (8%) or enlarged lymph nodes (5%)"
Graded REFUTE against the FREQUENT band, not against the phenotype. A larger prospective cohort finds splenomegaly in 8 per cent where the earlier series found 48 per cent by ultrasound. The two are very likely measuring different things - routine imaging of every patient versus splenomegaly noted clinically - and the entry keeps the imaging-based band while recording the disagreement rather than resolving it silently.
Head and Neck 2
Recurrent aphthous stomatitis FREQUENT 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.
Omitted from the first revision of this entry, and the reason is worth recording because it is a failure mode rather than an oversight. The deep research report offered HP:0100279 for this phenotype, which is Ulcerative colitis - a real CURIE carrying the wrong concept under a plausible label. Rejecting the identifier was right; dropping the phenotype along with it was not. The correct term was one lookup away.
Show evidence (1 reference)
PMID:27841775 SUPPORT Human Clinical
"Overall, recurrent aphthous stomatitis was observed in 45% of the patients."
The quantitative anchor, in a 108-patient adult series. 45 per cent sets the FREQUENT band directly.
Chronic rhinitis OCCASIONAL HP:0002257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is perennial rhinitis, annotated with Chronic rhinitis (HP:0002257). HP:0002257 is a phenotype from the Human Phenotype Ontology.
Deliberately left with no upstream node and no sequela link. The same screening study looked for environmental causes and found none, so this is the one environmental-adjacent finding in the entry and it is a correlation of unknown direction.
Show evidence (1 reference)
PMID:10466440 SUPPORT Human Clinical
"Neutropenic subjects had chronic (perennial) rhinitis 3.4 times more frequently than non-neutropenics."
A relative frequency, not an absolute one. It supports the association and sets no frequency band; the OCCASIONAL band reflects that no proportion of patients is reported.
Immune 1
Recurrent bacterial infections FREQUENT HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718). HP:0002718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39300133 SUPPORT Human Clinical
"rate of grade ≥ 2 infections was 42%, with 10% grade ≥ 3, irrespective of neutrophil counts, demographics, and anti-neutrophil antibodies positivity"
Quantifies infection rate over a median three-year follow-up in 131 patients, and records that it did not track the neutrophil count.
Musculoskeletal 1
Osteopenia FREQUENT HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11553265 SUPPORT Human Clinical
"osteopenia and/or osteoporosis in 60.0% of patients"
A measured prevalence, from the same cohort description.
🧬

Genetic Associations

1
GFI1 (Reported association whose relevance to the adult acquired disease is unclear)
Gene: GFI1 hgnc:4237 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GFI1 (hgnc:4237). hgnc:4237 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:12778173 SUPPORT Human Clinical
"We found dominant negative zinc finger mutations that disable transcriptional repressor activity."
The variant class and its molecular consequence, in the report OMIM's assignment rests on.
PMID:12778173 SUPPORT Human Clinical
"We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation."
The mechanism - ELANE derepression - which is a differentiation defect and not the progenitor-apoptosis mechanism this entry's pathograph describes. Cited to show what the gene association actually is, not to support it.
💊

Medical Actions

2
Granulocyte colony-stimulating factor
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: granulocyte colony-stimulating factor NCIT:C1474 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses granulocyte colony-stimulating factor, annotated with Filgrastim (NCIT:C1474). NCIT:C1474 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
Effective at raising the neutrophil count in almost all cases, and reserved for patients who actually have infections rather than given for the count alone. In the prospective natural-history cohort only six of 131 patients received it, which is the practical picture: most people with this diagnosis are not treated.
Target Phenotypes: Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27841775 SUPPORT Human Clinical
"Treatment with granulocyte colony stimulating factor (G-CSF) is effective to increase blood neutrophils in almost all cases; this treatment is reserved, however, for patients with both neutropenia and evidence of recurrent fevers, inflammatory symptoms and infections."
Both the efficacy and the restriction on when it is used.
PMID:27841775 SUPPORT Human Clinical
"There is little or no evidence to indicate that G-CSF treatment predisposes to myeloid malignancies in this population."
The safety question that matters here, given that G-CSF in severe congenital neutropenia does carry a leukaemia signal. Note the claim is an absence of evidence, and the quote says so.
Observation without treatment
The default. Most patients with a neutrophil count above 0.5 x 10^9/L are observed, without prophylactic antibiotics and without a growth factor.
Show evidence (2 references)
PMID:27841775 SUPPORT Human Clinical
"most patients can be observed and not treated prophylactically with antibiotics or a growth factor"
The recommendation itself, including both halves of it - no prophylactic antibiotics and no growth factor - which is what this treatment record claims. An earlier revision quoted the converse sentence ("When neutropenia is severe, treatment with G-CSF is often beneficial") and justified it by asserting that this sentence could not be quoted because of a superscript. That was wrong: the cache stores the threshold as "0.5 x 10/l" with the superscript already stripped, and this sub-span is an exact substring. The claim about the cache was never checked against the cache.
PMID:27841775 SUPPORT Human Clinical
"When neutropenia is severe, treatment with G-CSF is often beneficial."
Kept as the converse boundary, now beside the statement it is the converse of rather than standing in for it. It is what makes the observation policy a threshold rather than a blanket.
🔬

Diagnosis

2
Exclusion of secondary and immune causes of neutropenia
The diagnosis is made by ruling everything else out: drugs, nutritional deficiency, endocrinopathy, chronic infection, autoimmune disease, lymphoproliferative disorder, inborn errors of immunity and congenital neutropenia, plus antineutrophil antibody testing.
differential diagnostic evaluation for neutropenia NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27841775 SUPPORT Human Clinical
"Neutropenia lasting for at least for 3 months and not attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause is called chronic idiopathic neutropenia (CIN)."
Enumerates what has to be excluded, which is the diagnostic procedure.
Bone marrow examination
Recommended in adults, and it is not merely confirmatory. In a prospective cohort it found a large granular lymphocyte infiltrate in 52 per cent and hypocellularity in 31 per cent, and a fifth of tested patients carried somatic myeloid-gene mutations - findings that change the differential rather than confirm the label.
bone marrow examination NCIT:C15189 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39300133 SUPPORT Human Clinical
"Interestingly, 19% of tested patients displayed somatic mutations of myeloid genes with an association with age."
The finding that makes marrow assessment worth doing. Note the authors do not interpret these as causal, and neither does this entry.
📈

Progression

1
Long-term course
Benign in the medium term. Over a median three years of prospective follow-up there was no malignant evolution and no deaths, although infections of grade 2 or worse occurred in 42 per cent. Remission is common in children and rare in adults.
Show evidence (1 reference)
PMID:39300133 SUPPORT Human Clinical
"No malignant evolution nor deaths were observed."
The outcome that matters most to a patient told they have an unexplained marrow abnormality. Three years is not long enough to settle the question, which is why the phase is described rather than called benign outright.
📊

Prevalence

2
Apparently healthy adults on Crete (778 medical-school and hospital employees and their families, aged 15-79)
Point Prevalence 8230.0 per 100,000 >1 in 1,000
An earlier revision of this entry stated that no prevalence estimate exists. That was wrong: the group whose referral cohorts this entry's pathophysiology is built on also screened a non-patient population, and 8.23 per cent of it met their diagnostic criteria. The figure needs reading carefully rather than discounting. The sample was not randomly selected - the authors say so themselves - it is one island and one occupational group, and the criteria are the department's own rather than a consensus definition. More important for interpretation: none of the 64 had severe neutropenia, 6.81 per cent were mild and 1.41 per cent moderate, so what is 8.23 per cent common is a screen-detected laboratory phenotype, not the clinically significant disease that reaches a haematology clinic. That distinction is why no qualitative RARE/COMMON tier is recorded alongside the rate. The published clinical cohorts - 132 patients in the cytokine study, 131 in the prospective natural-history study, 37 in the telomere study - remain referral-based and give no denominator of their own. And the reference range for a normal neutrophil count differs by ancestry, so the threshold that produced this figure would not produce it everywhere.
Show evidence (3 references)
PMID:10466440 SUPPORT Human Clinical
"Among these there were 64 subjects (8.23%) who fulfilled the diagnostic criteria of CINA applied in our department."
The numerator, denominator and criterion in one sentence. Note the criterion is explicitly the department's own.
PMID:10466440 SUPPORT Human Clinical
"Mild neutropenia (neutrophils 1700-2499/microl) accounted for 6.81% and moderate neutropenia (neutrophils 600-1699/microl) for the remaining 1.41%. No cases of CINA with severe neutropenia (neutrophils below 600/microl) were found."
The severity breakdown, which is what keeps the headline figure from being read as the prevalence of a clinically significant disease. No severe case was found in 778 people.
PMID:10466440 SUPPORT Human Clinical
"despite the biased character of the study (population not randomly selected), our data provide a valuable estimation of the prevalence of CINA in the general"
The authors' own statement of the sampling limitation, quoted rather than paraphrased because it is the main reason to treat the rate as an estimate from one population and not a general prevalence.
Adult women relative to adult men, Crete
Point Prevalence >1 in 1,000
A sex ratio rather than a rate, recorded separately because it is a different claim from the overall prevalence and would be lost inside it. Two thirds of cases fell between 30 and 59 years, which is consistent with an acquired adult-onset disorder rather than a late-detected congenital one. No rate is given for either stratum, so none is recorded.
Show evidence (2 references)
PMID:10466440 SUPPORT Human Clinical
"CINA was more frequent in women, with a women to men ratio of about 3:2."
The female predominance in the screened population.
PMID:10466440 SUPPORT Human Clinical
"Approximately two thirds of the cases appeared in patients aged 30-59 years."
The age distribution, in the same screened population.
{ }

Source YAML

click to show 
name: Nonimmune Chronic Idiopathic Neutropenia of Adults
creation_date: "2026-09-11T13:20:00Z"
category: Complex
synonyms:
- NICIA
- chronic idiopathic neutropenia of adults
- CINA
- non-immune chronic idiopathic neutropenia of adult
description: >-
  Persistent unexplained neutropenia in adults, with no antineutrophil
  antibodies and no other cause found. It is a diagnosis of exclusion, which
  raises the fair question of whether it has a conserved enough mechanism to be
  a disease entry at all. It does, and the reason is a single sustained research
  programme: the granulopoietic defect has been localised to one cell
  compartment and attributed to one mediator class, repeatedly, in cohorts of
  30 to 130 patients.

  The mechanism is an inhibitory bone-marrow microenvironment rather than a
  circulating autoantibody. Activated, oligoclonal marrow T lymphocytes and
  marrow stromal cells produce myelosuppressive cytokines - TNF-alpha, TGF-beta1,
  IL-1beta, IL-6 - whose serum levels correlate inversely with the neutrophil
  count. The target is specific: committed CD34+/CD33+ granulocyte progenitors
  show accelerated apoptosis and Fas overexpression, while the CD34+/CD33-,
  CD34-/CD33+ and mature neutrophil compartments do not. That compartment
  specificity is the strongest single piece of evidence that this is one disease
  and not a label for several.

  Three things about this entry are deliberately awkward and are recorded rather
  than smoothed over. The "nonimmune" in the name means "not antibody-mediated",
  not "not immune": the mechanism is T-cell driven, so the term is a historical
  contrast with autoimmune neutropenia rather than a description. The
  nosological boundary with autoimmune neutropenia is genuinely unsettled, and
  the most recent natural-history cohort frames the whole entity as immune. And
  the gene OMIM attaches to this concept, GFI1, comes from patients with a
  congenital phenotype; it does not explain the adult acquired disease, and the
  entry says so instead of implying a Mendelian basis it does not have.

  No pathophysiology node declares conforms_to. kb/modules/myelosuppression was
  read and rejected: that module begins with a cytotoxic insult to proliferating
  progenitors and ends in multilineage cytopenias, whereas this disease has no
  exogenous insult and is lineage-restricted. Forcing the conformance would
  assert both a cause and a breadth the disease does not have.
disease_term:
  preferred_term: nonimmune chronic idiopathic neutropenia of adults
  term:
    id: MONDO:0011922
    label: nonimmune chronic idiopathic neutropenia of adults
parents:
- Chronic neutropenia
- Acquired bone marrow failure syndrome
pathophysiology:
- name: Low-Grade Chronic Inflammatory State in the Bone Marrow
  biological_scale: TISSUE
  description: >-
    The upstream end of the chain, and the least resolved part of it. What
    initiates the process is unknown; what is observed is a persistent low-grade
    inflammatory reaction in the marrow, with raised circulating inflammatory
    cytokines and chemokines and features of chronic antigenic stimulation.
  biological_processes:
  - preferred_term: cytokine production
    modifier: INCREASED
    term:
      id: GO:0001816
      label: cytokine production
  evidence:
  - reference: PMID:11553265
    reference_title: "Non-immune chronic idiopathic neutropenia of adult: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All these findings are suggestive of the existence of an unrecognized low-grade chronic inflammatory process which may be involved in the pathogenesis of the disorder."
    explanation: >-
      The synthesis this node represents, stated with the authors' own hedge
      ("may be involved") preserved.
  downstream:
  - target: Activation and Oligoclonal Expansion of Marrow T Lymphocytes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The antigen driving the T-cell response has not been identified, so what
      connects the inflammatory state to the clonal expansion is unknown.
    evidence:
    - reference: PMID:28535087
      reference_title: "Cytotoxic T cells in chronic idiopathic neutropenia express restricted antigen receptors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, these findings suggest that CIN may be driven by long-term exposure to a restricted set of specific CIN-associated antigens."
      explanation: >-
        Infers chronic antigen exposure from receptor restriction. The antigen
        itself is not identified, which is why this edge is indirect.
- name: Activation and Oligoclonal Expansion of Marrow T Lymphocytes
  biological_scale: CELLULAR
  description: >-
    Activated T lymphocytes with myelosuppressive properties are present in both
    blood and marrow. Sequencing the T-cell receptor beta repertoire of CD8+
    cells in 34 patients found marked skewing and oligoclonality, with clonotypes
    shared between unrelated patients - which is the finding that makes antigen
    selection, rather than bystander activation, the favoured reading.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  evidence:
  - reference: PMID:21047210
    reference_title: "Mesenchymal stem cells contribute to the abnormal bone marrow microenvironment in patients with chronic idiopathic neutropenia by overproduction of transforming growth factor-β1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic idiopathic neutropenia (CIN) is a granulopoiesis disorder associated with an inhibitory bone marrow (BM) microenvironment consisting of activated T-lymphocytes and pro-inflammatory mediators."
    explanation: "States the two components of the inhibitory microenvironment this node and the next represent."
  - reference: PMID:28535087
    reference_title: "Cytotoxic T cells in chronic idiopathic neutropenia express restricted antigen receptors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkable repertoire skewing and oligoclonality were observed, along with shared clonotypes between different patients, alluding to antigen selection."
    explanation: >-
      The clonality data. Shared clonotypes across unrelated patients is the
      specific observation that points at a common antigen.
  downstream:
  - target: Myelosuppressive Cytokine Production
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28535087
      reference_title: "Cytotoxic T cells in chronic idiopathic neutropenia express restricted antigen receptors."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Crucial to CIN pathophysiology is the presence of activated T lymphocytes with myelosuppressive properties in both peripheral blood (PB) and bone marrow (BM)."
      explanation: "Attributes the myelosuppressive property to the activated T cells, which is the step this edge asserts."
- name: Myelosuppressive Cytokine Production
  biological_scale: TISSUE
  description: >-
    Two sources, not one. Activated T cells supply part of it, and marrow
    mesenchymal stromal cells supply TGF-beta1 - a distinction that matters
    because the stromal contribution is cell-intrinsic and persists in culture.
    Serum IL-1beta, TNF-alpha, IL-6, TGF-beta1 and soluble TNF receptor p55 are
    all raised, and each correlates inversely with the neutrophil count.
  cell_types:
  - preferred_term: bone marrow stromal cell
    term:
      id: CL:0010001
      label: stromal cell of bone marrow
  biological_processes:
  - preferred_term: negative regulation of myeloid cell differentiation
    modifier: INCREASED
    term:
      id: GO:0045638
      label: negative regulation of myeloid cell differentiation
  evidence:
  - reference: PMID:11074551
    reference_title: "Patients with chronic idiopathic neutropenia of adults have increased serum concentrations of inflammatory cytokines and chemokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that serum interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor-beta(1) (TGF-beta(1)), and soluble tumor necrosis factor receptor p55 (sTNF-RI) were all significantly increased in CINA patients compared to controls."
    explanation: "The cytokine profile, in 132 patients against 34 controls."
  - reference: PMID:11074551
    reference_title: "Patients with chronic idiopathic neutropenia of adults have increased serum concentrations of inflammatory cytokines and chemokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual cytokine values inversely correlated with the number of circulating neutrophils."
    explanation: >-
      A dose-response relationship between mediator level and the phenotype,
      which is what raises this from association to plausible mechanism.
  - reference: PMID:21047210
    reference_title: "Mesenchymal stem cells contribute to the abnormal bone marrow microenvironment in patients with chronic idiopathic neutropenia by overproduction of transforming growth factor-β1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "transforming growth factor (TGF)-β1 levels were significantly elevated in patients, particularly in those displaying the -509C/T TGF-β1 polymorphism."
    explanation: >-
      Identifies the stromal cell as a second, independent source of TGF-beta1,
      measured in cultured mesenchymal stem cell supernatants rather than serum.
      Note the same study found TNF-alpha, IL-1beta and IL-6 NOT elevated in
      those supernatants, so the stromal contribution is specific to TGF-beta1.
  downstream:
  - target: Fas-Mediated Apoptosis of Committed Granulocyte Progenitors
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11553265
      reference_title: "Non-immune chronic idiopathic neutropenia of adult: an overview."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There is strong evidence that non-immune chronic idiopathic neutropenia of adult is a cytokine-mediated syndrome characterized by (a) neutropenia of varying degree associated with a low number of lineage-specific CD34+ cells and increased production of inhibitors of hematopoiesis, including transforming growth factor-beta1 and tumor necrosis factor-alpha"
      explanation: >-
        Links the inhibitor production to the reduced lineage-specific progenitor
        pool in one sentence, which is the causal step this edge makes.
- name: Fas-Mediated Apoptosis of Committed Granulocyte Progenitors
  biological_scale: CELLULAR
  description: >-
    The most specific finding in the disease, and the reason it holds together as
    an entity. Patients have a low percentage of CD34+/CD33+ cells with
    accelerated apoptosis and Fas overexpression in that compartment - and
    crucially no such excess in the CD34+/CD33- , CD34-/CD33+ or mature
    neutrophil fractions. The lesion is at the committed granulocyte progenitor
    and nowhere else along the lineage.
  cell_types:
  - preferred_term: granulocyte monocyte progenitor cell
    term:
      id: CL:0000557
      label: granulocyte monocyte progenitor cell
  biological_processes:
  - preferred_term: Fas-mediated extrinsic apoptotic signaling
    modifier: INCREASED
    term:
      id: GO:0097191
      label: extrinsic apoptotic signaling pathway
  evidence:
  - reference: PMID:12517813
    reference_title: "Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A low percentage of CD34(+)/CD33(+) cells in patients was associated with accelerated apoptosis and Fas overexpression within this cell compartment compared with controls."
    explanation: "The apoptosis and the death receptor, in the compartment this node names."
  - reference: PMID:12517813
    reference_title: "Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting that the underlying cellular defect in CIN probably concerns the committed granulocyte progenitors"
    explanation: >-
      The compartment specificity, which is what distinguishes this from a
      general marrow failure. Quoted with the authors' hedge intact.
  downstream:
  - target: Impaired Granulocytopoiesis
    causal_link_type: DIRECT
- name: Impaired Granulocytopoiesis
  biological_scale: TISSUE
  description: >-
    Functional confirmation that the apoptosis has consequences: defective
    granulocyte colony-forming unit growth from both marrow mononuclear cells and
    purified CD34+ cells, and low colony recovery in long-term marrow cultures.
  biological_processes:
  - preferred_term: granulocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030851
      label: granulocyte differentiation
  evidence:
  - reference: PMID:12517813
    reference_title: "Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that patients with CIN displayed a low percentage of CD34(+)/CD33(+) cells, defective granulocyte colony-forming unit (CFU-G) growth potential of BM mononuclear or purified CD34(+) cells, and low CFU-G recovery in long-term BM cultures (LTBMCs), compared with controls (n = 46)."
    explanation: >-
      Three independent readouts of the same functional deficit, against 46
      controls.
  downstream:
  - target: Decreased total neutrophil count
    causal_link_type: DIRECT
  - target: Granulocyte Replicative Senescence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Read as a consequence of sustained proliferative stress on a depleted
      progenitor pool. The direction of causation is inferred from the
      correlation with neutrophil count, not demonstrated.
- name: Granulocyte Replicative Senescence
  biological_scale: CELLULAR
  description: >-
    Telomeres are shorter than age predicts in both mononuclear cells and
    granulocytes, and telomerase activity is detectable less often than in
    controls. Telomere length correlates with the absolute neutrophil count. This
    is curated as a downstream consequence rather than a cause, but that reading
    is an interpretation and the alternative is recorded as a knowledge gap.
  biological_processes:
  - preferred_term: replicative senescence
    modifier: INCREASED
    term:
      id: GO:0090399
      label: replicative senescence
  evidence:
  - reference: PMID:22133767
    reference_title: "Abnormal telomere shortening of peripheral blood mononuclear cells and granulocytes in patients with chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean relative telomere values of peripheral blood mononuclear cells and granulocytes were significantly lower in patients compared to controls, and significantly lower than expected on the basis of the age-adjusted healthy control distribution."
    explanation: >-
      Age-adjusted shortening, which is what makes this a disease finding rather
      than an age effect.
  - reference: PMID:22133767
    reference_title: "Abnormal telomere shortening of peripheral blood mononuclear cells and granulocytes in patients with chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A significant correlation was observed between individual relative telomere values and absolute neutrophil counts."
    explanation: >-
      The correlation with disease severity. It is a correlation, which is
      exactly why the upstream edge is marked indirect.
phenotypes:
- category: Hematologic
  name: Decreased total neutrophil count
  description: >-
    Persistent for at least three months, of varying degree, and not attributable
    to a drug or to a definable genetic, infectious, inflammatory, autoimmune or
    malignant cause.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    temporality: CHRONIC
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neutropenia lasting for at least for 3 months and not attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause is called chronic idiopathic neutropenia (CIN)."
    explanation: "The definition of the entity, which is also the definition of this phenotype."
  - reference: PMID:39300133
    reference_title: "Natural history of chronic idiopathic neutropenia of the adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median absolute neutrophil count (ANC) at diagnosis was 0.8 × 109/L (interquartile range, IQR, 0.5–1.14), with moderate neutropenia (< 1 × 109/L) in 39% and severe (< 0.5 × 109/L) in 24%."
    explanation: >-
      The severity distribution, which is what grounds the 0.5 x 10^9/L
      threshold the treatment section turns on: about a quarter of patients sit
      below it. Quoted with the source's thin spaces and en dash intact.
- category: Immunologic
  name: Recurrent bacterial infections
  description: >-
    Usually mild and mucosal. Infection risk in a prospective cohort was largely
    independent of the neutrophil count, which is clinically counterintuitive and
    worth recording.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  frequency: FREQUENT
  evidence:
  - reference: PMID:39300133
    reference_title: "Natural history of chronic idiopathic neutropenia of the adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rate of grade ≥ 2 infections was 42%, with 10% grade ≥ 3, irrespective of neutrophil counts, demographics, and anti-neutrophil antibodies positivity"
    explanation: >-
      Quantifies infection rate over a median three-year follow-up in 131
      patients, and records that it did not track the neutrophil count.
- category: Hematologic
  name: Splenomegaly
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:11553265
    reference_title: "Non-immune chronic idiopathic neutropenia of adult: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased splenic volume on ultrasonography in 48.1% of patients"
    explanation: "A measured prevalence in the cohort, which is what sets the frequency band."
  - reference: PMID:39300133
    reference_title: "Natural history of chronic idiopathic neutropenia of the adult."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A minority of patients showed splenomegaly (8%) or enlarged lymph nodes (5%)"
    explanation: >-
      Graded REFUTE against the FREQUENT band, not against the phenotype. A
      larger prospective cohort finds splenomegaly in 8 per cent where the
      earlier series found 48 per cent by ultrasound. The two are very likely
      measuring different things - routine imaging of every patient versus
      splenomegaly noted clinically - and the entry keeps the imaging-based
      band while recording the disagreement rather than resolving it silently.
- category: Skeletal
  name: Osteopenia
  description: >-
    Present in the majority of patients in the original cohort. Plausibly related
    to the same macrophage-derived cytokines that affect bone metabolism, though
    nothing in this entry demonstrates that link.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  frequency: FREQUENT
  evidence:
  - reference: PMID:11553265
    reference_title: "Non-immune chronic idiopathic neutropenia of adult: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "osteopenia and/or osteoporosis in 60.0% of patients"
    explanation: "A measured prevalence, from the same cohort description."
- category: Gastrointestinal
  name: Recurrent aphthous stomatitis
  description: >-
    Mouth ulcers are the most frequent clinical event in this disease, and in
    the French registry series they were the presenting complaint in 10 per
    cent of patients. Their frequency makes them the one manifestation against
    which a treatment effect is visible at all.
  phenotype_term:
    preferred_term: Recurrent aphthous stomatitis
    term:
      id: HP:0011107
      label: Recurrent aphthous stomatitis
  frequency: FREQUENT
  evidence:
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, recurrent aphthous stomatitis was observed in 45% of the patients."
    explanation: >-
      The quantitative anchor, in a 108-patient adult series. 45 per cent sets
      the FREQUENT band directly.
  notes: >-
    Omitted from the first revision of this entry, and the reason is worth
    recording because it is a failure mode rather than an oversight. The deep
    research report offered HP:0100279 for this phenotype, which is Ulcerative
    colitis - a real CURIE carrying the wrong concept under a plausible label.
    Rejecting the identifier was right; dropping the phenotype along with it was
    not. The correct term was one lookup away.
- category: Respiratory
  name: Chronic rhinitis
  description: >-
    An association rather than a consequence. In the screening study neutropenic
    subjects had perennial rhinitis 3.4 times as often as non-neutropenic ones.
    No mechanism connects it to anything in this entry's pathograph, and the
    direction is not established either - a chronic mucosal inflammatory state
    would sit upstream of the marrow inflammation this disease starts from just
    as plausibly as downstream of the neutropenia.
  phenotype_term:
    preferred_term: perennial rhinitis
    term:
      id: HP:0002257
      label: Chronic rhinitis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:10466440
    reference_title: "Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neutropenic subjects had chronic (perennial) rhinitis 3.4 times more frequently than non-neutropenics."
    explanation: >-
      A relative frequency, not an absolute one. It supports the association
      and sets no frequency band; the OCCASIONAL band reflects that no
      proportion of patients is reported.
  notes: >-
    Deliberately left with no upstream node and no sequela link. The same
    screening study looked for environmental causes and found none, so this is
    the one environmental-adjacent finding in the entry and it is a correlation
    of unknown direction.
- category: Hematologic
  name: Decreased circulating total T cell count
  description: >-
    Lymphopenia from selective loss of primed/memory T cells and NK cells,
    reported alongside the neutropenia.
  phenotype_term:
    preferred_term: lymphopenia with selective loss of primed/memory T cells
    term:
      id: HP:0005403
      label: Decreased total T cell count
  frequency: FREQUENT
  evidence:
  - reference: PMID:11553265
    reference_title: "Non-immune chronic idiopathic neutropenia of adult: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphopenia due to selective loss of primed/memory T-cells and NK cells"
    explanation: >-
      Records the lymphoid abnormality. Worth having because it argues the
      disorder is not purely granulocytic even though the progenitor lesion is.
  - reference: PMID:40725177
    reference_title: "Genetic Landscape of Non-Remitting Neutropenia in Children and Chronic Idiopathic Neutropenia in Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no severe infections, presence of rheumathological signs, leukopenia in almost all patients and lymphocytopenia in one-third of the cohort"
    explanation: >-
      An independent cohort two decades later, with a proportion this time -
      lymphocytopenia in one third - and the same clinical picture of
      leukopenia without severe infection. Quoted with the source's own
      misspelling of "rheumatological".
genetic:
- name: GFI1
  gene_term:
    preferred_term: GFI1
    term:
      id: hgnc:4237
      label: GFI1
  association: Reported association whose relevance to the adult acquired disease is unclear
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Read this entry before using it. OMIM attaches GFI1 to the concept this MONDO
    term names, but the primary report describes dominant-negative zinc-finger
    variants in individuals with a CONGENITAL neutropenia phenotype - screened as
    an alternative to ELANE in severe congenital neutropenia - together with
    immunodeficient lymphocytes and circulating immature myeloid cells. The
    mechanism is derepression of ELANE, which GFI1 normally represses. That is a
    Mendelian disorder of myeloid differentiation, and it does not explain an
    acquired, adult-onset, T-cell-microenvironment disease. No GFI1 variant has
    been reported in a patient meeting the acquired-CIN definition used by the
    cohorts this entry's pathophysiology is built on. The relationship_type is
    SUSCEPTIBILITY rather than CAUSATIVE for that reason, and a case can be made
    that the gene should not be on this record at all.
  evidence:
  - reference: PMID:12778173
    reference_title: "Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found dominant negative zinc finger mutations that disable transcriptional repressor activity."
    explanation: "The variant class and its molecular consequence, in the report OMIM's assignment rests on."
  - reference: PMID:12778173
    reference_title: "Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation."
    explanation: >-
      The mechanism - ELANE derepression - which is a differentiation defect and
      not the progenitor-apoptosis mechanism this entry's pathograph describes.
      Cited to show what the gene association actually is, not to support it.
treatments:
- name: Granulocyte colony-stimulating factor
  description: >-
    Effective at raising the neutrophil count in almost all cases, and reserved
    for patients who actually have infections rather than given for the count
    alone. In the prospective natural-history cohort only six of 131 patients
    received it, which is the practical picture: most people with this diagnosis
    are not treated.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: granulocyte colony-stimulating factor
      term:
        id: NCIT:C1474
        label: Filgrastim
  target_phenotypes:
  - preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with granulocyte colony stimulating factor (G-CSF) is effective to increase blood neutrophils in almost all cases; this treatment is reserved, however, for patients with both neutropenia and evidence of recurrent fevers, inflammatory symptoms and infections."
    explanation: "Both the efficacy and the restriction on when it is used."
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is little or no evidence to indicate that G-CSF treatment predisposes to myeloid malignancies in this population."
    explanation: >-
      The safety question that matters here, given that G-CSF in severe
      congenital neutropenia does carry a leukaemia signal. Note the claim is an
      absence of evidence, and the quote says so.
  notes: >-
    The agent binding is filgrastim, which is the recombinant G-CSF actually
    used. The cited source says "G-CSF" generically and does not name a product;
    NCIT's only G-CSF entries reachable as therapeutic agents are the specific
    recombinant proteins, so the binding is one step more specific than the
    source. Flagged rather than hidden.
- name: Observation without treatment
  description: >-
    The default. Most patients with a neutrophil count above 0.5 x 10^9/L are
    observed, without prophylactic antibiotics and without a growth factor.
  treatment_term:
    preferred_term: observation without treatment
  evidence:
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most patients can be observed and not treated prophylactically with antibiotics or a growth factor"
    explanation: >-
      The recommendation itself, including both halves of it - no prophylactic
      antibiotics and no growth factor - which is what this treatment record
      claims. An earlier revision quoted the converse sentence ("When
      neutropenia is severe, treatment with G-CSF is often beneficial") and
      justified it by asserting that this sentence could not be quoted because
      of a superscript. That was wrong: the cache stores the threshold as
      "0.5 x 10/l" with the superscript already stripped, and this sub-span is
      an exact substring. The claim about the cache was never checked against
      the cache.
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When neutropenia is severe, treatment with G-CSF is often beneficial."
    explanation: >-
      Kept as the converse boundary, now beside the statement it is the converse
      of rather than standing in for it. It is what makes the observation policy
      a threshold rather than a blanket.
  notes: >-
    treatment_term carries no term: binding on purpose. NCIT:C15722 Patient
    Observation is the right concept but is not reachable from NCIT:C25218
    Clinical Intervention or Procedure, which is what TreatmentActionTerm is
    rooted at, so binding it fails dynamic-enum validation. Per CLAUDE.md the
    answer is to omit the binding rather than substitute a term that means
    something else - watchful waiting is not supportive care and not a
    therapeutic procedure. Recorded here so the gap is visible.
diagnosis:
- name: Exclusion of secondary and immune causes of neutropenia
  description: >-
    The diagnosis is made by ruling everything else out: drugs, nutritional
    deficiency, endocrinopathy, chronic infection, autoimmune disease,
    lymphoproliferative disorder, inborn errors of immunity and congenital
    neutropenia, plus antineutrophil antibody testing.
  diagnosis_term:
    preferred_term: differential diagnostic evaluation for neutropenia
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neutropenia lasting for at least for 3 months and not attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause is called chronic idiopathic neutropenia (CIN)."
    explanation: "Enumerates what has to be excluded, which is the diagnostic procedure."
- name: Bone marrow examination
  description: >-
    Recommended in adults, and it is not merely confirmatory. In a prospective
    cohort it found a large granular lymphocyte infiltrate in 52 per cent and
    hypocellularity in 31 per cent, and a fifth of tested patients carried
    somatic myeloid-gene mutations - findings that change the differential rather
    than confirm the label.
  diagnosis_term:
    preferred_term: bone marrow examination
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  evidence:
  - reference: PMID:39300133
    reference_title: "Natural history of chronic idiopathic neutropenia of the adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, 19% of tested patients displayed somatic mutations of myeloid genes with an association with age."
    explanation: >-
      The finding that makes marrow assessment worth doing. Note the authors do
      not interpret these as causal, and neither does this entry.
prevalence:
- population: Apparently healthy adults on Crete (778 medical-school and hospital employees and their families, aged 15-79)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 8230.0
  rate_denominator: POPULATION
  notes: >-
    An earlier revision of this entry stated that no prevalence estimate exists.
    That was wrong: the group whose referral cohorts this entry's
    pathophysiology is built on also screened a non-patient population, and
    8.23 per cent of it met their diagnostic criteria. The figure needs reading
    carefully rather than discounting. The sample was not randomly selected -
    the authors say so themselves - it is one island and one occupational
    group, and the criteria are the department's own rather than a consensus
    definition. More important for interpretation: none of the 64 had severe
    neutropenia, 6.81 per cent were mild and 1.41 per cent moderate, so what is
    8.23 per cent common is a screen-detected laboratory phenotype, not the
    clinically significant disease that reaches a haematology clinic. That
    distinction is why no qualitative RARE/COMMON tier is recorded alongside
    the rate. The published clinical cohorts - 132 patients in the cytokine
    study, 131 in the prospective natural-history study, 37 in the telomere
    study - remain referral-based and give no denominator of their own. And the
    reference range for a normal neutrophil count differs by ancestry, so the
    threshold that produced this figure would not produce it everywhere.
  evidence:
  - reference: PMID:10466440
    reference_title: "Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these there were 64 subjects (8.23%) who fulfilled the diagnostic criteria of CINA applied in our department."
    explanation: >-
      The numerator, denominator and criterion in one sentence. Note the
      criterion is explicitly the department's own.
  - reference: PMID:10466440
    reference_title: "Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mild neutropenia (neutrophils 1700-2499/microl) accounted for 6.81% and moderate neutropenia (neutrophils 600-1699/microl) for the remaining 1.41%. No cases of CINA with severe neutropenia (neutrophils below 600/microl) were found."
    explanation: >-
      The severity breakdown, which is what keeps the headline figure from
      being read as the prevalence of a clinically significant disease. No
      severe case was found in 778 people.
  - reference: PMID:10466440
    reference_title: "Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "despite the biased character of the study (population not randomly selected), our data provide a valuable estimation of the prevalence of CINA in the general"
    explanation: >-
      The authors' own statement of the sampling limitation, quoted rather than
      paraphrased because it is the main reason to treat the rate as an
      estimate from one population and not a general prevalence.
- population: Adult women relative to adult men, Crete
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  notes: >-
    A sex ratio rather than a rate, recorded separately because it is a
    different claim from the overall prevalence and would be lost inside it.
    Two thirds of cases fell between 30 and 59 years, which is consistent with
    an acquired adult-onset disorder rather than a late-detected congenital
    one. No rate is given for either stratum, so none is recorded.
  evidence:
  - reference: PMID:10466440
    reference_title: "Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CINA was more frequent in women, with a women to men ratio of about 3:2."
    explanation: The female predominance in the screened population.
  - reference: PMID:10466440
    reference_title: "Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately two thirds of the cases appeared in patients aged 30-59 years."
    explanation: The age distribution, in the same screened population.
progression:
- phase: Long-term course
  notes: >-
    Benign in the medium term. Over a median three years of prospective
    follow-up there was no malignant evolution and no deaths, although infections
    of grade 2 or worse occurred in 42 per cent. Remission is common in children
    and rare in adults.
  evidence:
  - reference: PMID:39300133
    reference_title: "Natural history of chronic idiopathic neutropenia of the adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No malignant evolution nor deaths were observed."
    explanation: >-
      The outcome that matters most to a patient told they have an unexplained
      marrow abnormality. Three years is not long enough to settle the question,
      which is why the phase is described rather than called benign outright.
discussions:
- discussion_id: nonimmune_boundary_with_autoimmune_neutropenia
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is nonimmune chronic idiopathic neutropenia of adults separable from
    autoimmune neutropenia, and does the "nonimmune" qualifier still describe
    anything?
  attaches_to:
  - disease#Nonimmune Chronic Idiopathic Neutropenia of Adults
  - pathophysiology#Activation and Oligoclonal Expansion of Marrow T Lymphocytes
  rationale: >-
    The qualifier means "not antibody-mediated" and was coined to contrast with
    autoimmune neutropenia, but the mechanism curated here is T-cell driven, so
    the disease is immune in every sense except the serological one. Meanwhile
    the two are hard to separate in practice: the antineutrophil antibody assay
    is of uncertain value in both children and adults, the 2017 review calls them
    very similar and overlapping conditions, and the 2024 prospective cohort
    enrols CIN and autoimmune neutropenia together and describes the whole group
    as an immune attack on neutrophils. This entry is built on the cohorts that
    kept the distinction, and a reader should know that the most recent
    natural-history data do not. Whether MONDO should keep a separate nonimmune
    term is a real question, not a curation quibble.

    Two numbers sharpen this, and both are quotable from references already in
    this entry. In the 2024 prospective cohort 56 per cent of patients carried
    anti-neutrophil autoantibodies at baseline and 31 per cent had an
    autoimmune comorbidity; in the earlier review 44 per cent of the registry
    patients had some evidence of thyroid disease. A majority-seropositive
    cohort is not what the word "nonimmune" leads a reader to expect, and the
    figures belong in the gap rather than only in the reviewer's head.
  evidence:
  - reference: PMID:39300133
    reference_title: "Natural history of chronic idiopathic neutropenia of the adult."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At baseline, 56% had anti-neutrophil autoantibodies and 31% had autoimmune comorbidities."
    explanation: >-
      The serological and clinical autoimmune burden in the cohort that enrols
      CIN and autoimmune neutropenia together. Cited here to state the gap, not
      to reclassify the disease: the cohort's composition is exactly what makes
      the boundary question open.
  - reference: PMID:27841775
    reference_title: "An update on the diagnosis and treatment of chronic idiopathic neutropenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these patients, 95 (44%) had some evidence of thyroid disease."
    explanation: >-
      An independent autoimmune association in the registry population,
      reported by the review this entry's diagnostic section is built on.
- discussion_id: gfi1_relevance_to_the_adult_entity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does GFI1 belong on this disease at all?
  attaches_to:
  - genetic#GFI1
  rationale: >-
    OMIM attaches GFI1 to this concept and the curation stub inherited that
    association, but the primary report describes a congenital phenotype
    ascertained as ELANE-negative severe congenital neutropenia, with
    immunodeficient lymphocytes and circulating immature myeloid cells, acting by
    derepression of ELANE. None of that is the acquired adult disease whose
    mechanism the rest of this entry describes, and no GFI1 variant has been
    reported in a patient meeting the acquired-CIN definition. The gene is
    recorded with relationship_type SUSCEPTIBILITY and a note saying this, rather
    than being silently dropped or silently promoted to CAUSATIVE. Resolving it
    probably requires someone to decide whether the MONDO concept is the OMIM
    concept.

    A 2025 exome study of 25 non-remitting-neutropenia and adult-CIN patients
    is the first direct evidence on the question, and it points away from
    GFI1. The variants it retrieved sit in immune-regulation and autoimmunity
    genes, not in the myeloid differentiation programme GFI1 belongs to, and
    the paediatric and adult groups shared no genes with each other. That is
    the genetic shape this entry's pathophysiology predicts, since the lesion
    it models is a T-cell-and-cytokine marrow microenvironment rather than a
    granulocyte differentiation block. It is 25 subjects with no replication
    cohort, so it is cited as a directional result rather than as a gene list,
    and no gene from it is added to the genetic section.
  evidence:
  - reference: PMID:40725177
    reference_title: "Genetic Landscape of Non-Remitting Neutropenia in Children and Chronic Idiopathic Neutropenia in Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SPINK5, RELA and CARD11 were retrieved and seem to be consistent with the clinical picture characterized by neutropenia associated to immune dysregulation."
    explanation: >-
      The genes retrieved, and the authors' own reading of what they mean.
  - reference: PMID:40725177
    reference_title: "Genetic Landscape of Non-Remitting Neutropenia in Children and Chronic Idiopathic Neutropenia in Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the products of expression by the variants involved belong to the autoimmunity and immune regulation pathways (i.e., SPINK5, PTPN22 and PSMB9)"
    explanation: >-
      The pathway-level result from the enrichment and burden tests, which is
      the part that bears on whether GFI1 belongs here: the signal is in
      immune regulation, not in myeloid differentiation.
- discussion_id: telomere_shortening_cause_or_consequence
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the age-inappropriate telomere shortening a consequence of chronic
    proliferative stress, or a predisposing defect?
  attaches_to:
  - pathophysiology#Granulocyte Replicative Senescence
  rationale: >-
    The entry models it as downstream, because that is the reading the authors
    favour and because the shortening correlates with neutrophil count. But the
    data are cross-sectional and a correlation is compatible with either
    direction. The observation that the difference from controls is most
    prominent in patients under 50 is the one that would need explaining under
    the consequence model, since those patients have had the disease for less
    time. Telomerase activity was detected less often in patients than controls,
    which would fit a primary defect. No longitudinal data exist.
- discussion_id: clonal_hematopoiesis_overlay
  kind: KNOWLEDGE_GAP
  prompt: >-
    Are the somatic myeloid-gene mutations found in a fifth of patients a
    consequence of a chronically inflamed marrow niche, an incidental
    age-related finding, or a competing diagnosis?
  attaches_to:
  - diagnosis#Bone marrow examination
  rationale: >-
    A prospective cohort found somatic myeloid-gene mutations in 19 per cent of
    tested patients, associated with age. Clonal haematopoiesis at that frequency
    in an older cohort may be entirely incidental; it may equally be selection
    within a cytokine-rich marrow; or it may mean some of these patients have an
    unrecognised clonal cytopenia rather than this disease. The same cohort saw
    no malignant evolution in three years, which constrains but does not settle
    it. This entry does not model clonal haematopoiesis as part of the mechanism
    for that reason.
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (3)

Review round: converse-supporting snippet replaced, a false claim about the cache corrected, aphthous stomatitis added · 2026-09-12T04:33:40Z · View source

Both blocking findings taken, plus three of the suggestions. Blocking 1 - the Observation without treatment evidence supported the converse of its claim, and my explanation defended that with a false statement about the cache. It said the supporting sentence 'uses a superscript that cannot be quoted verbatim'. The cache stores the threshold as '0.5 x 10/l' with the superscript already stripped, and the sub-span 'most patients can be observed and not treated prophylactically with antibiotics or a growth factor' is an exact substring. I asserted something about repository state without checking it against repository state, which is the same class of error as the false 'no prevalence estimate exists' corrected earlier on this entry. The correct quote is now the primary evidence and covers both halves of the claim - no prophylactic antibiotics and no growth factor - which the old snippet did not touch at all. The converse sentence is retained as a second item, beside the statement it is the converse of rather than standing in for it, and the explanation records the error. One correction to the review: it asked for the false sentence to be removed from notes. The false sentence was in the evidence explanation, not in notes. The notes on that treatment concern NCIT:C15722 not being reachable from NCIT:C25218, which is accurate and unchanged. Blocking 2 - Recurrent aphthous stomatitis added, bound to HP:0011107, FREQUENT, anchored on 'Overall, recurrent aphthous stomatitis was observed in 45% of the patients.' The reviewer's reconstruction of why it was missing is correct and is recorded in the phenotype notes: the deep research report offered HP:0100279 for it, which is Ulcerative colitis - a real CURIE with the wrong concept under a plausible label. Rejecting the identifier was right; dropping the phenotype with it was not. Suggestions taken: - Severity distribution from PMID:39300133 on the neutropenia phenotype (median ANC 0.8, moderate 39 per cent, severe 24 per cent), which grounds the 0.5 x 10^9/L threshold the treatment section turns on. - Splenomegaly tension recorded rather than resolved: the 8 per cent figure from the larger prospective cohort added as a REFUTE against the FREQUENT band, with an explanation that the two are probably measuring different things (routine ultrasound versus clinical detection). The imaging-based band is kept. - The autoimmune burden added to the nonimmune_boundary_with_autoimmune_neutropenia discussion with two evidence items: 56 per cent anti-neutrophil autoantibodies and 31 per cent autoimmune comorbidity at baseline, and 44 per cent with thyroid disease in the registry population. A majority-seropositive cohort is not what 'nonimmune' leads a reader to expect, and the gap is the right place for it. Not taken: the mappings block. DiseaseMappings has slots only for icd10cm, icd11f, mondo and ncit, so OMIM 607847, ORPHA:2688 and GARD 16605 have nowhere to go. ICD-10-CM D70.8 could be recorded, but the reviewer's own lump/split note argues the predicate choice there is a real decision rather than bookkeeping, and making it inside a single-disease curation PR would bury it. Validation: just validate-disorders (schema, terms, 42/42 snippets, was 36/36); all eleven offline gates clean; bulk OLS id/label comparison over 21 pairs, 0 mismatches. No cache rows added.

Self-review: a false 'no prevalence estimate exists' claim, corrected from PMID:10466440 · 2026-09-11T14:28:44Z · View source

Self-review round run while claude-review was unavailable (shared Claude account usage limit, resets 2026-09-12T20:00Z). I applied the automated reviewer's finding shape from the other PRs in this batch - a deep-research source present in the report and absent from the YAML - and it found a false statement in my own entry. The correction. The prevalence block asserted 'No prevalence estimate exists', with a note explaining that the published cohorts are all referral-based. That was wrong, and the paper refuting it was sitting uncited in this entry's own research report. PMID:10466440 is a population screening study by the same Crete group whose referral cohorts this entry's pathophysiology is built on: 778 apparently healthy adults, of whom 8.23 per cent met their diagnostic criteria for CINA. The figure is now curated as POINT_PREVALENCE, ABOVE_1_IN_1000, rate_per_100000 8230, with three evidence items and a long note, because the number is easy to misread. None of the 64 had severe neutropenia; 6.81 per cent were mild and 1.41 per cent moderate. So 8.23 per cent is the prevalence of a screen-detected laboratory phenotype, not of the clinical disease that reaches a haematology clinic. The authors state their own sampling limitation and that sentence is quoted rather than paraphrased. No qualitative RARE/COMMON tier is recorded alongside the rate, per the prevalence conventions, and the reason is stated in the note rather than left implicit. A second prevalence record carries the sex ratio (3:2 female) and age distribution (two thirds aged 30-59) as a separate claim from the rate. Also from PMID:10466440: Chronic rhinitis as a phenotype (3.4 times more frequent in neutropenic subjects), curated with no upstream node and no sequela link, because the direction of the association is not established - chronic mucosal inflammation would sit upstream of the marrow inflammation this disease starts from as plausibly as downstream of the neutropenia. From PMID:40725177 (2025 exome study, 25 subjects): a second evidence item on the lymphopenia phenotype, with a proportion this time; and, on the gfi1_relevance_to_the_adult_entity discussion, the first direct genetic evidence bearing on that question. The variants retrieved are in immune-regulation and autoimmunity genes rather than in the myeloid differentiation programme GFI1 belongs to, which is the genetic shape this entry's pathophysiology predicts. Cited as a directional result; no gene from it was added to the genetic section, since it is 25 subjects with no replication cohort. PMID:18328744 was fetched and rejected: it is a murine GFI1 study in severe congenital neutropenia, which is the disease this entry argues it is not. Its cache was deleted rather than committed. One error of my own, caught before it reached the file: I first wrote HP:0000440 for Chronic rhinitis from memory. That CURIE does not resolve in HPO; the correct term is HP:0002257. This is the failure mode CLAUDE.md documents under 'Every CURIE is read from a source in the same step it is written', and it was caught only because the lookup is a habit rather than because anything flagged it. Validation: just validate-disorders (schema, terms, 36/36 snippets); check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-grading, check-title-snippets, check-snippet-length, check-reference-titles, check-environmental-evidence, check-folded-hyphens all clean; bulk OLS id/label comparison over 20 pairs, 0 mismatches. No cache rows added.

Create: Nonimmune_Chronic_Idiopathic_Neutropenia_of_Adults · 2026-09-11T13:14:04Z · View source

De novo curation of nonimmune chronic idiopathic neutropenia of adults (MONDO:0011922). DEEP-RESEARCH PROVIDER: the brief asked for perplexity; the account quota was exhausted mid-run (HTTP 401 insufficient_quota) after two of five reports. Re-run with just dr_fallback='--fallback' so the substitution is recorded in data rather than prose: research/Nonimmune_Chronic_Idiopathic_Neutropenia_of_Adults-deep-research-claude_code.md, requested_provider perplexity, fell_back true, 22 citations. Report reference_validation 13/13 resolved, 11/13 on topic; term_validation 3 of 7 labels mismatched (HP:0100279 offered as 'Recurrent aphthous stomatitis' when HPO calls it Ulcerative colitis). No CURIE taken from the report. The report contributed PMID:12517813, the Papadaki 2003 progenitor-apoptosis study, which is the single most important mechanism paper for this disease and which my relevance-sorted PubMed searches had not surfaced. SCOPE DECISION. The claim issue asked whether a diagnosis of exclusion has a conserved enough pathograph to be a Disease at all. It does, and the reason is recorded in the entry description: one sustained research programme has localised the defect to the committed CD34+/CD33+ granulocyte progenitor compartment specifically, with no excess apoptosis in the CD34+/CD33-, CD34-/CD33+ or mature neutrophil fractions. That compartment specificity is what makes it one disease rather than a label. Three things curated as awkward rather than smoothed over, each with a discussion entry: (1) 'nonimmune' means not-antibody-mediated, not not-immune - the mechanism is T-cell driven, and the most recent prospective cohort frames the whole entity as immune and enrols CIN and autoimmune neutropenia together, which undercuts the MONDO distinction this entry is named for; (2) GFI1, the gene OMIM attaches to this concept and the one the stub carried, comes from patients with a CONGENITAL phenotype ascertained as ELANE-negative severe congenital neutropenia, acting by ELANE derepression - a differentiation defect, not the progenitor-apoptosis mechanism of the adult disease - so it is recorded as SUSCEPTIBILITY with a note saying it may not belong on this record at all, rather than being silently promoted to CAUSATIVE or silently dropped; (3) the telomere shortening is modelled as downstream but the data are cross-sectional and compatible with either direction. No conforms_to. kb/modules/myelosuppression was read and rejected because it begins with a cytotoxic insult and ends in multilineage cytopenias, neither of which applies here. THREE FABRICATED CURIEs CAUGHT BEFORE VALIDATION. NCIT:C1428 written as 'Filgrastim' is Stavudine; NCIT:C15220 as 'Diagnostic Procedure' is Diagnosis Assessment; NCIT:C69141 as 'Watchful Waiting' is Curator. All three were written from recall rather than from a lookup performed in the same step, which is precisely the failure CLAUDE.md documents. They were caught by a bulk id/label checker run against OLS before just validate, added to the loop after two single instances of the same slip earlier in this run. Correct bindings are NCIT:C1474 Filgrastim and NCIT:C18020 Diagnostic Procedure. The third has no correct binding: NCIT:C15722 Patient Observation is the right concept but is not reachable from NCIT:C25218, so treatment_term carries preferred_term only, with a note saying why. Two further validation failures: ProgressionInfo has no 'description' slot (it has 'notes'), and NCIT:C15722 failed the TreatmentActionTerm dynamic enum as above. Evidence: 27 snippets across 9 PMIDs, all exact-quote verified. PMID:11202431 (HLA-DRB1*1302 association) was fetched but has no cached abstract text, so it is not cited and the HLA predisposition is not claimed in the entry. Validated with just validate (schema, terms, 27/27 snippets), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values.

Claude Code ▸
Nonimmune Chronic Idiopathic Neutropenia of Adults — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 22 citations 2026-09-11T13:01:53.004068

Nonimmune Chronic Idiopathic Neutropenia of Adults — Comprehensive Research Report

1. Disease Information

Overview and terminology (a critical naming caveat)

"Nonimmune Chronic Idiopathic Neutropenia of Adults" (NI‑CINA) names two overlapping but distinct concepts in the literature, and curators should be careful not to conflate them:

  1. OMIM #607847 "NEUTROPENIA, NONIMMUNE CHRONIC IDIOPATHIC, OF ADULTS" — a specific, rare, autosomal dominant Mendelian entity caused by a heterozygous missense mutation (N382S) in GFI1 (Growth Factor Independent 1 transcriptional repressor), reported in a single large multigenerational kindred by Person et al. (2003) (Nature Genetics; PubMed 12778173). This is the entity MONDO:0011922 formally maps to.
  2. "Chronic Idiopathic Neutropenia" (CIN) as a clinical syndrome — a much more commonly described, acquired, adult-onset, immune-microenvironment-mediated neutropenia (Papadaki and colleagues, University of Crete, and others), affecting a substantial minority of the general adult population, with no identified monogenic cause in the vast majority of cases. Confusingly, despite the "nonimmune" label, contemporary mechanistic work (see §6) shows this syndrome is driven by local bone-marrow T-lymphocyte/cytokine-mediated immune suppression of granulopoiesis — it is "nonimmune" only in the narrower sense of lacking demonstrable anti-neutrophil autoantibodies against circulating/mature neutrophils, distinguishing it from classic autoimmune neutropenia (AIN).

Most of the epidemiological, mechanistic, natural-history, and treatment literature available (and cited below) is about sense 2 (the clinical syndrome), because the GFI1 kindred (sense 1) is a single reported family. A curator populating a KB entry under MONDO:0011922 should decide explicitly whether the entry models the GFI1 monogenic disorder, the broader acquired clinical syndrome, or both with clear differentiation — this is a genuine lump/split judgment call, not a research gap that more literature searching will resolve.

Key identifiers

  • MONDO: 0011922
  • OMIM: #607847 (omim.org/entry/607847)
  • Orphanet: ORPHA:2688 (orpha.net/en/disease/detail/2688)
  • GARD (NIH): Disease ID 16605
  • ICD-10-CM: D70.8 (Other neutropenia) is the most specific code for a defined idiopathic/chronic neutropenia; D70.9 (Neutropenia, unspecified) is used when no further specification is coded (icd10data.com D70)
  • Causal gene (GFI1-associated form): GFI1, HGNC:4238, OMIM *600871

Synonyms

  • NI-CINA
  • Adult idiopathic neutropenia
  • Chronic idiopathic neutropenia (CIN) of adults
  • Chronic benign neutropenia of adults (used loosely, though CIN is not formally classified as "benign" congenital neutropenia)

Source of information

Nearly all clinical and mechanistic data derive from aggregated disease-level cohort studies and case series (notably a multi-decade Cretan cohort under H. A. Papadaki, and a recent French prospective CYTOPAN study, NCT05931718), not individual EHR mining. The Person et al. 2003 genetic report derives from a single multigenerational pedigree.

2. Etiology

Disease causal factors

  • GFI1-associated monogenic form (OMIM #607847): heterozygous GFI1 c.1145A>G (p.Asn382Ser, N382S) mutation, autosomal dominant, reported in one large kindred with variably mild-to-moderate neutropenia across generations (Person et al. 2003, Nat Genet 33:373-377, PMID 12778173). N382S disrupts GFI1's zinc-finger DNA-binding domain, producing a dominant-negative effect on GFI1 target-gene repression.
  • Sporadic/acquired CIN (the more common syndrome): cause remains formally "idiopathic" — no infectious, drug, autoimmune-systemic, or malignant etiology is identifiable. Emerging evidence (see §6) implicates a chronic, low-grade, polyclonal T-lymphocyte-driven inflammatory bone-marrow microenvironment, not a primary marrow stem-cell defect.
  • A recent whole-exome sequencing comparison of pediatric non-remitting neutropenia vs. adult CIN (Genetic Landscape study, PMID 40725177, 2025) found candidate rare variants in SPINK5, BRCA1, RELA, and CARD11 in individual cases, and enrichment of rare variants in PTPN22, PSMB9, and MYOF, implicating innate/adaptive immune-regulatory pathways rather than a shared monogenic cause; pediatric and adult cohorts shared no common causal variants, supporting a polygenic/complex rather than Mendelian model for most adult CIN.

Risk factors

Genetic: - Heterozygous GFI1 N382S (family-specific; autosomal dominant) for the OMIM entity. - HLA class II susceptibility: increased frequency of HLA-DRB1*1302 haplotype reported in NI-CINA patients (Papadaki et al., Blood 97:580, ashpublications.org/blood/article/97/2/580) — evidence of an immunogenetic (HLA class II) predisposition to the acquired syndrome. - Age-related clonal hematopoiesis (CHIP): somatic mutations in DNMT3A, TET2, IDH1/2, RNA-splicing genes (SRSF2, ZRSR2), and an ETV6-CHIC2 rearrangement detected in ~19% of tested CIN patients, strongly age-associated (median 68 vs. 51 years in mutated vs. non-mutated, p=0.002) (Scientific Reports 2024, PMID via PMC11412994). TET2 mutations specifically carry a modest independent neutropenic effect (~9%, p=0.012) in general CHIP cohorts.

Environmental/demographic: - Sex: strong female predominance (women:men ≈ 3:2 to as high as 77% female in the largest prospective cohort). - Age: typically diagnosed in adulthood; roughly two-thirds of cases occur between ages 30–59, though the largest reclassification cohort (n=266) spanned ages 19–92 (median 61). - Ancestry: baseline population prevalence differs by ancestry group for "benign ethnic neutropenia," a condition that must be excluded (see Diagnostics); this is now formally reclassified as ADAN (absolute neutrophil count [ANC] Duffy-Associated Neutropenia) in the newest nosology, not part of true CIN.

Protective factors

No specific genetic or environmental protective factors have been established in the literature for this condition; it is not modeled as a disease with known protective alleles or exposures.

Gene-environment interactions

Not characterized specifically for CIN; the leading model is intrinsic bone-marrow immune dysregulation (HLA-linked genetic susceptibility interacting with an unidentified triggering low-grade inflammatory process) rather than a defined exogenous exposure interacting with genotype.

3. Phenotypes

Core hematologic finding

  • Chronic neutropenia, defined by most recent series as ANC persistently <1.5 × 10⁹/L on ≥3 occasions over ≥3 months (some define using a lower ULN cutoff, e.g., <1.8 ×10⁹/L, adjusted for ancestry to exclude ADAN/benign ethnic neutropenia).
  • Suggested HPO term: HP:0001875 (Neutropenia)
  • Severity distribution (French CYTOPAN cohort, n=131): median ANC 0.8 ×10⁹/L; moderate (<1×10⁹/L) in 39%; severe (<0.5×10⁹/L) in 24% (PMC11412994).
  • Onset: adult-onset (median age 55–61 years across cohorts), though can be diagnosed earlier.
  • Course: chronic, typically stable/non-progressive; a subset show spontaneous partial recovery.

Mucocutaneous/oral phenotypes

  • Recurrent aphthous stomatitis — frequent, characteristic feature. HPO: HP:0100279 (Recurrent aphthous stomatitis).
  • Exaggerated/severe gingivitis, aggressive periodontitis, premature exfoliation of primary dentition (pediatric-onset overlap syndromes). HPO: HP:0000230 (Gingivitis).
  • Recurrent mild bacterial infections (skin, upper respiratory, oral) — generally not life-threatening. HPO candidate: HP:0002718 (Recurrent infections).

Immunologic/laboratory phenotypes

  • Increased proportions of activated bone-marrow T-lymphocytes (HLA-DR+, CD25+, CD38+, CD69+, Fas+).
  • Immunoglobulin disturbances, lymphopenia, reduced memory B cells.
  • Altered monocyte subsets (Bizymi et al., PMC6863791).
  • Anti-neutrophil autoantibodies: positive in a substantial minority when tested (56% in one cohort) — presence does not correlate with distinct clinical severity or prognosis, undermining the traditional CIN-vs-AIN dichotomy.
  • Splenomegaly (~8%) and lymphadenopathy (~5%) in a minority.
  • Autoimmune comorbidities (thyroiditis, Sjögren's syndrome) in ~31% of one cohort — raising the question of whether "isolated" CIN and organ-specific autoimmunity share a predisposing immunogenetic background.

Frequency/severity table (from the largest prospective natural-history cohort, n=131, PMC11412994)

Feature Frequency
Moderate neutropenia (<1×10⁹/L) 39%
Severe neutropenia (<0.5×10⁹/L) 24%
Anti-neutrophil autoantibody positive 56% (57/102 tested)
Autoimmune comorbidity 31%
Splenomegaly 8%
Lymphadenopathy 5%
Grade >1 infection pre-enrollment 26%
Grade >1 infection during 3-yr follow-up 28% (0.09/person-year)
Grade ≥3 infection during follow-up 10%

Quality of life

No dedicated disease-specific QoL instrument identified in the literature; general infection burden is low, and the largest natural history study explicitly characterizes the condition as benign with minimal life impact for most patients, aside from anxiety related to chronic laboratory abnormality and periodic hematologic surveillance.

4. Genetic/Molecular Information

Causal gene (Mendelian form)

  • GFI1 (Growth Factor Independent 1 transcriptional repressor), HGNC:4238, chromosome 1p22.
  • Variant: c.1145A>G, p.Asn382Ser (N382S), heterozygous, missense, located in the C-terminal zinc-finger DNA-binding domain.
  • Classification: dominant-negative; disrupts GFI1 DNA binding.
  • Mechanism: GFI1 normally represses transcription of ELANE (ELA2, neutrophil elastase). The N382S mutant fails to repress ELANE, and quantitative RT-PCR showed elevated ELA2 expression in myeloid colonies from an affected family member vs. an unaffected relative — mechanistically linking GFI1 and ELANE (the gene mutated in classic severe congenital neutropenia / ELANE-related neutropenia) in a shared pathway (Person et al. 2003, Nature Genetics).
  • Functional studies in murine systems confirm that GFI1 disease mutations produce a dominant-negative block to granulopoiesis via murine colony-stimulating factor–responsive assays (PMID 18328744).

Somatic/clonal findings in the acquired syndrome

  • Clonal hematopoiesis detected in ~19% of a genotyped cohort (n=36): DNMT3A, TET2, IDH1, and an ETV6-CHIC2 rearrangement, VAF range 4.6–18.8%.
  • Longitudinal studies show these clones are generally stable over time with limited VAF expansion (P836 abstract, PMC9430755).
  • Clonal hematopoiesis (CH) confers markedly increased relative risk (RR ≈ 31.24) for progression to overt MDS/AML compared with non-clonal CIN, particularly with IDH1/2, splicing-gene (SRSF2, ZRSR2), or combined age-related CH gene mutations, and when VAF >10%.
  • No progression to myeloid neoplasm was observed during the follow-up period of the largest prospective natural history study, despite the presence of clonal mutations — underscoring that CH in this context is a risk marker requiring surveillance, not a diagnostic pivot to malignancy at baseline.
  • No shared causal genetic variant was found between pediatric non-remitting neutropenia and adult CIN in a comparative WES study, and candidate immune-regulatory gene variants (SPINK5, BRCA1, RELA, CARD11, PTPN22, PSMB9, MYOF) were individually rare, supporting complex/polygenic rather than monogenic causation for most adult CIN (PMID 40725177).

Allele frequency / population genetics

No population allele-frequency data are available for the GFI1 N382S variant beyond the single reported kindred (not present in large population databases such as gnomAD, consistent with a private, family-specific variant).

Epigenetic information

  • Abnormal, age-inappropriate telomere shortening of peripheral-blood mononuclear cells and granulocytes has been demonstrated in CIN patients, with significantly lower telomerase activity frequency vs. controls, and granulocyte telomere length correlating with ANC (Pavlaki et al. 2012, Haematologica 97:743-750, PMC3342978). This suggests replicative/senescence stress on the granulocytic compartment, likely secondary to chronic immune-mediated marrow suppression rather than a primary telomere-biology disorder.

5. Environmental Information

No specific toxin, occupational, radiation, or infectious agent has been established as causal for CIN; by definition, secondary causes (drugs, infections, known autoimmune/rheumatologic disease, malignancy) are excluded prior to diagnosis. Environmental/lifestyle contributions are not characterized in the literature reviewed; this remains an area without mechanistic data (a legitimate knowledge gap to record rather than a search failure).

6. Mechanism / Pathophysiology

Ordered causal chain (acquired/sporadic CIN — the dominant mechanistic model)

  1. An HLA class II-linked immunogenetic predisposition (notably increased frequency of HLA-DRB1*1302) predisposes to an unidentified triggering process that establishes a localized, low-grade chronic inflammatory reaction within the bone-marrow microenvironment — inferred from HLA association studies rather than directly observed at the trigger step.
  2. This inflammatory state leads to activation and clonal/oligoclonal expansion of CD3+ T-lymphocytes within the bone marrow, marked by increased HLA-DR+, CD25+, CD38+, CD69+, and Fas+ expression on the T-cell fraction (demonstrated directly by immunophenotyping of marrow aspirates).
  3. Activated marrow T-lymphocytes (not CD14+ monocyte/macrophages) produce myelosuppressive cytokines — IFN-γ, Fas-ligand, TNF-α (and soluble TNF-RI), IL-1β, IL-6, IL-8, RANTES/CCL5, and TGF-β1 — demonstrated by cytokine profiling of bone-marrow stromal/mononuclear supernatants, with levels correlating with neutropenia severity.
  4. These cytokines result in Fas-mediated apoptosis of CD34+/CD33+ myeloid progenitor cells, evidenced by a low percentage of CD34+/CD33+ cells associated with accelerated apoptosis and Fas overexpression in that compartment, and by an inverse correlation between bone-marrow stromal TNF-α production and progenitor cell numbers (directly demonstrated: Papadaki et al., Blood 101:2591-2600, PMID 12517813).
  5. Accelerated progenitor apoptosis causes impaired granulocytopoiesis — reduced myeloid colony formation in vitro and (in a subset) a late maturation-arrest pattern on bone-marrow morphology, though whether the arrest reflects a genuine terminal differentiation block or increased peripheral release of mature cells from marrow remains unresolved (inferred/uncertain, per the largest series' own characterization).
  6. Chronically stressed, apoptosis-prone granulocytic precursors show premature replicative senescence, reflected in abnormal telomere shortening and reduced telomerase activity of granulocytes, correlating with ANC — a downstream cellular consequence rather than an independent causal branch.
  7. The net effect manifests clinically as persistent peripheral neutropenia with recurrent mild mucosal/bacterial infections and aphthous stomatitis.
  8. Branch — clonal hematopoiesis overlay: in a subset of (typically older) patients, age-related somatic mutations (DNMT3A, TET2, IDH1/2, splicing genes) arise independently in hematopoietic stem/progenitor cells within this chronically stressed, cytokine-rich marrow niche; most clones remain stable, but higher-risk mutations (IDH1/2, spliceosome genes, VAF >10%) predispose to eventual clonal evolution toward MDS/AML — a distinct, age-dependent risk pathway layered on top of the primary immune-mediated mechanism rather than its direct consequence.

GFI1-associated (Mendelian) branch, mechanistically distinct: heterozygous dominant-negative GFI1 N382S impairs GFI1's transcriptional repression of its target genes, in particular derepressing ELANE (neutrophil elastase) expression in myeloid progenitors, which disrupts normal granulocytic differentiation — paralleling (but molecularly distinct from) the ELANE-mutant mechanism of classic severe congenital neutropenia. Murine Gfi1-null models independently confirm that loss of Gfi1 function blocks granulocytic maturation, causing accumulation of an atypical immature myelomonocytic population, severe neutropenia, and relative monocytosis.

Molecular pathways

  • GFI1 → ELANE repression axis (GFI1 as an upstream transcriptional repressor of neutrophil elastase; suggested GO term: GO:0030851, granulocyte differentiation; also GO:0045892, negative regulation of DNA-templated transcription).
  • Fas/FasL apoptotic signaling in myeloid progenitors (GO:0007165 signal transduction; GO:0006915 apoptotic process; GO:0036462 TRAIL-activated apoptotic signaling pathway is a related but not identical pathway — Fas pathway is more precisely GO:0097191, extrinsic apoptotic signaling pathway).
  • TNF-α / TNFR1 signaling suppressing granulopoiesis.
  • IFN-γ–JAK/STAT signaling in the marrow T-cell compartment.

Cellular processes

  • Increased apoptosis of CD34+/CD33+ myeloid progenitors (GO:0006915 apoptotic process; GO:0043069 negative regulation of programmed cell death is inversely relevant).
  • T-lymphocyte activation (GO:0042110 T cell activation).
  • Impaired granulocyte colony formation / granulocytopoiesis (GO:0030851).
  • Cellular senescence of the granulocytic lineage, reflected by telomere attrition (GO:0090399 replicative senescence).

Protein dysfunction

  • GFI1 N382S: loss of normal zinc-finger DNA-binding function → dominant-negative transcriptional dysregulation (loss of repressor activity at target loci, notably ELANE).

Immune system involvement

Central to the acquired form: bone-marrow-localized T-cell-mediated immune dysregulation causing paracrine myelosuppression (not classic autoantibody-mediated peripheral neutrophil destruction, which instead characterizes primary autoimmune neutropenia, AIN — a related but formally distinct diagnosis in current nosology).

Tissue damage mechanisms

Cytokine-driven apoptosis is the principal damage mechanism (no fibrosis or necrosis reported as primary features; marrow fibrosis grade MF-1/2 was noted incidentally in 16% of one large cohort but is not considered a defining pathophysiologic feature).

Molecular profiling

  • Cytokine/transcriptomic profiling of bone-marrow stromal and mononuclear cell supernatants: elevated IL-1β, IL-6, TGF-β1, IL-8, RANTES/CCL5, TNF-α, sTNF-RI (Papadaki et al., multiple studies).
  • Whole-exome sequencing in a small comparative cohort (25 subjects total) identified candidate rare variants without a shared adult-cohort signature (PMC12295308).
  • NGS myeloid gene panels in the largest prospective series (n=36 tested of 266-patient reclassification cohort) identified somatic clonal mutations in 19–7/36 tested patients.

Suggested ontology terms for pathophysiology curation

  • GO:0030851 granulocyte differentiation
  • GO:0002548 monocyte chemotaxis (context: altered monocyte subsets)
  • GO:0006915 apoptotic process
  • GO:0042110 T cell activation
  • CL:0000094 granulocyte; CL:0000576 monocyte; CL:0000084 T cell; CL:0000838 lineage-negative hematopoietic progenitor cell (myeloid progenitor, CD34+/CD33+)
  • CL:0002191 granulocyte monocyte progenitor cell

7. Anatomical Structures Affected

  • Primary organ: bone marrow (UBERON:0002371) — site of the T-cell/cytokine-mediated myelosuppression and impaired granulocytopoiesis.
  • Secondary/peripheral: peripheral blood (UBERON:0000178) — site of the resultant neutropenia; oral mucosa (UBERON:0006920) — site of recurrent aphthous stomatitis and gingivitis; spleen (UBERON:0002106) — mild splenomegaly in a minority.
  • Cellular targets: myeloid progenitor cells / granulocyte-monocyte progenitors (CD34+/CD33+) in bone marrow; mature circulating neutrophils (target of autoantibodies in the antibody-positive subset); bone-marrow T-lymphocytes (site of aberrant activation, the proximate immune effector).
  • Subcellular: no specific organelle-level pathology reported; apoptotic (mitochondrial/Fas-extrinsic) pathway activation in progenitor cells is implicated at the biochemical level.
  • Laterality: not applicable (systemic hematologic disorder).

8. Temporal Development

  • Onset: adult-onset by definition; median age at diagnosis 55–61 years across the largest cohorts, though range spans 19–93 years.
  • Onset pattern: insidious/chronic; typically detected incidentally on routine complete blood count rather than through acute symptomatic presentation.
  • Course: chronic and generally stable, non-progressive in the majority; a subset shows spontaneous partial recovery of ANC over time regardless of anti-neutrophil antibody status.
  • Progression: low overall rate of clinical worsening; infection frequency does not correlate with baseline neutropenia severity, antibody status, or demographics in the largest longitudinal study.
  • Critical branch point: presence and molecular class of clonal hematopoiesis (IDH1/2, spliceosome genes, VAF>10%) identifies a subset at meaningfully higher risk of eventual clonal evolution to MDS/AML — this is the key prognostic inflection point identified in recent literature, distinguishing "benign stable CIN" from "CIN with high-risk CH" as a quasi-distinct disease trajectory.
  • Remission: spontaneous, partial ANC normalization reported in some patients over years of follow-up; no treatment-induced remission is described as curative (G-CSF is supportive, not disease-modifying).

9. Inheritance and Population

Epidemiology

  • Prevalence: the classic Cretan population screening study found 8.23% of an apparently healthy adult population fulfilled CIN diagnostic criteria on repeated testing (Ann Hematol, PMID 10466440) — a strikingly high figure reflecting broad screening criteria in a specific population, and should be treated cautiously as an upper-bound/local estimate rather than a global prevalence. Some general sources cite population estimates around 1% in White and up to 5% in Black populations for "idiopathic"/benign neutropenia broadly (note: much of the Black-population estimate reflects benign ethnic neutropenia / ADAN, which is now nosologically separated from true CIN in current classification schemes — see §10).
  • Incidence: not separately reported as an incidence rate; CIN is typically described via point-prevalence in screened or referred cohorts.

Inheritance (GFI1-associated form)

  • Pattern: autosomal dominant.
  • Penetrance: appears high within the reported kindred but severity is variable across generations (variable expressivity).
  • Anticipation, mosaicism, founder effects: not reported/characterized for this single-family variant.

Inheritance (sporadic CIN)

  • Not Mendelian; HLA-DRB1*1302 association indicates a polygenic/immunogenetic susceptibility rather than a single-gene inheritance pattern. A minority of the reclassified large cohort (6.8%) were ultimately characterized as "familial with undefined genetic defect," indicating unresolved heritable components in some cases.

Population demographics

  • Sex ratio: strong female predominance, ~3:2 to 77:23 (F:M) across cohorts.
  • Age distribution: predominantly middle-aged to older adults (median 55–61 years); ~two-thirds of cases aged 30–59 in earlier series.
  • Geographic/ancestry notes: original large descriptive cohorts are heavily Greek/Cretan (single-center, potential ascertainment bias); newer reclassification work (French CYTOPAN cohort) broadens the geographic base. Ancestry-specific normal ANC ranges (relevant to excluding ADAN/benign ethnic neutropenia, historically overrepresented in individuals of African ancestry) must be applied before diagnosing true CIN.

10. Diagnostics

Diagnostic criteria

  • ANC persistently <1.5 ×10⁹/L (adjusted for ancestry-specific normal ranges) on ≥3 occasions over a ≥3-month period, with exclusion of drug-induced, infectious, autoimmune-systemic, congenital, and malignant causes.

Laboratory tests

  • Serial CBC with differential to establish chronicity and exclude cyclic neutropenia (which requires serial counts 2–3×/week over 6 weeks to detect ~21-day periodicity).
  • Anti-neutrophil autoantibody testing (GIFT/GIIFT assays) — recommended in patients with ANC <1×10⁹/L, with re-testing of initially negative results, per current European guidelines cited in the natural-history study.
  • Immunoglobulin levels, ANA, and rheumatologic serologies to screen for underlying autoimmune disease.

Bone marrow evaluation

Recommended as part of a "proper" diagnostic workup (per recent guideline-referencing literature): morphology (looking for the late maturation-arrest pattern seen in a subset), flow cytometry, cytogenetics, and immunohistochemistry (IgG/IgM/C3/C4d deposition patterns, reported present in >80% of biopsies in the largest cohort — notably, patients with negative C3 deposition had significantly higher baseline ANC, p<0.01).

Genetic/molecular testing

  • NGS myeloid gene panel to detect clonal hematopoiesis (DNMT3A, TET2, IDH1/2, ASXL1, splicing genes, ETV6 rearrangements) — recommended especially in older patients, given prognostic implications for MDS/AML risk.
  • Targeted GFI1 (and ELANE) sequencing should be considered when there is a clear autosomal-dominant family history consistent with the Mendelian entity, or overlapping features with congenital neutropenia.
  • Newer machine-learning-assisted diagnostic/prognostic tools are emerging from large-cohort reclassification work (Tsaknakis et al., 266-patient cohort, Blood 2025) to better stratify patients labeled CIN into true CIN, CCUS, primary AIN, familial undefined, ADAN, secondary neutropenia, and unrecognized severe congenital neutropenia.

Differential diagnosis (reclassification data from the largest cohort, n=266)

Final classification % of cohort
True CIN 66.5%
Clonal cytopenia of undetermined significance (CCUS) 12.8%
Primary autoimmune neutropenia (pAIN) 6.0%
Familial, undefined genetic defect 6.8%
ADAN (ethnic neutropenia) 1.1%
Secondary neutropenia 4.5%
Severe congenital neutropenia (previously missed) 2.2%

This reclassification data (from Tsaknakis et al., ASH abstract, Blood 2025) is directly relevant to knowledge-base curation: roughly a third of patients historically labeled "CIN" carry a more specific diagnosis on thorough re-evaluation, underscoring that "idiopathic" is a diagnosis of exclusion that shrinks as diagnostic tools improve — a live nosological caveat rather than settled fact.

Screening

No population-level or newborn screening program exists for CIN; diagnosis is reactive, based on incidental or symptom-triggered CBC abnormalities.

11. Outcome/Prognosis

  • Mortality: minimal and not disease-attributable — in the largest prospective cohort (n=131, median 3-year follow-up), only 2 deaths occurred (myocardial infarction, colorectal cancer), unrelated to neutropenia.
  • Malignant transformation: zero cases of evolution to hematologic malignancy in the largest prospective natural-history cohort despite clonal hematopoiesis findings in a subset; however, retrospective/cross-sectional data on clonal-hematopoiesis-positive CIN patients show a substantially elevated relative risk (~31×) for eventual MDS/AML transformation versus non-clonal CIN, particularly with high-risk mutation classes (IDH1/2, spliceosome genes) or VAF >10%.
  • Infection burden: low; grade ≥3 infections occurred in only 10% of patients over 3-year follow-up, with no correlation to neutropenia severity, demographics, or antibody status — an important and somewhat counterintuitive finding, suggesting ANC threshold alone is a poor infection-risk predictor in this specific syndrome (unlike classic congenital/chemotherapy-induced neutropenia).
  • Overall characterization: the condition is repeatedly described in the primary literature as a "benign condition without life-threatening infections" warranting extensive hematologic evaluation (including bone marrow assessment) primarily to inform differential diagnosis and identify the clonal-hematopoiesis-positive subset needing surveillance, rather than because the baseline course itself is dangerous.
  • Prognostic factors: presence/class of clonal hematopoiesis mutation and VAF; older age (associated with higher CH prevalence); negative marrow C3 deposition (associated with higher baseline ANC, i.e., milder disease).

12. Treatment

Pharmacotherapy

  • Granulocyte colony-stimulating factor (G-CSF, filgrastim): the primary specific pharmacologic intervention, but used sparingly in practice — only 4.6% of patients in the largest natural-history cohort received G-CSF, and only 2 patients (of 131) received it chronically, reflecting the generally low infection burden and benign course.
  • Dosing: typically initiated at ~3 μg/kg subcutaneously daily, titrated to a target ANC of 1,500–2,000/μL; patients with cyclic/idiopathic neutropenia generally respond at lower doses than those with congenital neutropenia.
  • Long-term safety: no loss of efficacy with prolonged use reported; long-term G-CSF use does not appear to independently increase AML risk in this population, though caution/monitoring is still advised given the theoretical concern (relevant NCIT term: NCIT:C1177, Filgrastim; treatment action NCIT:C15986, Pharmacotherapy).
  • Corticosteroids/immunosuppressants: current expert recommendation, per the recent natural-history study, is to avoid steroids unless there is a clearly established co-existing autoimmune diagnosis — reflecting the recognition that antibody positivity alone does not warrant immunosuppression given no demonstrated prognostic benefit.
  • Ezatiostat (TLK199), a glutathione S-transferase P1-1 inhibitor, has shown case-report efficacy in G-CSF-resistant idiopathic chronic neutropenia (PMC3235963) — an investigational/off-label approach for refractory cases, not a standard-of-care agent.

Surgical/interventional

Not applicable as primary therapy; splenectomy is not indicated for isolated CIN (contrasts with some AIN/hypersplenism-associated cytopenias).

Supportive care

  • Dental/oral hygiene surveillance and management of recurrent aphthous stomatitis and gingivitis.
  • Antibiotic therapy for documented infections; no evidence supports prophylactic antibiotics in the absence of severe/recurrent infection.

Experimental

Registered trial: CYTOPAN (NCT05931718), the French prospective observational study underlying much of the modern natural-history and immunohistochemistry data cited above.

Treatment strategy

Because infection risk correlates poorly with ANC severity in this specific syndrome, treatment is generally symptom- and infection-triggered rather than ANC-threshold-triggered — a notable departure from management paradigms for congenital or chemotherapy-induced neutropenia, and a point worth explicit note in a KB treatments: block or notes:.

13. Prevention

No primary, secondary, or tertiary prevention strategies are described in the literature, consistent with CIN's idiopathic/immune-microenvironmental etiology and lack of an identified modifiable environmental trigger. Genetic counseling is relevant only for the rare GFI1-associated autosomal dominant kindred (risk assessment for at-risk relatives, prenatal/preimplantation testing not reported as utilized). No vaccination-based, screening-based, or public-health-level prevention approach applies.

14. Other Species / Natural Disease

  • Mouse (Mus musculus, NCBITaxon:10090): Gfi1-null mice are severely neutropenic, showing a block in myeloid differentiation with accumulation of an atypical immature myelomonocytic population, absence of mature granulocytes, and relative monocytosis — directly recapitulating the human GFI1-mutant neutropenia phenotype at the level of blocked granulopoiesis (though via null rather than dominant-negative mechanism in most mouse models). Gfi1 knock-in models bearing SCN-associated point mutations further reveal stage-specific Gfi1-dependent checkpoints in myeloid development.
  • No naturally occurring veterinary disease analog specific to GFI1-mutant or Papadaki-type immune-mediated adult CIN was identified in this search (distinct from canine cyclic neutropenia/"grey collie syndrome," which is an ELANE-pathway, not GFI1-pathway, disorder and a different clinical entity).
  • Orthologous gene: murine Gfi1 (MGI:95662), human GFI1 ortholog, high evolutionary conservation of the zinc-finger repressor domain relevant to the N382S mutation.

15. Model Organisms

Model Type Genetic modification Recapitulation Key resource
Mouse (Gfi1⁻/⁻) Genetic knockout Complete Gfi1 loss Severe neutropenia, block in granulocytic differentiation, immature myelomonocytic accumulation MGI
Mouse (Gfi1 knock-in, SCN mutations) Genetic knock-in Point mutations modeling human SCN-associated GFI1 alleles Stage-specific block in granulopoiesis; used to dissect differentiation checkpoints Blood ASH abstract
Mouse (reduced Gfi1 expression, hypomorphic) Genetic (dose-dependent) Partial Gfi1 reduction (not full deficiency) Distinct from full knockout: causes a fatal myeloproliferative disease rather than isolated neutropenia — illustrating that GFI1 dosage, not just presence/absence, determines phenotype (Leukemia, Nature)
Human iPSC/primary CD34+ progenitor cultures In vitro Patient-derived or CRISPR-edited GFI1/ELANE variants Used to demonstrate elevated ELA2 (ELANE) expression consequent to GFI1 N382S Person et al. 2003

Model limitations: the complete Gfi1 knockout is a more severe phenotype than the human heterozygous dominant-negative N382S carrier state (variable, generally milder neutropenia in the reported kindred), and murine models do not capture the T-cell/cytokine-driven immune-microenvironmental mechanism believed to underlie the far more common sporadic/acquired CIN syndrome — there is currently no established animal model for the acquired, HLA-linked, T-cell-mediated form of adult CIN, which is a genuine translational gap rather than an unsearched area.

Summary of Key Citations (PMID-first where available)

  • Person RE et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet 2003;33:373-377. PMID 12778173 / Nature Genetics
  • Papadaki HA et al. Non-immune chronic idiopathic neutropenia of adult: an overview. Eur J Haematol 2001;66:1-8. PMID 11553265
  • Papadaki HA et al. Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells. Blood 2003;101:2591-2600. PMID 12517813
  • Papadaki HA et al. Increased frequency of HLA-DRB11302 haplotype in patients with nonimmune chronic idiopathic neutropenia of adults. Blood* 2001;97:580-582. ashpublications.org
  • Pavlaki KI et al. Abnormal telomere shortening of peripheral blood mononuclear cells and granulocytes in patients with chronic idiopathic neutropenia. Haematologica 2012;97:743-750. PMC3342978
  • Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete. Ann Hematol 1999. PMID 10466440
  • Natural history of chronic idiopathic neutropenia of the adult. Sci Rep 2024. nature.com/articles/s41598-024-71719-2 / PMC11412994
  • Severe chronic primary neutropenia in adults: report on a series of 108 patients. Blood 2015;126:1643-1651. ashpublications.org
  • Genetic Landscape of Non-Remitting Neutropenia in Children and Chronic Idiopathic Neutropenia in Adults. 2025. PMID 40725177. PMC12295308
  • Tsaknakis et al. Novel diagnostic and prognostic tools for patients with chronic idiopathic neutropenia: Data on a cohort of 266 patients. Blood 2025;146(Suppl 1):623. ashpublications.org
  • Long-term dynamics of clonal hematopoiesis in chronic idiopathic neutropenia (CIN). PMC9430755
  • Bizymi N et al. Altered Monocyte Subsets in Patients with Chronic Idiopathic Neutropenia. 2019. PMC6863791
  • Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative disease in mice. Leukemia 2018. PMC6326955

Curatorial note on gaps and ambiguities (explicitly flagged, not silently omitted)

  1. Scope decision required: whether the dismech entry under MONDO:0011922 should center on the GFI1 monogenic kindred (matching the strict OMIM title), the broad acquired CIN syndrome (matching nearly all available mechanistic/epidemiologic/treatment literature), or both with clear has_subtypes separation — this is a lump/split call, not resolved by further search, and should be checked against docs/explanation/design-decisions.md and the granularity conventions before curation begins.
  2. Bone-marrow maturation-arrest pattern: whether it reflects a true terminal differentiation block or increased marrow release of mature cells is explicitly stated as unresolved in the primary literature — should be modeled as a HUMAN_MODEL_MISMATCH/knowledge-gap-flavored uncertainty, not asserted as settled mechanism.
  3. No animal model exists for the T-cell/cytokine-driven acquired form — only the Mendelian GFI1 form has a validated murine model; this asymmetry should be reflected honestly in any animal_models: block.
  4. Prevalence figures are population/cohort-specific (8.23% Cretan screening cohort vs. more conservative "~1% White/~5% Black" general estimates, the latter partly confounded by ADAN/ethnic-neutropenia inclusion) — a single number should not be asserted without qualifying the source population.

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All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 30
Resolved 27
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 7
Terms named correctly 1
Terms named as a different term 3
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0100279 (1 mention) - the report calls it "Recurrent aphthous stomatitis"; HP calls it Ulcerative colitis
  • GO:0030851 (3 mentions) - the report calls it "Impaired granulocyte colony formation / granulocytopoiesis"; GO calls it granulocyte differentiation
  • UBERON:0000178 (1 mention) - the report calls it "Secondary/peripheral: peripheral blood"; UBERON calls it blood**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001875 (1 mention) - the report calls it "Neutropenia"; HP calls it Decreased total neutrophil count, and lists "Neutropenia" among its other names
  • HP:0002718 (1 mention) - the report calls it "Recurrent infections"; HP calls it Recurrent bacterial infections, and lists "Recurrent pyogenic infections" among its other names
  • UBERON:0002371 (1 mention) - the report calls it "bone marrow", "Primary organ: bone marrow"; UBERON calls it bone marrow

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • UBERON:0002371 - called "bone marrow", "Primary organ: bone marrow"
  • MGI:95662 - called "Gfi1", "Orthologous gene:* murine Gfi1"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.