Cyclic Hematopoiesis

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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant, occurring both as inherited and as sporadic disease. The kindred described by Newburger and colleagues also demonstrates paternal gonadal mosaicism as a mechanism of recurrence in apparently sporadic families.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:11957190 SUPPORT Human Clinical

"Recent genetic, molecular, and cellular studies have shown that autosomal-dominant cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene for neutrophil elastase (ELA2), located at 19p13.3."

States the autosomal dominant inheritance and the existence of sporadic cases.

PMID:20582973 SUPPORT Human Clinical

"The mutant allele was detected in the donor's spermatozoa, representing 18% of the ELANE gene pool, but not in DNA from his lymphocytes, neutrophils, or buccal mucosa, indicating gonadal mosaicism."

Documents gonadal mosaicism, which is relevant to recurrence risk counselling in families with no detectable parental mutation.

PMID:20301705 SUPPORT Human Clinical

"One parent of a proband is usually affected. De novo pathogenic variants have been identified; their frequency is unknown."

Gives the transmission pattern and records that de novo variants occur without a known rate, which is the counselling-relevant qualifier alongside the mosaicism finding.

+ 1 more reference

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Pathophysiology

5

ELANE Mutation and Neutrophil Elastase Misfolding

The initiating lesion. A heterozygous mutation in ELANE yields a neutrophil elastase that misfolds. Elastase is synthesised in neutrophil precursors early in primary granule formation, which is why the consequences fall on the granulocytic lineage specifically rather than on cells generally.

promyelocyte CL:0000836

ELANE hgnc:3309

Downstream

Endoplasmic Reticulum Stress and Unfolded Protein Response Misfolded elastase accumulating in the endoplasmic reticulum triggers the stress response.

Show evidence (1 reference)

PMID:11957190 SUPPORT Human Clinical

"Recent genetic, molecular, and cellular studies have shown that autosomal-dominant cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene for neutrophil elastase (ELA2), located at 19p13.3. This enzyme is synthesized in neutrophil precursors early in the process..."

Names the causal gene and locates elastase synthesis in neutrophil precursors, which is the basis for lineage specificity.

Endoplasmic Reticulum Stress and Unfolded Protein Response

In CD34+ cells taken at the neutrophil nadir, ELANE and the unfolded protein response genes ATF6, BiP, CHOP and PERK are all raised while the antiapoptotic genes BCL2 and BCL2L1 are reduced, with increased reactive oxygen species and gH2AX. The measurement is made in patient marrow at a defined point in the cycle, which is what makes this node unusually well grounded for a mechanism of this kind.

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED PERK-mediated unfolded protein response GO:0036499 ↑ INCREASED

Animal models

G193X Elane transgenic mouse Mouse partially recapitulates Granulocytic precursors carrying the mutation are selectively sensitive to endoplasmic reticulum stress, which supports the mechanism, but they show no basal unfolded protein response activation.

Downstream

Apoptosis of Granulocytic Progenitors The unfolded protein response, with antiapoptotic gene expression suppressed, kills the progenitors rather than merely stalling them.

Show evidence (2 references)

PMID:32083314 SUPPORT Human Clinical

"we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34+ cells tested at the ANC nadir."

Direct measurement of unfolded protein response activation and loss of antiapoptotic signalling in patient progenitors at the nadir.

PMID:32299910 REFUTE In Vitro

"Using an inducible expression system, we observed that this ELANE mutation diminishes enzymatic activity and granulocytic differentiation without significantly affecting cell proliferation, cell death, or UPR induction in murine myeloblast 32D and human promyelocytic NB4 cells."

Argues against the unfolded protein response being necessary, since impaired differentiation occurred without it. Recorded here as a genuine challenge to this node, with the caveat that the mutation studied (p.G185R) is a severe congenital neutropenia allele rather than a cyclic one.

Apoptosis of Granulocytic Progenitors

Accelerated death of neutrophil precursors, producing ineffective granulopoiesis and, in the marrow, myeloid maturation arrest. This is the step that converts a protein-folding defect into a blood count.

hematopoietic stem cell CL:0000037

apoptotic process GO:0006915 ↑ INCREASED granulocyte differentiation GO:0030851 ↓ DECREASED

Animal models

G193X Elane transgenic mouse Mouse fails to recapitulate The mice do not develop neutropenia. Basal and stress granulopoiesis are normal, so the model does not reproduce the ineffective granulopoiesis that defines the human disease.

Downstream

Oscillatory Granulopoiesis Progenitor depletion raises G-CSF, which drives compensatory proliferation; the repopulated compartment is then hit by the unfolded protein response again, and the loop repeats with a period of about three weeks.

Show evidence (1 reference)

PMID:11957190 SUPPORT Human Clinical

"It is currently presumed that the mutant neutrophil elastase functions aberrantly within the cells to accelerate apoptosis of the precursors, resulting in effective and oscillatory production."

States accelerated precursor apoptosis as the mechanism linking the mutant protein to oscillatory production. The source is explicit that this is presumed.

Oscillatory Granulopoiesis

The defining feature, and the reason this disease is interesting beyond haematology: a genetic lesion producing not a fixed deficit but a stable oscillation. Marrow sampling at the two ends of the cycle shows the mechanism in motion, with stem and progenitor cells accumulating at the nadir and producing fewer granulocyte colonies at the peak.

neutrophil CL:0000775

Animal models

Grey Collie canine cyclic hematopoiesis Dog partially recapitulates Reproduces a genuine cyclic oscillation of neutrophils originating in the bone marrow, confirmed by reciprocal bone marrow transplantation.

Downstream

Cyclically Decreased Neutrophil Count Oscillating marrow output is measured directly as the oscillating peripheral absolute neutrophil count.

Myeloid Maturation Arrest in Bone Marrow The same cycle is visible in the marrow as reduced granulocytic colony output and a fall in granulocyte numbers during the neutropenic phase.

Recurrent Infection and Mucosal Inflammation At each nadir the neutrophil count is severely low for several days, and it is during those windows that infection and mucosal breakdown occur.

Show evidence (2 references)

PMID:32083314 SUPPORT Human Clinical

"We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak."

Documents the marrow compartment shifting in antiphase with the blood count, which is the direct observation of the oscillation.

PMID:11957190 SUPPORT Human Clinical

"Fluctuations in blood cells are due to oscillatory production of cells by the bone marrow."

Locates the oscillation in marrow production rather than in peripheral consumption or margination.

Recurrent Infection and Mucosal Inflammation

The clinical disease: recurrent fever, mouth ulcers, gingivitis, pharyngitis, sinusitis, cervical adenopathy and cellulitis, all timed to the nadirs. It is less severe than in congenital neutropenia, and between episodes patients are well.

Downstream

Recurrent Fever Fever recurs with each neutropenic episode.

Recurrent Oral Ulceration Oral ulceration accompanies each nadir, alongside the fever.

Gingivitis Gingival inflammation is part of the oropharyngeal inflammatory response to repeated neutropenic episodes.

Cervical Lymphadenopathy Cervical adenopathy accompanies the recurrent oropharyngeal inflammation.

Cellulitis Soft tissue infection, characteristically perianal, occurring specifically during the neutropenic windows.

Periodontitis Repeated episodes of neutropenic gingival infection produce cumulative periodontal destruction.

Show evidence (2 references)

PMID:20301705 SUPPORT Human Clinical

"ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy."

Enumerates the clinical manifestations that constitute this endpoint.

PMID:20301705 SUPPORT Human Clinical

"Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia."

Grades the severity of this endpoint against the allelic disorder, which is the main clinical distinction between the two.

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Pathograph

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Phenotypes

8

Blood 2

Cyclically Decreased Neutrophil Count Cyclically decreased total neutrophil count HP:0040289

Temporal: RECURRENT

Show evidence (1 reference)

PMID:32083314 SUPPORT Human Clinical

"Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21-day intervals."

Defines the oscillation and its period, which is the phenotype itself.

Myeloid Maturation Arrest in Bone Marrow Cyclic neutropenia in myeloid maturation arrest in bone marrow HP:0410254

Show evidence (2 references)

PMID:32083314 SUPPORT Human Clinical

"BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak."

Demonstrates impaired proliferation and maturation of myeloid progenitors, which is what the HPO term asserts, rather than only a reduced granulocyte count.

PMID:23855177 SUPPORT Human Clinical

"A bone marrow cytology test during a neutropenic period demonstrated a decrease in granulocyte count."

The corresponding cytological finding in an individual patient during the neutropenic phase.

Cardiovascular 1

Cervical Lymphadenopathy HP:0025289

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy."

Names cervical adenopathy among the defining manifestations.

Head and Neck 3

Recurrent Oral Ulceration FREQUENT Recurrent aphthous stomatitis HP:0011107

Temporal: RECURRENT

Show evidence (2 references)

PMID:20301705 SUPPORT Human Clinical

"Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts."

Names oral ulceration at three-weekly intervals as a defining feature, which supports both the phenotype and the FREQUENT band.

PMID:23855177 SUPPORT Human Clinical

"CN can easily be misdiagnosed as major recurrent aphthous stomatitis (MaRAS) or aggressive periodontitis (AP) in dental clinics."

Records the specific misdiagnosis risk that makes this phenotype clinically important to recognise.

Periodontitis HP:0000704

Show evidence (1 reference)

PMID:23855177 SUPPORT Human Clinical

"An 8-year-old boy presented with a history of recurrent oral ulcers, periodontal destruction, pharyngitis and otitis media since the age of 3 months."

Documents periodontal destruction as a presenting feature.

Gingivitis HP:0000230

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia, both of which are primary hematologic disorders characterized by recurrent fever, skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis), and cervical adenopathy."

Names gingivitis among the oropharyngeal manifestations.

Metabolism 1

Recurrent Fever FREQUENT HP:0001954

Temporal: RECURRENT

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts."

Establishes recurrent fever at three-weekly intervals as a defining feature, which supports both the phenotype and the FREQUENT band.

Musculoskeletal 1

Cellulitis HP:0100658

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Cellulitis, especially perianal cellulitis, is common during neutropenic periods."

Names cellulitis and its characteristic site, timed to the neutropenic periods.

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Genetic Associations

1

ELANE (Heterozygous Missense Mutation, Autosomal Dominant)

Gene: ELANE hgnc:3309 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:23463630 SUPPORT Human Clinical

"CyN-associated mutations were predicted to be more benign than CN-associated mutations, but the mutation severity largely overlapped."

Establishes that the two mutation spectra differ in tendency but overlap, which is why genotype is not predictive.

PMID:20582973 SUPPORT Human Clinical

"One patient with CN had the same S97L ELANE mutation as seven patients with the SCN phenotype."

The single strongest piece of evidence that the ELANE allele alone does not determine which of the two phenotypes appears.

PMID:20582973 SUPPORT Human Clinical

"The coexistence of CN and SCN phenotypes in this kindred with a shared paternal haplotype strongly suggests both a role for modifying genes in determination of congenital neutropenia disease phenotypes, and the classification of CN and SCN within a spectrum of phenotypes expressing varying..."

States the modifier-gene interpretation and the spectrum classification that this entry adopts.

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Medical Actions

3

Granulocyte Colony-Stimulating Factor

Action: colony-stimulating factor therapy Ontology label: Colony-Stimulating Factor Therapy NCIT:C15515

Agent: filgrastim NCIT:C1474

The mainstay. Long-term daily or alternate-day G-CSF at 1 to 5 micrograms per kilogram per day reduces fever, mouth ulcers and other inflammatory events. Note the mechanistic irony: G-CSF-driven compensatory proliferation is part of the oscillation in the first place, and treatment works by raising the nadir rather than by abolishing the cycle.

Mechanism Target:

MODULATES Oscillatory Granulopoiesis — Pharmacological G-CSF drives granulocytic proliferation and differentiation, raising the neutrophil count achieved at the nadir.

Show evidence (1 reference)

PMID:32083314 SUPPORT Human Clinical

"There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation."

Identifies G-CSF-stimulated proliferation as the arm of the cycle that this treatment augments.

Show evidence (2 references)

PMID:11957190 SUPPORT Human Clinical

"Cyclic neutropenia is effectively treated with granulocyte colony-stimulating factor (G-CSF), usually at doses of 1 to 5 microg/kg/d (median dose, 2.5 microg/kg/d). Long-term, daily, or alternate-day administration reduces fever, mouth ulcers, and other inflammatory events associated with this disorder."

Gives the dose range and the clinical benefit obtained.

PMID:23855177 SUPPORT Human Clinical

"During a 2-year follow-up, his symptoms were well controlled by regular administration of granulocyte colony-stimulating factor and periodontal maintenance."

Individual-level confirmation of symptom control on maintenance G-CSF, alongside dental care.

Prompt Antimicrobial Treatment of Febrile Episodes

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

All fevers and infections require prompt evaluation and treatment. Abdominal pain in particular needs assessment, because of the risk of a lethal complication during the neutropenic window.

Mechanism Target:

INHIBITS Recurrent Infection and Mucosal Inflammation — Treats the infectious consequence of each nadir. It does not touch the granulopoietic defect upstream, which is why it is symptomatic rather than disease-modifying.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Treatment of manifestations: All fevers and infections require prompt evaluation and treatment."

States that the infectious manifestations are what this intervention targets.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Treatment of manifestations: All fevers and infections require prompt evaluation and treatment."

States the management principle for febrile episodes.

Dental Hygiene and Periodontal Maintenance

Platform: Behavioral / lifestyle

Good dental hygiene with regular periodontal maintenance, alongside G-CSF. It is listed here rather than folded into supportive care because periodontitis and gingivitis are modelled as phenotypes of this disease, and this is the intervention that addresses them.

Mechanism Target:

INHIBITS Recurrent Infection and Mucosal Inflammation — Reduces the oral bacterial burden that the neutropenic windows would otherwise allow to produce gingival and periodontal destruction.

Show evidence (1 reference)

PMID:23855177 SUPPORT Human Clinical

"During a 2-year follow-up, his symptoms were well controlled by regular administration of granulocyte colony-stimulating factor and periodontal maintenance."

Records periodontal maintenance as part of what controlled the oral manifestations, alongside G-CSF.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Prevention of secondary complications: Good dental hygiene; routine immunizations."

States dental hygiene as a recommended preventive measure in this condition.

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Diagnosis

2

Serial absolute neutrophil counts (PRESENT)

The diagnosis rests on demonstrating the oscillation, which requires repeated counts over at least six weeks rather than a single measurement. A single normal count does not exclude the disease, because it may have been taken at the peak.

Show evidence (1 reference)

PMID:23855177 SUPPORT Human Clinical

"Repeated, routine blood tests showed 1-week-long neutropenic periods that occurred at intervals of 2 weeks."

Shows that repeated sampling is what reveals the pattern, and incidentally that the period is not always the textbook twenty-one days.

ELANE molecular genetic testing (PRESENT)

Identification of a heterozygous pathogenic ELANE variant confirms the diagnosis. A negative result does not exclude it, since ELANE mutations are found in only about 55% of cyclic neutropenia patients.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"The diagnosis of ELANE-related neutropenia is established in a proband with suggestive clinical findings and the identification of a heterozygous pathogenic variant in ELANE through molecular genetic testing."

States the molecular diagnostic criterion.

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Progression

3

Childhood and adolescence

Diagnosed usually within the first year of life. The course is a rhythm rather than a decline: fever, oral ulceration and infection at each nadir, good health between them. Cellulitis, characteristically perianal, occurs in the neutropenic windows.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy."

Describes the alternating pattern that characterises this phase.

Adulthood

Symptoms improve with age, which is the opposite of the trajectory in severe congenital neutropenia.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood."

States the improvement with age, alongside the inter-episode good health that characterises the earlier phase.

Long-term outcome

The point at which this disease diverges completely from its allelic partner, and the reason the two are curated separately. Severe congenital neutropenia carries a 15 to 25% risk of myelodysplasia or acute myeloid leukaemia after fifteen years of G-CSF. Cyclic neutropenia carries no recognised risk, treated or untreated. The divergence is attributed to disease severity rather than to the ELANE mutation itself, so it is not predictable from the genotype.

Show evidence (3 references)

PMID:20301705 SUPPORT Human Clinical

"Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia."

States the absence of malignant risk directly.

PMID:11957190 SUPPORT Human Clinical

"Leukemic transformation is not a recognized risk for cyclic neutropenia, with or without treatment with G-CSF."

Confirms the absence of risk and specifies that it holds under G-CSF treatment, which is the clinically relevant question.

PMID:23463630 SUPPORT Human Clinical

"Specific ELANE mutations have limited predictive value for leukemogenesis; the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation."

Attributes leukaemic risk to severity rather than to the gene, which is why the allelic disorder diverges here.

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Epidemiology

2

Age at diagnosis

Usually recognised within the first year of life, from the pattern of approximately three-weekly fever and oral ulceration together with regular oscillation of the blood counts. Symptoms tend to improve in adulthood.

Show evidence (1 reference)

PMID:20301705 SUPPORT Human Clinical

"Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts."

Gives the typical age at diagnosis and the clinical pattern that prompts it.

ELANE mutation frequency

In the largest screened series, ELANE mutations were found in 55% of cyclic neutropenia patients, a higher detection rate than in severe congenital neutropenia.

Show evidence (1 reference)

PMID:23463630 SUPPORT Human Clinical

"We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN patients, 69 of them were novel."

Gives the ELANE detection rate in cyclic neutropenia alongside the congenital neutropenia comparison.

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Animal Models

2

G193X Elane transgenic mouse

A targeted Elane mutation reproducing a human severe congenital neutropenia allele. It is included here because of what it fails to do: the mice are not neutropenic, which is a real problem for the unfolded protein response model as a complete account.

Species

Mouse

Genotype

G193X Elane

Publication

PMID:21285438

Pathograph links

Endoplasmic Reticulum Stress and Unfolded Protein Response partially recapitulates fidelity: low Granulocytic precursors carrying the mutation are selectively sensitive to endoplasmic reticulum stress, which supports the mechanism, but they show no basal unfolded protein response activation.

Limitations: The sensitivity is only revealed by chemical or proteasome-inhibitor challenge; unstressed animals look normal. The allele is also a severe congenital neutropenia allele rather than a cyclic one.

Show evidence (1 reference)

PMID:21285438 SUPPORT Model Organism

"The selective sensitivity of G913X Elane granulocytic cells to ER stress provides new and strong support for the UPR model of disease patho-genesis in SCN."

The authors' own summary of what the model does and does not establish. Note that the abstract itself contains a typographical error, writing G913X for G193X.

Apoptosis of Granulocytic Progenitors fails to recapitulate fidelity: low The mice do not develop neutropenia. Basal and stress granulopoiesis are normal, so the model does not reproduce the ineffective granulopoiesis that defines the human disease.

Limitations: Recorded as a negative result rather than omitted, because a model that fails at the key phenotype constrains the mechanism more informatively than one that succeeds.

Show evidence (1 reference)

PMID:21285438 SUPPORT Model Organism

"Granulocytic precursors from G193X Elane mice, though without significant basal UPR activation, are sensitive to chemical induction of ER stress. Basal and stress granulopoiesis after myeloablative therapy are normal in these mice."

States directly that granulopoiesis is normal in these animals, which is the failure this link records.

Show evidence (1 reference)

PMID:21285438 SUPPORT Model Organism

"To test this model, we generated transgenic mice carrying a targeted mutation of Elane (G193X) reproducing a mutation found in SCN."

Establishes the model and the human allele it reproduces.

Grey Collie canine cyclic hematopoiesis

The classical animal model, described in Grey Collies as the lethal grey syndrome. It reproduces the oscillation itself, on a twelve-day rather than a twenty-one-day cycle, and historically it shaped how the human disease was understood. It is genetically distinct: the canine disease is a recessive AP3B1 defect, not an ELANE one.

Species

Dog

Genotype

AP3B1 frameshift, homozygous

Publication

PMID:35904319

Pathograph links

Oscillatory Granulopoiesis partially recapitulates fidelity: moderate Reproduces a genuine cyclic oscillation of neutrophils originating in the bone marrow, confirmed by reciprocal bone marrow transplantation.

Limitations: Genetically distinct from the human disease: a homozygous recessive AP3B1 frameshift rather than a heterozygous dominant ELANE mutation, with a twelve to fourteen day period rather than twenty-one, and a lethal course in the first months of life. It therefore models the oscillation as a phenomenon of marrow regulation, not the ELANE mechanism.

Show evidence (2 references)

PMID:2979797 SUPPORT Model Organism

"Reciprocal bone marrow transplantation indicates that the defect resides in the bone marrow, but the actual site and mechanism of the defect has not been established."

Localises the defect to the marrow, which is the feature shared with the human disease, while stating that the mechanism was unresolved.

+ 1 more reference

Show evidence (1 reference)

PMID:2979797 SUPPORT Model Organism

"Canine cyclic hematopoiesis (CH) was first described in Gray Collies as the lethal gray syndrome, and was subsequently shown to be a counterpart of human cyclic neutropenia (CN)."

Establishes the model and its relationship to the human disease.

{ }

Source YAML

click to show

name: Cyclic Hematopoiesis
creation_date: '2026-09-03T09:00:00Z'
description: >-
An autosomal dominant disorder of granulopoiesis in which the absolute
neutrophil count oscillates on a regular cycle of roughly 21 days, falling to
severely neutropenic levels and recovering to near normal. Most cases carry a
heterozygous ELANE mutation. The prevailing model is that mutant neutrophil
elastase misfolds, provokes endoplasmic reticulum stress and an unfolded
protein response in granulocytic progenitors, and kills them; the oscillation
arises because progenitor depletion drives compensatory G-CSF-stimulated
proliferation, which then repopulates the compartment until the unfolded
protein response overtakes it again. Clinically the disease is a rhythm of
fever, mouth ulceration and infection at each nadir, with good health in
between. Unlike severe congenital neutropenia, which shares the same gene, it
carries no recognised risk of leukaemic transformation.
categories:
- Inborn Error of Immunity
- Disorder of Granulopoiesis
- Protein Misfolding Disorder
parents:
- congenital neutropenia
synonyms:
- cyclic neutropenia
- periodic neutropenia
- cyclic agranulocytosis
epidemiology:
- name: Age at diagnosis
description: >-
Usually recognised within the first year of life, from the pattern of
approximately three-weekly fever and oral ulceration together with regular
oscillation of the blood counts. Symptoms tend to improve in adulthood.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cyclic neutropenia is usually diagnosed within the first year of life based on
approximately three-week intervals of fever and oral ulcerations and regular oscillations
of blood cell counts.
explanation: Gives the typical age at diagnosis and the clinical pattern that prompts it.
- name: ELANE mutation frequency
description: >-
In the largest screened series, ELANE mutations were found in 55% of cyclic
neutropenia patients, a higher detection rate than in severe congenital
neutropenia.
evidence:
- reference: PMID:23463630
reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic
neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN
patients, 69 of them were novel.
explanation: Gives the ELANE detection rate in cyclic neutropenia alongside the congenital
neutropenia comparison.
pathophysiology:
- name: ELANE Mutation and Neutrophil Elastase Misfolding
description: >-
The initiating lesion. A heterozygous mutation in ELANE yields a neutrophil
elastase that misfolds. Elastase is synthesised in neutrophil precursors early
in primary granule formation, which is why the consequences fall on the
granulocytic lineage specifically rather than on cells generally.
genes:
- preferred_term: ELANE
term:
id: hgnc:3309
label: ELANE
cell_types:
- preferred_term: promyelocyte
term:
id: CL:0000836
label: promyelocyte
evidence:
- reference: PMID:11957190
reference_title: Cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Recent genetic, molecular, and cellular studies have shown that autosomal-dominant
cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene
for neutrophil elastase (ELA2), located at 19p13.3. This enzyme is synthesized in neutrophil
precursors early in the process of primary granule formation.
explanation: Names the causal gene and locates elastase synthesis in neutrophil precursors,
which is the basis for lineage specificity.
downstream:
- target: Endoplasmic Reticulum Stress and Unfolded Protein Response
causal_link_type: DIRECT
description: Misfolded elastase accumulating in the endoplasmic reticulum triggers the
stress response.
evidence:
- reference: PMID:21285438
reference_title: Activation of the unfolded protein response is associated with impaired granulopoiesis
in transgenic mice expressing mutant Elane.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 'Recent data suggest a model in which ELANE mutations result in NE protein misfolding,
induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response
(UPR), and ultimately a block in granulocytic differentiation.'
explanation: States the misfolding-to-ER-stress step that this edge asserts, and is
explicit that it is a model.
- name: Endoplasmic Reticulum Stress and Unfolded Protein Response
description: >-
In CD34+ cells taken at the neutrophil nadir, ELANE and the unfolded protein
response genes ATF6, BiP, CHOP and PERK are all raised while the antiapoptotic
genes BCL2 and BCL2L1 are reduced, with increased reactive oxygen species and
gH2AX. The measurement is made in patient marrow at a defined point in the
cycle, which is what makes this node unusually well grounded for a mechanism
of this kind.
biological_processes:
- preferred_term: response to endoplasmic reticulum stress
modifier: INCREASED
term:
id: GO:0034976
label: response to endoplasmic reticulum stress
- preferred_term: PERK-mediated unfolded protein response
modifier: INCREASED
term:
id: GO:0036499
label: PERK-mediated unfolded protein response
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related
genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic
genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34+ cells tested at the ANC
nadir.'
explanation: Direct measurement of unfolded protein response activation and loss of
antiapoptotic signalling in patient progenitors at the nadir.
- reference: PMID:32299910
reference_title: 'Inducible expression of a disease-associated ELANE mutation impairs granulocytic differentiation,
without eliciting an unfolded protein response.'
supports: REFUTE
evidence_source: IN_VITRO
snippet: 'Using an inducible expression system, we observed that this ELANE mutation diminishes
enzymatic activity and granulocytic differentiation without significantly affecting cell
proliferation, cell death, or UPR induction in murine myeloblast 32D and human promyelocytic
NB4 cells.'
explanation: Argues against the unfolded protein response being necessary, since impaired
differentiation occurred without it. Recorded here as a genuine challenge to this node,
with the caveat that the mutation studied (p.G185R) is a severe congenital neutropenia
allele rather than a cyclic one.
downstream:
- target: Apoptosis of Granulocytic Progenitors
causal_link_type: DIRECT
description: The unfolded protein response, with antiapoptotic gene expression suppressed,
kills the progenitors rather than merely stalling them.
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: There is a cyclic balance between ER stress-induced apoptosis of HSPCs and
compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation.
explanation: Names ER-stress-induced apoptosis of progenitors as one arm of the balance.
- name: Apoptosis of Granulocytic Progenitors
description: >-
Accelerated death of neutrophil precursors, producing ineffective granulopoiesis
and, in the marrow, myeloid maturation arrest. This is the step that converts a
protein-folding defect into a blood count.
cell_types:
- preferred_term: hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
biological_processes:
- preferred_term: apoptotic process
modifier: INCREASED
term:
id: GO:0006915
label: apoptotic process
- preferred_term: granulocyte differentiation
modifier: DECREASED
term:
id: GO:0030851
label: granulocyte differentiation
evidence:
- reference: PMID:11957190
reference_title: Cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: It is currently presumed that the mutant neutrophil elastase functions aberrantly
within the cells to accelerate apoptosis of the precursors, resulting in effective and
oscillatory production.
explanation: States accelerated precursor apoptosis as the mechanism linking the mutant
protein to oscillatory production. The source is explicit that this is presumed.
downstream:
- target: Oscillatory Granulopoiesis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Progenitor depletion raises G-CSF, which drives compensatory proliferation; the
repopulated compartment is then hit by the unfolded protein response again, and the loop
repeats with a period of about three weeks.
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'We suggest that in CyN patients, some HSPCs escape the UPR-induced endoplasmic
reticulum (ER) stress and proliferate in response to granulocyte colony-stimulating factor
(G-CSF) to a certain threshold at which UPR again affects the majority of HSPCs.'
explanation: States the feedback loop that generates the oscillation, and does so as an
explicit suggestion rather than an established fact.
- name: Oscillatory Granulopoiesis
description: >-
The defining feature, and the reason this disease is interesting beyond
haematology: a genetic lesion producing not a fixed deficit but a stable
oscillation. Marrow sampling at the two ends of the cycle shows the mechanism
in motion, with stem and progenitor cells accumulating at the nadir and
producing fewer granulocyte colonies at the peak.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'We performed analysis of bone marrow (BM) subpopulations in CyN patients at the
peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic
stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of
the ANC cycle, as compared with the peak.'
explanation: Documents the marrow compartment shifting in antiphase with the blood count,
which is the direct observation of the oscillation.
- reference: PMID:11957190
reference_title: Cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fluctuations in blood cells are due to oscillatory production of cells by the bone
marrow.
explanation: Locates the oscillation in marrow production rather than in peripheral
consumption or margination.
downstream:
- target: Cyclically Decreased Neutrophil Count
causal_link_type: DIRECT
description: Oscillating marrow output is measured directly as the oscillating peripheral
absolute neutrophil count.
evidence:
- reference: PMID:11957190
reference_title: Cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fluctuations in blood cells are due to oscillatory production of cells by the bone
marrow.
explanation: States that the blood-count oscillation is produced by the marrow oscillation,
which is exactly this edge.
- target: Myeloid Maturation Arrest in Bone Marrow
causal_link_type: DIRECT
description: The same cycle is visible in the marrow as reduced granulocytic colony output
and a fall in granulocyte numbers during the neutropenic phase.
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak.
explanation: The marrow correlate of the cycle, measured at a defined point in it.
- target: Recurrent Infection and Mucosal Inflammation
causal_link_type: DIRECT
description: At each nadir the neutrophil count is severely low for several days, and it is
during those windows that infection and mucosal breakdown occur.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cellulitis, especially perianal cellulitis, is common during neutropenic periods.
Between neutropenic periods, affected individuals are generally healthy.
explanation: Ties the infectious events specifically to the neutropenic windows, which is
what makes this edge cyclical rather than constant.
- name: Recurrent Infection and Mucosal Inflammation
description: >-
The clinical disease: recurrent fever, mouth ulcers, gingivitis, pharyngitis,
sinusitis, cervical adenopathy and cellulitis, all timed to the nadirs. It is
less severe than in congenital neutropenia, and between episodes patients are
well.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia,
both of which are primary hematologic disorders characterized by recurrent fever, skin
and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis),
and cervical adenopathy.'
explanation: Enumerates the clinical manifestations that constitute this endpoint.
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Infectious complications are generally more severe in congenital neutropenia than
in cyclic neutropenia.
explanation: Grades the severity of this endpoint against the allelic disorder, which is the
main clinical distinction between the two.
downstream:
- target: Recurrent Fever
causal_link_type: DIRECT
description: Fever recurs with each neutropenic episode.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cyclic neutropenia is usually diagnosed within the first year of life based on
approximately three-week intervals of fever and oral ulcerations and regular oscillations
of blood cell counts.
explanation: Ties the fever to the three-weekly cycle of this endpoint.
- target: Recurrent Oral Ulceration
causal_link_type: DIRECT
description: Oral ulceration accompanies each nadir, alongside the fever.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cyclic neutropenia is usually diagnosed within the first year of life based on
approximately three-week intervals of fever and oral ulcerations and regular oscillations
of blood cell counts.
explanation: Ties the oral ulceration to the same cycle.
- target: Gingivitis
causal_link_type: DIRECT
description: Gingival inflammation is part of the oropharyngeal inflammatory response to
repeated neutropenic episodes.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia,
both of which are primary hematologic disorders characterized by recurrent fever, skin
and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis),
and cervical adenopathy.'
explanation: Names gingivitis among the oropharyngeal manifestations of this endpoint.
- target: Cervical Lymphadenopathy
causal_link_type: DIRECT
description: Cervical adenopathy accompanies the recurrent oropharyngeal inflammation.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia,
both of which are primary hematologic disorders characterized by recurrent fever, skin
and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis),
and cervical adenopathy.'
explanation: Names cervical adenopathy among the manifestations of this endpoint.
- target: Cellulitis
causal_link_type: DIRECT
description: Soft tissue infection, characteristically perianal, occurring specifically during
the neutropenic windows.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cellulitis, especially perianal cellulitis, is common during neutropenic periods.
explanation: Times the cellulitis to the neutropenic periods, which is what makes it a
consequence of this endpoint.
- target: Periodontitis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Repeated episodes of neutropenic gingival infection produce cumulative
periodontal destruction.
evidence:
- reference: PMID:23855177
reference_title: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: An 8-year-old boy presented with a history of recurrent oral ulcers, periodontal
destruction, pharyngitis and otitis media since the age of 3 months.
explanation: Documents periodontal destruction developing on a background of recurrent
oral ulceration and infection, which is the sequence this edge asserts.

phenotypes:
- category: Hematologic
name: Cyclically Decreased Neutrophil Count
description: >-
The defining laboratory phenotype: regular oscillation of the absolute
neutrophil count from near normal to severely low, with a period of about
twenty-one days.
phenotype_term:
preferred_term: Cyclically decreased total neutrophil count
term:
id: HP:0040289
label: Cyclically decreased total neutrophil count
temporality: RECURRENT
diagnostic: true
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute
neutrophil counts (ANCs) show cycles of approximately 21-day intervals.
explanation: Defines the oscillation and its period, which is the phenotype itself.
- category: Hematologic
name: Myeloid Maturation Arrest in Bone Marrow
description: >-
The marrow correlate of the blood phenotype, seen as a fall in granulocyte
numbers during the neutropenic phase.
phenotype_term:
preferred_term: Cyclic neutropenia in myeloid maturation arrest in bone marrow
term:
id: HP:0410254
label: Cyclic neutropenia in myeloid maturation arrest in bone marrow
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak.
explanation: Demonstrates impaired proliferation and maturation of myeloid progenitors,
which is what the HPO term asserts, rather than only a reduced granulocyte count.
- reference: PMID:23855177
reference_title: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A bone marrow cytology test during a neutropenic period demonstrated a decrease in
granulocyte count.
explanation: The corresponding cytological finding in an individual patient during the
neutropenic phase.
- category: Constitutional
name: Recurrent Fever
frequency: FREQUENT
description: >-
Fever recurring at roughly three-weekly intervals, in step with the neutrophil
nadir. The regularity of the interval is itself the diagnostic clue.
phenotype_term:
preferred_term: Recurrent fever
term:
id: HP:0001954
label: Recurrent fever
temporality: RECURRENT
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cyclic neutropenia is usually diagnosed within the first year of life based on
approximately three-week intervals of fever and oral ulcerations and regular oscillations
of blood cell counts.
explanation: Establishes recurrent fever at three-weekly intervals as a defining feature,
which supports both the phenotype and the FREQUENT band.
- category: Oral
name: Recurrent Oral Ulceration
frequency: FREQUENT
description: >-
Painful recurrent oral ulcers accompanying each nadir. In practice this is
frequently misread as major recurrent aphthous stomatitis, and the dentist is
often the first clinician to see the patient.
phenotype_term:
preferred_term: Recurrent aphthous stomatitis
term:
id: HP:0011107
label: Recurrent aphthous stomatitis
temporality: RECURRENT
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cyclic neutropenia is usually diagnosed within the first year of life based on
approximately three-week intervals of fever and oral ulcerations and regular oscillations
of blood cell counts.
explanation: Names oral ulceration at three-weekly intervals as a defining feature, which
supports both the phenotype and the FREQUENT band.
- reference: PMID:23855177
reference_title: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: CN can easily be misdiagnosed as major recurrent aphthous stomatitis (MaRAS) or
aggressive periodontitis (AP) in dental clinics.
explanation: Records the specific misdiagnosis risk that makes this phenotype clinically
important to recognise.
- category: Oral
name: Periodontitis
description: >-
Periodontal destruction from repeated neutropenic episodes, which can be the
presenting problem and can progress to permanent tissue loss if the underlying
cause is missed.
phenotype_term:
preferred_term: Periodontitis
term:
id: HP:0000704
label: Periodontitis
evidence:
- reference: PMID:23855177
reference_title: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: An 8-year-old boy presented with a history of recurrent oral ulcers, periodontal
destruction, pharyngitis and otitis media since the age of 3 months.
explanation: Documents periodontal destruction as a presenting feature.
- category: Oral
name: Gingivitis
description: >-
Gingival inflammation, part of the oropharyngeal inflammatory picture common
to ELANE-related neutropenia.
phenotype_term:
preferred_term: Gingivitis
term:
id: HP:0000230
label: Gingivitis
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia,
both of which are primary hematologic disorders characterized by recurrent fever, skin
and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis),
and cervical adenopathy.'
explanation: Names gingivitis among the oropharyngeal manifestations.
- category: Immunologic
name: Cellulitis
description: >-
Soft tissue infection during neutropenic windows, characteristically perianal.
phenotype_term:
preferred_term: Cellulitis
term:
id: HP:0100658
label: Cellulitis
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cellulitis, especially perianal cellulitis, is common during neutropenic periods.
explanation: Names cellulitis and its characteristic site, timed to the neutropenic periods.
- category: Immunologic
name: Cervical Lymphadenopathy
description: >-
Cervical adenopathy accompanying the recurrent oropharyngeal inflammation.
phenotype_term:
preferred_term: Cervical lymphadenopathy
term:
id: HP:0025289
label: Cervical lymphadenopathy
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'ELANE-related neutropenia includes congenital neutropenia and cyclic neutropenia,
both of which are primary hematologic disorders characterized by recurrent fever, skin
and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, and pharyngitis),
and cervical adenopathy.'
explanation: Names cervical adenopathy among the defining manifestations.
genetic:
- name: ELANE
gene_term:
preferred_term: ELANE
term:
id: hgnc:3309
label: ELANE
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: Heterozygous Missense Mutation, Autosomal Dominant
case_fractions:
- population: Cyclic neutropenia patients screened in the Hannover/SCNIR cohort
case_fraction_percent: 55.0
cohort_size: 51
notes: Detection rate is higher in cyclic neutropenia than in severe congenital
neutropenia, where the same screen found 41%.
evidence:
- reference: PMID:23463630
reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic
neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN
patients, 69 of them were novel.
explanation: Gives the cyclic-neutropenia denominator and detection rate alongside the
congenital-neutropenia comparison.
notes: >-
Genotype does not cleanly predict phenotype. Cyclic and severe congenital
neutropenia have partly distinct mutation spectra, but the severity
distributions overlap, and one kindred is documented in which the same S97L
allele on a shared paternal haplotype produced cyclic neutropenia in one child
and severe congenital neutropenia in seven others. That observation argues for
modifying genes and for treating the two conditions as a phenotypic spectrum
rather than as separate diseases.
evidence:
- reference: PMID:23463630
reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic
neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: CyN-associated mutations were predicted to be more benign than CN-associated
mutations, but the mutation severity largely overlapped.
explanation: Establishes that the two mutation spectra differ in tendency but overlap, which
is why genotype is not predictive.
- reference: PMID:20582973
reference_title: 'Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE
mutation and paternal haplotype: evidence for phenotype determination by modifying genes.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: One patient with CN had the same S97L ELANE mutation as seven patients with the
SCN phenotype.
explanation: The single strongest piece of evidence that the ELANE allele alone does not
determine which of the two phenotypes appears.
- reference: PMID:20582973
reference_title: 'Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE
mutation and paternal haplotype: evidence for phenotype determination by modifying genes.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The coexistence of CN and SCN phenotypes in this kindred with a shared paternal
haplotype strongly suggests both a role for modifying genes in determination of congenital
neutropenia disease phenotypes, and the classification of CN and SCN within a spectrum
of phenotypes expressing varying degrees of the same disease process.
explanation: States the modifier-gene interpretation and the spectrum classification that
this entry adopts.
inheritance:
- name: Autosomal dominant
description: >-
Autosomal dominant, occurring both as inherited and as sporadic disease. The
kindred described by Newburger and colleagues also demonstrates paternal
gonadal mosaicism as a mechanism of recurrence in apparently sporadic families.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:11957190
reference_title: Cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Recent genetic, molecular, and cellular studies have shown that autosomal-dominant
cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene
for neutrophil elastase (ELA2), located at 19p13.3.
explanation: States the autosomal dominant inheritance and the existence of sporadic cases.
- reference: PMID:20582973
reference_title: 'Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE
mutation and paternal haplotype: evidence for phenotype determination by modifying genes.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The mutant allele was detected in the donor's spermatozoa, representing 18% of the
ELANE gene pool, but not in DNA from his lymphocytes, neutrophils, or buccal mucosa,
indicating gonadal mosaicism.
explanation: Documents gonadal mosaicism, which is relevant to recurrence risk counselling in
families with no detectable parental mutation.
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: One parent of a proband is usually affected. De novo pathogenic variants have been
identified; their frequency is unknown.
explanation: Gives the transmission pattern and records that de novo variants occur without
a known rate, which is the counselling-relevant qualifier alongside the mosaicism finding.
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Each child of an individual with an ELANE pathogenic variant has a 50% chance of
inheriting the variant.
explanation: The recurrence risk figure itself.
progression:
- phase: Childhood and adolescence
notes: >-
Diagnosed usually within the first year of life. The course is a rhythm rather
than a decline: fever, oral ulceration and infection at each nadir, good health
between them. Cellulitis, characteristically perianal, occurs in the
neutropenic windows.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cellulitis, especially perianal cellulitis, is common during neutropenic periods.
Between neutropenic periods, affected individuals are generally healthy.
explanation: Describes the alternating pattern that characterises this phase.
- phase: Adulthood
notes: >-
Symptoms improve with age, which is the opposite of the trajectory in severe
congenital neutropenia.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Between neutropenic periods, affected individuals are generally healthy. Symptoms
improve in adulthood.
explanation: States the improvement with age, alongside the inter-episode good health that
characterises the earlier phase.
- phase: Long-term outcome
notes: >-
The point at which this disease diverges completely from its allelic partner,
and the reason the two are curated separately. Severe congenital neutropenia
carries a 15 to 25% risk of myelodysplasia or acute myeloid leukaemia after
fifteen years of G-CSF. Cyclic neutropenia carries no recognised risk, treated
or untreated. The divergence is attributed to disease severity rather than to
the ELANE mutation itself, so it is not predictable from the genotype.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Cyclic neutropenia is not associated with risk of malignancy or conversion to
leukemia.
explanation: States the absence of malignant risk directly.
- reference: PMID:11957190
reference_title: Cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Leukemic transformation is not a recognized risk for cyclic neutropenia, with or
without treatment with G-CSF.
explanation: Confirms the absence of risk and specifies that it holds under G-CSF treatment,
which is the clinically relevant question.
- reference: PMID:23463630
reference_title: The spectrum of ELANE mutations and their implications in severe congenital and cyclic
neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Specific ELANE mutations have limited predictive value for leukemogenesis; the risk
for leukemia was correlated with disease severity rather than with occurrence of an ELANE
mutation.
explanation: Attributes leukaemic risk to severity rather than to the gene, which is why the
allelic disorder diverges here.
diagnosis:
- name: Serial absolute neutrophil counts
presence: PRESENT
description: >-
The diagnosis rests on demonstrating the oscillation, which requires repeated
counts over at least six weeks rather than a single measurement. A single
normal count does not exclude the disease, because it may have been taken at
the peak.
evidence:
- reference: PMID:23855177
reference_title: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Repeated, routine blood tests showed 1-week-long neutropenic periods that occurred
at intervals of 2 weeks.
explanation: Shows that repeated sampling is what reveals the pattern, and incidentally that
the period is not always the textbook twenty-one days.
- name: ELANE molecular genetic testing
presence: PRESENT
description: >-
Identification of a heterozygous pathogenic ELANE variant confirms the
diagnosis. A negative result does not exclude it, since ELANE mutations are
found in only about 55% of cyclic neutropenia patients.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The diagnosis of ELANE-related neutropenia is established in a proband with
suggestive clinical findings and the identification of a heterozygous pathogenic variant
in ELANE through molecular genetic testing.
explanation: States the molecular diagnostic criterion.
treatments:
- name: Granulocyte Colony-Stimulating Factor
description: >-
The mainstay. Long-term daily or alternate-day G-CSF at 1 to 5 micrograms per
kilogram per day reduces fever, mouth ulcers and other inflammatory events.
Note the mechanistic irony: G-CSF-driven compensatory proliferation is part of
the oscillation in the first place, and treatment works by raising the nadir
rather than by abolishing the cycle.
treatment_term:
preferred_term: colony-stimulating factor therapy
term:
id: NCIT:C15515
label: Colony-Stimulating Factor Therapy
therapeutic_agent:
- preferred_term: filgrastim
term:
id: NCIT:C1474
label: Filgrastim
target_mechanisms:
- target: Oscillatory Granulopoiesis
treatment_effect: MODULATES
description: Pharmacological G-CSF drives granulocytic proliferation and differentiation,
raising the neutrophil count achieved at the nadir.
evidence:
- reference: PMID:32083314
reference_title: New insights into the pathomechanism of cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: There is a cyclic balance between ER stress-induced apoptosis of HSPCs and
compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation.
explanation: Identifies G-CSF-stimulated proliferation as the arm of the cycle that this
treatment augments.
evidence:
- reference: PMID:11957190
reference_title: Cyclic neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Cyclic neutropenia is effectively treated with granulocyte colony-stimulating factor
(G-CSF), usually at doses of 1 to 5 microg/kg/d (median dose, 2.5 microg/kg/d). Long-term,
daily, or alternate-day administration reduces fever, mouth ulcers, and other inflammatory
events associated with this disorder.'
explanation: Gives the dose range and the clinical benefit obtained.
- reference: PMID:23855177
reference_title: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: During a 2-year follow-up, his symptoms were well controlled by regular
administration of granulocyte colony-stimulating factor and periodontal maintenance.
explanation: Individual-level confirmation of symptom control on maintenance G-CSF, alongside
dental care.
- name: Prompt Antimicrobial Treatment of Febrile Episodes
description: >-
All fevers and infections require prompt evaluation and treatment. Abdominal
pain in particular needs assessment, because of the risk of a lethal
complication during the neutropenic window.
treatment_term:
preferred_term: antibiotic therapy
term:
id: NCIT:C15620
label: Antibiotic Therapy
target_mechanisms:
- target: Recurrent Infection and Mucosal Inflammation
treatment_effect: INHIBITS
description: Treats the infectious consequence of each nadir. It does not touch the
granulopoietic defect upstream, which is why it is symptomatic rather than
disease-modifying.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Treatment of manifestations: All fevers and infections require prompt evaluation
and treatment.'
explanation: States that the infectious manifestations are what this intervention targets.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Treatment of manifestations: All fevers and infections require prompt evaluation
and treatment.'
explanation: States the management principle for febrile episodes.
- name: Dental Hygiene and Periodontal Maintenance
therapeutic_modality: BEHAVIORAL
description: >-
Good dental hygiene with regular periodontal maintenance, alongside G-CSF. It
is listed here rather than folded into supportive care because periodontitis
and gingivitis are modelled as phenotypes of this disease, and this is the
intervention that addresses them.
target_mechanisms:
- target: Recurrent Infection and Mucosal Inflammation
treatment_effect: INHIBITS
description: Reduces the oral bacterial burden that the neutropenic windows would otherwise
allow to produce gingival and periodontal destruction.
evidence:
- reference: PMID:23855177
reference_title: Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: During a 2-year follow-up, his symptoms were well controlled by regular
administration of granulocyte colony-stimulating factor and periodontal maintenance.
explanation: Records periodontal maintenance as part of what controlled the oral
manifestations, alongside G-CSF.
evidence:
- reference: PMID:20301705
reference_title: ELANE-Related Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'Prevention of secondary complications: Good dental hygiene; routine immunizations.'
explanation: States dental hygiene as a recommended preventive measure in this condition.
animal_models:
- name: G193X Elane transgenic mouse
species: Mouse
genotype: G193X Elane
publication: PMID:21285438
description: >-
A targeted Elane mutation reproducing a human severe congenital neutropenia
allele. It is included here because of what it fails to do: the mice are not
neutropenic, which is a real problem for the unfolded protein response model as
a complete account.
evidence:
- reference: PMID:21285438
reference_title: Activation of the unfolded protein response is associated with impaired granulopoiesis
in transgenic mice expressing mutant Elane.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 'To test this model, we generated transgenic mice carrying a targeted mutation of
Elane (G193X) reproducing a mutation found in SCN.'
explanation: Establishes the model and the human allele it reproduces.
modeled_mechanisms:
- target: Endoplasmic Reticulum Stress and Unfolded Protein Response
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: >-
Granulocytic precursors carrying the mutation are selectively sensitive to
endoplasmic reticulum stress, which supports the mechanism, but they show no
basal unfolded protein response activation.
limitations: >-
The sensitivity is only revealed by chemical or proteasome-inhibitor
challenge; unstressed animals look normal. The allele is also a severe
congenital neutropenia allele rather than a cyclic one.
evidence:
- reference: PMID:21285438
reference_title: Activation of the unfolded protein response is associated with impaired granulopoiesis
in transgenic mice expressing mutant Elane.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: The selective sensitivity of G913X Elane granulocytic cells to ER stress provides
new and strong support for the UPR model of disease patho-genesis in SCN.
explanation: The authors' own summary of what the model does and does not establish. Note
that the abstract itself contains a typographical error, writing G913X for G193X.
- target: Apoptosis of Granulocytic Progenitors
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
The mice do not develop neutropenia. Basal and stress granulopoiesis are
normal, so the model does not reproduce the ineffective granulopoiesis that
defines the human disease.
limitations: >-
Recorded as a negative result rather than omitted, because a model that fails
at the key phenotype constrains the mechanism more informatively than one
that succeeds.
evidence:
- reference: PMID:21285438
reference_title: Activation of the unfolded protein response is associated with impaired granulopoiesis
in transgenic mice expressing mutant Elane.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Granulocytic precursors from G193X Elane mice, though without significant basal
UPR activation, are sensitive to chemical induction of ER stress. Basal and stress
granulopoiesis after myeloablative therapy are normal in these mice.
explanation: States directly that granulopoiesis is normal in these animals, which is the
failure this link records.
- name: Grey Collie canine cyclic hematopoiesis
species: Dog
genotype: AP3B1 frameshift, homozygous
publication: PMID:35904319
description: >-
The classical animal model, described in Grey Collies as the lethal grey
syndrome. It reproduces the oscillation itself, on a twelve-day rather than a
twenty-one-day cycle, and historically it shaped how the human disease was
understood. It is genetically distinct: the canine disease is a recessive AP3B1
defect, not an ELANE one.
evidence:
- reference: PMID:2979797
reference_title: Pathobiology of canine cyclic hematopoiesis (review).
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Canine cyclic hematopoiesis (CH) was first described in Gray Collies as the lethal
gray syndrome, and was subsequently shown to be a counterpart of human cyclic neutropenia
(CN).
explanation: Establishes the model and its relationship to the human disease.
modeled_mechanisms:
- target: Oscillatory Granulopoiesis
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
Reproduces a genuine cyclic oscillation of neutrophils originating in the
bone marrow, confirmed by reciprocal bone marrow transplantation.
limitations: >-
Genetically distinct from the human disease: a homozygous recessive AP3B1
frameshift rather than a heterozygous dominant ELANE mutation, with a twelve
to fourteen day period rather than twenty-one, and a lethal course in the
first months of life. It therefore models the oscillation as a phenomenon of
marrow regulation, not the ELANE mechanism.
evidence:
- reference: PMID:2979797
reference_title: Pathobiology of canine cyclic hematopoiesis (review).
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Reciprocal bone marrow transplantation indicates that the defect resides in the
bone marrow, but the actual site and mechanism of the defect has not been established.
explanation: Localises the defect to the marrow, which is the feature shared with the human
disease, while stating that the mechanism was unresolved.
- reference: PMID:35904319
reference_title: 'Cyclic hematopoiesis in a mixed-breed dog: case report and brief review.'
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: 'Genetic testing determined that the patient was homozygous mutant for the frameshift
mutation in the adaptor protein complex 3 β-subunit (AP3B1) gene, originally identified
in gray collies with cyclic hematopoiesis (CH).'
explanation: Identifies the canine gene as AP3B1, which is the basis for the limitation
recorded on this link.
references:
- reference: PMID:2979797
title: "Pathobiology of canine cyclic hematopoiesis (review)."
- reference: PMID:11957190
title: "Cyclic neutropenia."
- reference: PMID:20301705
title: "ELANE-Related Neutropenia."
tags:
- GeneReviews
- reference: PMID:20582973
title: "Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes."
- reference: PMID:21285438
title: "Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane."
- reference: PMID:23463630
title: "The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia."
- reference: PMID:23855177
title: "Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis."
- reference: PMID:32083314
title: "New insights into the pathomechanism of cyclic neutropenia."
- reference: PMID:32299910
title: "Inducible expression of a disease-associated ELANE mutation impairs granulocytic differentiation, without eliciting an unfolded protein response."
- reference: PMID:35904319
title: "Cyclic hematopoiesis in a mixed-breed dog: case report and brief review."
disease_term:
preferred_term: cyclic hematopoiesis
term:
id: MONDO:0008090
label: cyclic hematopoiesis
notes: >-
Scope and naming. MONDO labels this entity cyclic hematopoiesis; the clinical
literature almost always calls it cyclic neutropenia. Both are recorded, with
the MONDO label as the disease_term and the clinical name as a synonym.

Relationship to severe congenital neutropenia. The two are allelic and are best
read as a spectrum rather than as separate diseases, on the evidence of a
kindred in which one S97L allele on a shared paternal haplotype produced both
phenotypes. They are nevertheless curated separately here, because the clinical
consequence diverges completely at the point that matters most: severe
congenital neutropenia carries a 15 to 25% risk of myelodysplasia or acute
myeloid leukaemia after fifteen years of G-CSF, and cyclic neutropenia carries
none. That divergence is recorded explicitly, under the Long-term outcome phase
of progression, because the naive inference from a shared gene is wrong and
worth contradicting rather than leaving to be inferred. It was initially modelled
as a pathophysiology node; review round 1 was right that a negative clinical
observation with no cell types, no processes and no edges is not a mechanism, and
it renders as a floating node in the causal graph. The progression section is the
correct home for it and the evidence moved intact.

Mechanism confidence. The unfolded protein response model is well supported for
this disease specifically, because PMID:32083314 measured it in patient CD34+
cells at defined points in the cycle. It is not unchallenged. PMID:32299910 is
recorded with supports REFUTE on that node: an inducible system showed impaired
granulocytic differentiation without any unfolded protein response. That paper
studied p.G185R, a severe congenital neutropenia allele, so it does not
straightforwardly transfer, and the caveat is stated in the evidence
explanation rather than left for a reader to notice. The G193X mouse is
recorded with one FAILS_TO_RECAPITULATE link for the same reason: it does not
become neutropenic, and that is more informative than omitting it.

A quoting note. The snippet taken from PMID:21285438 reads "G913X" where the
paper means G193X; the typographical error is in the source abstract. It is
quoted verbatim because snippets must match the cached reference exactly, and
the discrepancy is flagged in that evidence item's explanation.

Ontology notes. HPO has an exact term for the defining phenotype
(HP:0040289 Cyclically decreased total neutrophil count) and a child term that
adds the marrow finding (HP:0410254), so both are used rather than a generic
neutropenia parent. MAXO is not used in this repository, so treatments bind to
NCIT actions with NCIT therapeutic agents; filgrastim has no CHEBI term.

Known extension points: prevalence, for which no cleanly quotable figure was
found in the cached abstracts; clinical_trials; the mathematical modelling
literature on the oscillation, which is substantial and would justify a
computational_models section; and stem cell transplantation, which is used in
severe congenital neutropenia but is rarely indicated here and would need
cyclic-specific evidence rather than borrowed evidence.

Provenance. Curated directly from PubMed rather than from a deep-research
report: both configured research providers remain unavailable
(openscientist.io returns CloudFront 403 on POST and 401 on authenticated GET;
the cyberian backend returns 500). Every snippet was fetched with
just fetch-reference and verified as an exact substring of the cached abstract.

📚

References & Deep Research

References

10

PMID:2979797

Pathobiology of canine cyclic hematopoiesis (review).

No top-level findings curated for this source.

PMID:11957190

Cyclic neutropenia.

No top-level findings curated for this source.

PMID:20301705

ELANE-Related Neutropenia.

No top-level findings curated for this source.

PMID:20582973

Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes.

No top-level findings curated for this source.

PMID:21285438

Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane.

No top-level findings curated for this source.

PMID:23463630

The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia.

No top-level findings curated for this source.

PMID:23855177

Cyclic neutropenia presenting as recurrent oral ulcers and periodontitis.

No top-level findings curated for this source.

PMID:32083314

New insights into the pathomechanism of cyclic neutropenia.

No top-level findings curated for this source.

PMID:32299910

Inducible expression of a disease-associated ELANE mutation impairs granulocytic differentiation, without eliciting an unfolded protein response.

No top-level findings curated for this source.

PMID:35904319

Cyclic hematopoiesis in a mixed-breed dog: case report and brief review.

No top-level findings curated for this source.

Cyclic Hematopoiesis

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