Pelger-Huet Anomaly

Mendelian MONDO:0008214 Pathograph 10 Show in embeddings browser Laminopathy Leukocyte Disorder

Pelger-Huet anomaly is an autosomal dominant trait in which blood granulocytes fail to segment their nuclei. Neutrophils that should carry three to five lobes instead show two lobes joined by a thin filament - the "pince-nez" form - or a single unsegmented nucleus, and the chromatin inside them is unusually coarse. The cause is heterozygous loss-of-function variation in LBR, encoding the lamin B receptor, an inner nuclear membrane protein whose nucleoplasmic N-terminal domain tethers heterochromatin to the nuclear periphery. What makes the anomaly unusual mechanistically is that the phenotype tracks protein dose rather than any qualitative change: heterozygous cells carry reduced LBR and give hypolobulated nuclei, cells with two mutant alleles carry only traces and give frankly ovoid nuclei, and the relationship was shown to be dose-dependent in the same experiment that identified the gene. So the entry is a haploinsufficiency, not a dominant-negative one, and the "dominant" in autosomal dominant describes the pedigree rather than the allele's behaviour. The clinical point of the entry is almost entirely diagnostic rather than therapeutic. Carriers are healthy - neutrophil migration, phagocytosis and killing are not meaningfully impaired, and the trait is usually found incidentally on a blood film. Its importance is that the same morphology is acquired in myelodysplastic syndromes, acute leukaemia, severe infection and as a drug reaction, where it is called pseudo-Pelger-Huet anomaly and is a marker of dysplasia. Mistaking the inherited trait for the acquired one can precipitate a bone marrow biopsy and a haematological work-up in a well person; mistaking the acquired one for the inherited trait can delay a diagnosis of MDS. LBR carries a second, unrelated function in its transmembrane segments - the 3-beta-hydroxysterol delta-14-reductase step of post-squalene cholesterol synthesis - and the allelic series at this locus separates the two. Alleles that reduce LBR protein level give this anomaly; alleles that abolish the reductase activity give the prenatally lethal Greenberg dysplasia, which is curated separately. The separation is not clean in the direction one would assume: a homozygous missense allele has been reported that produces a non-lethal skeletal dysplasia with no Pelger-Huet anomaly at all, so the nuclear-shape phenotype is not an obligate accompaniment of biallelic LBR disease.

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0008214 Pelger-Huet anomaly

The dismech entry and the MONDO class denote the same entity: the LBR-related inherited granulocyte nuclear hypolobulation trait. The other LBR phenotypes (Greenberg dysplasia, the mild biallelic anadysplasia-like spondylometaphyseal dysplasia, the reported non-lethal skeletal dysplasia without Pelger-Huet anomaly) are discussed here as an allelic series but are not part of this class.

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Inheritance

Autosomal dominant HP:0000006

Transmitted as an autosomal dominant trait. The label describes the pedigree, not the allele's mode of action: the underlying lesion is haploinsufficiency, and the biallelic state is both viable and more severe, which a true dominant-negative would not predict in this form.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:19468205 SUPPORT DIRECT Human Clinical

"Pelger-Huët anomaly (PHA), an autosomal dominant haematological trait is characterised by neutrophil nuclear hypolobulation and modified chromatin distribution."

States the inheritance mode.

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Subtypes

Heterozygous Pelger-Huet anomaly (the classic trait)

One LBR loss-of-function allele. Neutrophil nuclei are hypolobulated with coarse chromatin, and the carrier is otherwise healthy. This is what is meant by "Pelger-Huet anomaly" without qualification, and it is the state ascertained on blood films.

Show evidence (1 reference)

PMID:12118250 SUPPORT DIRECT Human Clinical

"Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin."

States the morphology that defines the heterozygous trait.

Homozygous Pelger-Huet anomaly (ovoid nuclei with systemic features)

Two LBR loss-of-function alleles, with only trace amounts of the protein. Granulocyte nuclei are frankly ovoid rather than merely hypolobulated, and the reported individuals also carry developmental delay, epilepsy and skeletal abnormalities in varying degree - so the biallelic state is not simply a more marked version of the same benign trait. This is a distinct band of the LBR allelic series from Greenberg dysplasia, which is prenatally lethal and is curated separately.

Show evidence (2 references)

PMID:12118250 SUPPORT DIRECT Human Clinical

"Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities."

Establishes both the nuclear morphology and the extra-haematological features of the biallelic state. Note the authors' own hedge - "presumed homozygous" - which is why this entry does not treat the systemic features as fully established.

PMID:42622427 REFUTE DIRECT Human Clinical

"Already in 1981, a homozygous Pelger-Huët proband with ovoid neutrophil nuclei but without special clinical symptoms has been reported."

Recorded as REFUTE against treating the systemic features as an obligate part of the biallelic state. A molecularly re-analysed homozygous proband had the ovoid nuclei and no clinical symptoms, so the developmental delay, epilepsy and skeletal abnormalities of the other report are not a necessary consequence of two mutant alleles. This is the strongest reason the entry keeps its hedge.

Discussions and Knowledge Gaps

Does Pelger-Huet anomaly arise from loss of LBR's heterochromatin-tethering function, from loss of its sterol C14-reductase function, or from neither individually?

KNOWLEDGE GAP lbr_domain_attribution

Attached to

pathophysiology#Heterochromatin Redistribution in the Granulocyte Nucleus pathophysiology#Reduced LBR Sterol C14-Reductase Activity

Three positions are defended in the literature and they are not reconcilable by emphasis. The structural reading is that less LBR means less heterochromatin tethered at the nuclear periphery and therefore no lobulation. It is the intuitive one, and the quantitative human dose-response result cited below is what it is usually taken to rest on: across 26 subjects carrying zero to three wild-type LBR alleles, about 65 per cent of the variance in nuclear segmentation tracks allele count. Note that this establishes dose-dependence on LBR quantity, not which of LBR's two domains does the work - so on its own it is equally consistent with the third position below. The metabolic reading is that the mutations causing both Pelger-Huet anomaly and Greenberg dysplasia lie in the transmembrane segments and act through cholesterol synthesis, and that no harmful mutation of the anchoring function has been reported at all. Against the metabolic reading there is a direct mouse experiment, and it is the strongest single piece of evidence here. DHCR14 encodes a second sterol delta-14-reductase, so LBR is not the only one. Disrupting Dhcr14 in mice produces essentially normal animals, Lbr-null mice do not resemble the Dhcr14 mutants, and no sterol abnormalities were detected in liver or kidney of either. On that basis the authors argue these disorders are laminopathies rather than inborn errors of cholesterol synthesis. Note this cuts against the metabolic account for the LBR disorders as a class, which includes Greenberg dysplasia, where a separate line of yeast-complementation evidence supports the enzymatic reading - so the contradiction is live rather than settled. A third possibility, consistent with the truncation-instability finding, is that the operative variable is total LBR protein quantity and neither domain function is separately causal for the nuclear phenotype. One experiment does bear on the domain question directly, and it favours the metabolic reading: in the EML ic/ic line, expressing the C-terminal sterol reductase domain alone rescued nuclear lobulation as well as growth arrest, lipid production and the respiratory burst. Two things keep this from settling the argument. It is a cultured myeloid line rather than an animal or a patient, so it inherits the in-vitro caveat recorded on the same system elsewhere in this entry; and a domain that is sufficient in a rescue construct is not thereby the domain whose loss causes the human disease, since an over-expressed fragment can restore a phenotype by a route the endogenous protein does not take. The distinction is not academic: it determines whether the anomaly belongs with the laminopathies or with the inborn errors of sterol metabolism, and this entry lists both as parents rather than choosing.

Show evidence (7 references)

PMID:28858257 REFUTE DIRECT Other

"Mutations within the transmembrane segments result in defects in cholesterol synthesis and are associated with diseases such as the Pelger-Huët anomaly and Greenberg skeletal dysplasia, whereas no such harmful mutations related to the anchoring properties of LBR have been reported so far."

Recorded as REFUTE against the heterochromatin-tethering account of this disease. The sentence asserts that no disease-causing mutation of the anchoring function has been reported, which cuts directly against the reading that lost tethering is what produces the anomaly.

PMID:21327094 SUPPORT DIRECT In Vitro

"The exact mechanisms of this nuclear shape change and of heterochromatin redistribution remain largely unknown."

An explicit statement from within the field that the mechanism is open, which is the claim this knowledge gap makes.

PMID:27684937 SUPPORT INDIRECT Human Clinical

"Approximately 65% of the observed phenotypic variance was explainable by the number of LBR wild type alleles."

The quantitative human dose-response measurement the structural reading is usually taken to rest on, and the strongest human support for treating LBR protein quantity as the operative variable. INDIRECT because allele count is a proxy for protein level and because the result says nothing about which domain is responsible.

+ 4 more references

If the lobulated granulocyte nucleus exists to make the cell deformable enough to migrate through tight tissue spaces, why are Pelger-Huet carriers not measurably more susceptible to infection?

KNOWLEDGE GAP lobulation_function_without_burden

Attached to

phenotypes#Hyposegmentation of Neutrophil Nuclei

The functional rationale for nuclear lobulation is migration through constricted spaces, and the anomaly abolishes lobulation in essentially every granulocyte for life. The trait is nonetheless described as asymptomatic. Two murine studies have asked the question directly and they disagree. A gene-trap Lbr mouse whose granulocytes lack a segmented nucleus kills Staphylococcus aureus normally, and its authors conclude LBR is needed for morphological but not functional granulocyte maturation. Neutrophils derived from the ichthyosis allele, by contrast, show abnormal chemotaxis and a deficient respiratory burst. The sharpest asymmetry between them is not the allele but the system. The gene-trap result is measured in granulocytes taken from a living animal; the ichthyosis result is measured in an EML progenitor cell line derived from an ic/ic mouse and induced to mature in culture, with no in vivo arm. A cultured line induced to a neutrophil-like state is not obliged to reproduce the proliferative and respiratory-burst competence of a marrow-matured cell, so a candidate adjudication does exist and is not the one this entry previously implied: repeat the chemotaxis and respiratory-burst assays on primary granulocytes from the same animal. Different alleles and different assays remain confounded on top of that. The human question is untouched either way, and the source itself says why. Both experiments are homozygous, and the human trait called asymptomatic is the heterozygous one, where far more LBR remains - the same paper notes that every prior human PHA functional study used heterozygous neutrophils. Carriers are ascertained incidentally, so no cohort has been assembled to look for a mild susceptibility with adequate power. This entry records the absence of an infection-susceptibility clinical burden as a claim about the literature rather than about the biology. It is a separate claim from the diagnostic hazard, which is documented and is curated in diagnosis:.

Show evidence (6 references)

PMID:17245605 SUPPORT INDIRECT Other

"This deformable nucleus enhances rapid migration."

States the functional claim that makes the absence of a clinical phenotype surprising. INDIRECT: it describes normal physiology, and the tension with the asymptomatic trait is an inference from it.

PMID:18550262 SUPPORT DIRECT Other

"All of these studies were performed with neutrophils heterozygous for the PHA mutation, which is not surprising since homozygous forms of PHA are most commonly fatal due to associated skeletal abnormalities"

Sharpens the gap rather than closing it: it says the human functional literature is entirely heterozygous, and names the reason it cannot easily be otherwise. Graded OTHER because this sentence is the paper's review of prior work, not a result of its own experiment, which is graded IN_VITRO where it is cited.

PMID:19468205 SUPPORT DIRECT Human Clinical

"Due to its asymptomatic nature or lack of observer familiarity, PHA is often overlooked."

States the asymptomatic nature, and simultaneously names the ascertainment problem that would hide a mild susceptibility.

+ 3 more references

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Pathophysiology

LBR Loss-of-Function Allele

A heterozygous germline loss-of-function variant in LBR. The mutational spectrum reported with the anomaly is dominated by alleles that destroy or truncate the transcript rather than by missense alleles acting on a specific residue, which is the first hint that the mechanism is one of protein quantity.

Genetic context LBR hgnc:6518 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Splice-site, frameshift and nonsense alleles account for the originally reported families; missense alleles are also described. The biallelic state, curated here as the Homozygous PHA subtype, gives ovoid nuclei rather than a qualitatively different disease.

inner nuclear membrane GO:0005637

Downstream

Reduced Lamin B Receptor Protein Level A single null allele is not compensated: heterozygous cells carry measurably less LBR protein than controls.

Show evidence (2 references)

PMID:12118250 SUPPORT DIRECT Human Clinical

"We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor."

Identifies LBR as the causal gene and gives the mutational classes - all loss-of-function - found in the mapping families.

PMID:14617022 SUPPORT DIRECT Human Clinical

"The LBR gene (LBR) was also sequenced from a single English man with Pelger-Huët anomaly and a heterozygous C-->G mutation was found in codon 569 of exon 14, predicted to cause a proline-->arginine."

Independent replication in a separate family, and the one that extends the spectrum to missense alleles.

Reduced Lamin B Receptor Protein Level

The quantity of lamin B receptor at the inner nuclear membrane falls below the level the differentiating granulocyte needs. This node, not the allele, is what the phenotype tracks: nuclear shape and chromatin distribution vary with LBR dose across the wild-type, heterozygous and biallelic states, so the same lesion at two doses gives hypolobulation and then frank ovoid nuclei.

inner nuclear membrane GO:0005637

Downstream

Heterochromatin Redistribution in the Granulocyte Nucleus LBR's nucleoplasmic N-terminal domain is what holds heterochromatin against the nuclear periphery. With less of the protein, that peripheral tethering is lost and heterochromatin redistributes, which is seen on the film as the coarse chromatin.

Failure of Granulocyte Nuclear Lobulation LBR is required for the granulocyte nucleus to depart from the ovoid default shape of other cell types. The requirement is not merely correlative: reducing LBR is sufficient to keep the nucleus ovoid through induced granulopoiesis.

Show evidence (2 references)

PMID:12118250 SUPPORT DIRECT In Vitro

"We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner."

The dose-response is the substantive claim of this node, and it is what rules out a dominant-negative reading of the dominant pedigree.

PMID:22338047 SUPPORT DIRECT Other

"PHA is caused by a decreased amount of the lamin B receptor (LBR)."

An independent review states the mechanism as a quantity defect. Graded OTHER because it is a review's summary statement rather than a reported experiment.

Heterochromatin Redistribution in the Granulocyte Nucleus

Heterochromatin that would sit against the inner nuclear membrane is released into the nuclear interior. On a stained film this is the "coarse", clumped chromatin that accompanies the shape change, and it is a separate observable from lobe count.

neutrophil CL:0000775

heterochromatin organization GO:0070828 ↓ DECREASED

heterochromatin GO:0000792

Downstream

Failure of Granulocyte Nuclear Lobulation Whether the chromatin change causes the shape change, or the two are parallel consequences of losing LBR, is not settled - see the knowledge gap recorded in discussions. The edge is drawn because the two are consistently reported together and heterochromatin tethering is the structural function LBR is losing, but it is the weakest link in this pathograph.

Show evidence (1 reference)

PMID:12118250 SUPPORT DIRECT Human Clinical

"Pelger-Huët anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes."

Names chromatin organization as a defining abnormality alongside nuclear shape, so the two are curated as separate nodes rather than one.

Failure of Granulocyte Nuclear Lobulation

The maturing granulocyte nucleus does not undergo the segmentation that normally converts it from a round to a multi-lobed shape. In the heterozygous state it stops at two lobes joined by a filament; with essentially no LBR it stays ovoid. The lobulated shape is thought to serve deformability during migration through tight tissue spaces, which is why the failure is a plausible candidate for functional consequence - and why the absence of one in carriers is itself worth recording. Why a ubiquitously expressed nuclear-envelope protein produces a granulocyte-restricted phenotype is answered at this node rather than upstream: LBR is transcriptionally upregulated by C/EBPepsilon during terminal granulopoiesis, against a reciprocal downregulation of lamins, so the granulocyte is the lineage that depends on a rising LBR level at exactly the point where a halved gene dosage cannot supply it. That reading is what the HL-60 knockdown's lineage-specificity readout probes: macrophage forms induced from the same knockdown cells were indistinguishable from the parent.

neutrophil CL:0000775 granulocyte CL:0000094

granulocyte differentiation GO:0030851

Experimental models

LBR-knockdown HL-60 subline CELL LINE Knockdown cells retain an ovoid nucleus through retinoic-acid-induced granulopoiesis while the parent line lobulates, reproducing the biallelic end of the human phenotype.

Animal models

Ichthyosis (ic) mouse Mouse recapitulates Reproduces the granulocyte nuclear phenotype from an Lbr lesion, in vivo and across three independent alleles.

Lbr gene-trap mouse Mouse recapitulates Granulocytes lack a mature segmented nucleus and show a block in late maturation.

Downstream

Hyposegmentation of Neutrophil Nuclei The failure of lobulation is what is seen on the blood film as the bilobed "pince-nez" neutrophil, and it is the observation the diagnosis rests on.

Coarse Granulocyte Nuclear Chromatin The second film finding, reported alongside hypolobulation rather than as a consequence of it.

Show evidence (4 references)

PMID:21327094 SUPPORT DIRECT In Vitro

"During in vitro granulopoiesis induced with retinoic acid, the LBR knockdown cells retain an ovoid shaped nucleus with reduced levels of lamin A/C; while, the parent cells develop highly lobulated nuclei."

An isogenic knockdown reproduces the failure of lobulation during granulopoiesis, which is the strongest available evidence that reduced LBR is sufficient for this node rather than merely associated with it. The clause about lamin A/C is the reciprocal half of the envelope remodelling described above.

PMID:18621876 SUPPORT INDIRECT Model Organism

"We identified C/EBPepsilon binding sites within the Lbr promoter and used EMSAs and luciferase assays to show that Lbr is transcriptionally regulated by C/EBPepsilon."

The transcriptional link that makes the lineage restriction of this node explicable rather than merely observed. INDIRECT: it establishes the regulation, and the step from there to "which is why the defect is granulocyte-specific" is an inference.

PMID:18550262 SUPPORT DIRECT Other

"LBR expression is increased during neutrophil differentiation, while the expression of certain lamins is downregulated"

The reciprocal remodelling itself, stated as established background. Graded OTHER because the sentence reviews prior HL-60 work rather than reporting this paper's own experiment.

+ 1 more reference

Reduced LBR Sterol C14-Reductase Activity

Mechanism confidence: Hypothetical

LBR's transmembrane segments carry the 3-beta-hydroxysterol delta-14-reductase step of post-squalene cholesterol synthesis, and a variant that lowers LBR level or stability lowers that activity too. Whether this arm contributes to the granulocyte nuclear phenotype, or is simply the arm that produces the skeletal end of the allelic series, is unresolved - which is why the node is marked HYPOTHETICAL and carries no downstream edge to the nuclear nodes. It is recorded because one authoritative review places Pelger-Huet anomaly on the cholesterol-synthesis side, against the reading that the trait is a pure heterochromatin-tethering defect.

3-beta-hydroxysterol delta-14-reductase activity GO:0050613 ↓ DECREASED

Show evidence (2 references)

PMID:27830109 SUPPORT INDIRECT In Vitro

"The study furthermore determined that disease-associated LBR point mutations reduce sterol C14 reductase activity by decreasing the affinity of LBR for the reducing agent NADPH."

Gives a mechanism by which disease alleles lower the enzymatic activity. INDIRECT because the assayed alleles are described as disease-associated for the LBR disorders as a class, and the quote does not separate the Pelger-Huet alleles from the Greenberg ones.

PMID:27830109 SUPPORT INDIRECT In Vitro

"Moreover, two disease-associated LBR truncation mutants were found to be highly unstable at the protein level and are rapidly turned over by a novel nuclear membrane-based protein quality control pathway."

Supplies a route from a truncating allele to reduced protein quantity, which is the node above. INDIRECT for the same reason - the alleles are not separated by phenotype in the quoted sentence.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 1

Hyposegmentation of Neutrophil Nuclei HP:0011447

Show evidence (1 reference)

PMID:19468205 SUPPORT DIRECT Human Clinical

"Pelger-Huët anomaly (PHA), an autosomal dominant haematological trait is characterised by neutrophil nuclear hypolobulation and modified chromatin distribution."

Names hypolobulation as the defining feature of the trait.

Musculoskeletal 1

Skeletal Abnormalities Abnormality of the skeletal system HP:0000924

Show evidence (1 reference)

PMID:12118250 SUPPORT DIRECT Human Clinical

"Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities."

Same sentence and same "presumed" genotype qualifier; skeletal abnormalities is the third listed biallelic feature.

Nervous System 2

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:12118250 SUPPORT DIRECT Human Clinical

"Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities."

Reports the feature in the biallelic state, with the authors' own "presumed" qualifier on the genotype call preserved.

Seizure HP:0001250

Show evidence (1 reference)

PMID:12118250 SUPPORT DIRECT Human Clinical

"Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities."

Same sentence; epilepsy is one of the listed biallelic features.

Other 2

Coarse Granulocyte Nuclear Chromatin

Show evidence (1 reference)

PMID:12118250 SUPPORT DIRECT Human Clinical

"Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin."

Reports the chromatin finding in affected heterozygotes.

Ovoid Granulocyte Nuclei

Show evidence (1 reference)

PMID:17245605 SUPPORT DIRECT Human Clinical

"A single dominant mutation in humans leads to neutrophils with hypolobulated nuclei (Pelger-Huet anomaly); homozygosity leads to ovoid granulocyte nuclei."

Assigns the ovoid morphology specifically to the biallelic genotype.

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Genetic Associations

LBR

Gene: LBR hgnc:6518 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:12118250 SUPPORT DIRECT Human Clinical

"We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor."

Establishes the gene-disease relationship in the mapping families.

PMID:28858257 SUPPORT DIRECT Other

"Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane, containing a hydrophilic N-terminal end protruding into the nucleoplasm, eight hydrophobic segments that span the membrane and a short, nucleoplasmic C-terminal tail."

Describes the protein architecture the two functional domains sit in.

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Diagnosis

Peripheral Blood Film Morphology

The anomaly is a morphological diagnosis made on a stained peripheral blood film, and it is usually incidental. The finding affects all granulocytes but is most easily seen in neutrophils. Because the same morphology is acquired in myelodysplasia and other states, recognising it should prompt the question of which it is, not a conclusion.

Show evidence (1 reference)

PMID:22338047 SUPPORT DIRECT Other

"The Pelger-Huët anomaly (PHA) is a recognized morphologic variant affecting all granulocytes but is most evident in polymorphonuclear neutrophils (PMNs)."

Establishes what is examined and in which cells the finding is clearest.

LBR Sequencing

Sequencing LBR confirms the inherited trait and is what separates it from an acquired pseudo-Pelger-Huet picture when the film alone cannot.

Show evidence (1 reference)

PMID:22338047 SUPPORT DIRECT Other

"Recognition of PHA morphologic features serves as a marker for mutations in the LBR gene."

Ties the morphological finding to the confirmatory genetic test.

Spurious Band-Form Count on the Automated Differential

The one consequence the anomaly reliably has. Hyposegmented neutrophils are counted as band forms, so an untroubled carrier's differential shows a marked left shift with a normal total white cell count - a picture that reads as bacterial infection and can trigger an infection work-up, or, in the acquired mimic, as myelodysplasia. The hazard is iatrogenic rather than a feature of the disease, which is why it is curated here as a diagnostic pitfall and not as clinical burden: nothing happens to the patient because of their neutrophils, only because of what is inferred from them. The remedy is the blood-film entry above.

Show evidence (2 references)

PMID:26634137 SUPPORT DIRECT Human Clinical

"It does not cause neutrophilia, but it can cause a false increase in band forms."

States the artifact and, in the same sentence, what distinguishes it from real infection: the band fraction moves and the total count does not.

PMID:26634137 SUPPORT DIRECT Human Clinical

"The presented case showed that we should think of PHA\PPHA in any case with normal total WBC count and significant shift to the lift with no apparent explanation."

The authors' own diagnostic rule, curated separately because it is a recommendation rather than a description of the artifact. Quoted with the source's typo for "left" intact, as a snippet never corrects what it quotes.

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Prevalence

Worldwide

Unknown Rare

No reliable numeric estimate is curated here. Published figures rest on blood-film ascertainment, and the review literature says explicitly that the anomaly is often missed, so any denominator drawn from routine haematology under-counts by an unknown factor. Founder effects are described in specific populations, which makes a single worldwide rate misleading in any case.

Show evidence (2 references)

PMID:19468205 SUPPORT INDIRECT Human Clinical

"Due to its asymptomatic nature or lack of observer familiarity, PHA is often overlooked."

Supports the ascertainment caveat rather than a rate. Quoted as the reason no numeric prevalence is asserted, so the inference step from "often overlooked" to "published rates under-count" is why this is marked INDIRECT.

PMID:35650273 SUPPORT INDIRECT Human Clinical

"To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders."

The one population-scale measurement available, and the reason this entry can say the LBR locus effect on nuclear morphology is not confined to rare pedigrees. It does not give a prevalence for the anomaly itself - band neutrophil fraction is a quantitative proxy, not a diagnosis - which is why it is INDIRECT and why no rate is asserted.

Worldwide

Point Prevalence 16.7 per 100,000 1–9 per 10,000

The published figure, roughly 1 in 6,000, carried as a second record rather than in place of the one above. It is stated in a case report as background rather than measured there, and it rests on the same blood-film ascertainment the first record's caveat is about, so it should be read as the number the literature repeats rather than as an established rate. Recording it is still better than omitting it: a reader looking for the figure will otherwise conclude the entry did not find one.

Show evidence (1 reference)

PMID:26634137 SUPPORT DIRECT Human Clinical

"Pelger-Huët anomaly (PHA) is a rare benign autosomal-dominant anomaly with an incidence of ∼1 in 6000."

States the figure directly. Note the source calls it an incidence while describing a lifelong congenital trait, so it is curated as a point prevalence; the wording is preserved in the quote rather than corrected.

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Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Pelger-Huet Anomaly:

Pseudo-Pelger-Huet anomaly

Overlapping Features Acquired hyposegmentation of neutrophil nuclei, seen in myelodysplastic syndromes, acute leukaemia, severe infection and as a drug effect. Morphologically it can be indistinguishable from the inherited trait on a single film, which is the whole clinical problem: here the finding is a marker of dysplasia and demands a haematological work-up, whereas in the inherited trait it demands nothing.

Distinguishing Features

Acquired rather than lifelong, so an earlier normal film settles it where one exists
Typically affects a proportion of neutrophils rather than nearly all of them
Accompanied by other dysplastic features and by cytopenias
No LBR germline variant, and no affected first-degree relatives

Show evidence (1 reference)

PMID:22338047 SUPPORT DIRECT Other

"Guidance is given for distinguishing PHA from other hematologic disorders in which granulocytes may show similar changes."

Confirms that other haematological disorders produce a similar granulocyte appearance and that the distinction is a recognised diagnostic task.

Greenberg dysplasia

Overlapping Features The other end of the LBR allelic series: biallelic alleles that abolish sterol C14-reductase activity give a prenatally lethal skeletal dysplasia. It is not a severe form of this anomaly and is curated as a separate dismech entry.

Distinguishing Features

Prenatally lethal, presenting as fetal hydrops with markedly short limbs
Driven by loss of the enzymatic function rather than by reduced protein quantity
Biallelic; obligate carriers are healthy apart from the Pelger-Huet trait

Show evidence (1 reference)

PMID:27830109 SUPPORT DIRECT Other

"Lamin B Receptor (LBR) is an inner nuclear membrane protein associated with the rare human diseases Pelger-Huët anomaly and Greenberg skeletal dysplasia."

Establishes the two as distinct diseases of the same gene.

Non-LBR hyposegmentation of granulocytes in animals

Overlapping Features Hyposegmented granulocytes occur in domestic animals and are often called Pelger-Huet anomaly by analogy. That analogy should not be assumed to extend to the gene. In Australian Shepherd Dogs with an autosomal recessive hyposegmentation phenotype, linkage analysis excluded LBR and implicated LMBR1L instead. The row is here because a veterinary report of "Pelger-Huet anomaly" is not evidence about LBR, and a curator reaching for cross-species support should check which gene was actually mapped.

Distinguishing Features

LBR excluded by linkage in the reported canine phenotype
Autosomal recessive with stillbirth in the affected litter, unlike the benign human heterozygous trait

Show evidence (1 reference)

PMID:37347778 REFUTE DIRECT Model Organism

"HG phenotypes have also been described in domestic animals and homology to human PHA has been claimed in the literature."

Recorded as REFUTE against the assumption that animal hyposegmentation phenotypes are LBR-related. The sentence states the claim that the paper then goes on to test, and the study's own finding excludes LBR for this breed.

SOPH syndrome (NBAS)

Overlapping Features Short stature with optic nerve atrophy and Pelger-Huet anomaly, an autosomal recessive syndrome caused by the NBAS founder variant G5741A (R1914H) and first described in Yakuts, where heterozygous carriage averages 13 per 1000. The neutrophil finding is part of the named phenotype, so a film alone does not separate it from the isolated trait - but everything around the film does, and the carrier frequency means ancestry is a real prior rather than a curiosity.

Distinguishing Features

Autosomal recessive, so parents are unaffected where the isolated trait is dominant
Proportionate postnatal short stature and optic nerve atrophy, neither a feature of the isolated trait
Facial dysmorphism, micromelia of hands and feet, lax skin
NBAS rather than LBR on sequencing
Sakha (Yakut) ancestry raises the prior substantially

Show evidence (2 references)

PMID:29369590 SUPPORT DIRECT Human Clinical

"SOPH syndrome (Short stature with Optic nerve atrophy and Pelger–Huët anomaly syndrome, OMIM#614800) is an autosomal recessive hereditary disease characterized by the following main clinical symptoms: postnatal hypoplasia, proportionately short stature, facial dysmorphism, micromelia of feet and..."

Establishes the syndrome, its inheritance and the fact that the neutrophil anomaly is one of its defining features, which is what makes it a differential rather than an unrelated disorder.

PMID:29369590 SUPPORT DIRECT Human Clinical

"The frequency of heterozygous carriers of mutation G5741→A (R1914H) in gene NBAS was found, which averaged 13 per 1000 healthy Yakuts."

Curated as its own item because the carrier frequency is a separate claim from the phenotype, and it is the part that makes ancestry diagnostically useful here.

TMEM147-related syndromic pseudo-Pelger-Huet anomaly

Overlapping Features Biallelic loss of function in TMEM147, which anchors LBR to the inner nuclear membrane, causes moderate to profound intellectual disability with coarse facies and abnormal nuclear segmentation in about a fifth of neutrophils. Mechanistically this is the closest of the differentials to the entry itself: it reaches the same nuclear phenotype by removing LBR's anchor rather than LBR, which is why it produces a partial rather than a near-universal neutrophil picture.

Distinguishing Features

Autosomal recessive, and syndromic rather than isolated
Moderate to profound intellectual disability, behavioural problems, coarse facies
Roughly 20 per cent of neutrophils affected rather than nearly all
TMEM147 rather than LBR on sequencing, with LBR itself intact

Show evidence (2 references)

PMID:36044892 SUPPORT DIRECT Human Clinical

"Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly."

States the neutrophil finding and its partial penetrance across the cell population, which is the feature that separates it from the isolated trait on a film.

PMID:32694168 SUPPORT INDIRECT In Vitro

"Silencing of TMEM147 drastically reduces the level of lamin B receptor (LBR) at the inner nuclear membrane and results in mistargeting of LBR to the ER."

The mechanistic link, and the reason this differential converges on the same node as the entry rather than mimicking it coincidentally: losing TMEM147 lowers LBR where it has to act. INDIRECT on two counts - it is HeLa silencing rather than the patient genotype, and the step to the neutrophil phenotype in affected individuals is an inference.

🧫

Experimental Models

LBR-knockdown HL-60 subline CELL_LINE

A stable LBR-knockdown subline of the human promyelocytic HL-60 line, differentiated down the granulocyte lineage with retinoic acid. It is the closest thing to an isogenic in vitro model of the anomaly: the same genetic background with and without LBR, taken through granulopoiesis, so the nuclear phenotype can be attributed to LBR dose rather than to line-to-line variation.

Publication

PMID:21327094

Pathograph links

Failure of Granulocyte Nuclear Lobulation recapitulates fidelity: moderate observes: cellular Knockdown cells retain an ovoid nucleus through retinoic-acid-induced granulopoiesis while the parent line lobulates, reproducing the biallelic end of the human phenotype.

Limitations: HL-60 is a leukaemia-derived line carrying its own karyotypic abnormalities, and retinoic-acid-induced granulopoiesis in culture is not marrow granulopoiesis. Knockdown gives a graded reduction rather than the defined one- or two-allele human genotypes, so the model reproduces the ovoid extreme rather than the heterozygous hypolobulation that defines the trait clinically.

Readouts

Nuclear shape after retinoic-acid-induced granulopoiesis

Direction: ALTERED

Interpretation: Ovoid rather than lobulated nuclei in the knockdown line is the structural correlate of this node.

Show evidence (1 reference)

PMID:21327094 SUPPORT DIRECT In Vitro

Reports the measurement and its direction against an isogenic control.

Nuclear shape after phorbol-ester-induced macrophage differentiation

Direction: UNCHANGED

Interpretation: A real negative result, and the one that gives the model its specificity: losing LBR does not disturb nuclear shape down the macrophage lineage, so the defect is specific to granulopoiesis rather than a general nuclear-morphology artefact of the knockdown.

Show evidence (1 reference)

PMID:21327094 SUPPORT DIRECT In Vitro

"In contrast, macrophage forms induced in LBR knockdown cells by in vitro treatment with phorbol ester were indistinguishable from the parent cells, judged by both nuclear shape and attached cell morphology."

Reports the lineage-specificity control. Recorded as UNCHANGED because the measurement was made and found equal, which is different from not having been made.

Show evidence (1 reference)

PMID:21327094 SUPPORT DIRECT In Vitro

"As a tool to facilitate analysis of these mechanisms, a stable LBR knockdown subline of HL-60 cells was established."

States that the line was built for the purpose of studying this mechanism, which is what makes it informative for the node rather than incidentally relevant.

🐁

Animal Models

Ichthyosis (ic) mouse

The classical mouse counterpart, and a case where the mouse locus was known long before the gene. Mice homozygous at the ichthyosis locus have a blood phenotype like Pelger-Huet anomaly, and the causal mutations were shown to lie in Lbr. Note the mouse is homozygous where the human trait is heterozygous, and carries extra features - alopecia, variable syndactyly, hydrocephalus - that the human heterozygous trait does not.

Species

Mouse

Genotype

Lbr(ic/ic), Lbr(icJ/icJ), Lbr(ic4J/ic4J) - nonsense and frameshift alleles

Publication

PMID:12490533

Pathograph links

Failure of Granulocyte Nuclear Lobulation recapitulates fidelity: moderate observes: cellular Reproduces the granulocyte nuclear phenotype from an Lbr lesion, in vivo and across three independent alleles.

Limitations: Homozygous, where the defining human trait is heterozygous, so the model corresponds to the Homozygous PHA subtype rather than to the common presentation. It also carries alopecia, syndactyly and hydrocephalus, which are not features of the human heterozygous trait, so the model is not phenotypically clean.

Divergences from the human mechanism

species mismatch qualifying

The extra murine features (alopecia, syndactyly, hydrocephalus) have no counterpart in human heterozygous Pelger-Huet anomaly, so the allele's consequences are not equivalent across species.

population mismatch invalidating

The model is homozygous and the human trait this entry is named for is heterozygous. For a dosage-dependent phenotype that is the difference between the two bands of the allelic series, not a matter of degree.

Readouts

Granulocyte nuclear morphology

Direction: ALTERED

Interpretation: A blood phenotype resembling the human anomaly.

Show evidence (1 reference)

PMID:12490533 SUPPORT DIRECT Model Organism

"Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype similar to PHA, and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly and hydrocephalus."

States both the resemblance and the divergence in one sentence, which is why it is quoted whole rather than trimmed to the supportive clause.

Show evidence (1 reference)

PMID:12490533 SUPPORT DIRECT Model Organism

"In this study, we identified one nonsense (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus."

Establishes that the mouse locus is Lbr, across three independent alleles, which is what makes this a model of the same gene rather than a phenocopy.

Lbr gene-trap mouse

A gene-trap insertion at Lbr, described by its authors as a model for Pelger-Huet anomaly. Its interest here is not the nuclear phenotype, which is expected, but the functional result: the granulocytes look immature and kill bacteria normally. The same study also places Lbr downstream of C/EBP-epsilon, which links this entry to the transcriptional program of granulocyte maturation.

Species

Mouse

Genotype

Lbr(GT/GT)

Publication

PMID:18621876

Pathograph links

Failure of Granulocyte Nuclear Lobulation recapitulates fidelity: moderate observes: cellular Granulocytes lack a mature segmented nucleus and show a block in late maturation.

Limitations: Homozygous gene-trap, against a heterozygous human trait. A gene trap may leave residual transcript, so the effective dose is not necessarily null, and the study does not quantify it.

Divergences from the human mechanism

population mismatch invalidating

Homozygous model, heterozygous human trait, in a phenotype that tracks protein dose.

Readouts

Granulocyte nuclear segmentation and maturation

Direction: ALTERED

Interpretation: The nuclear phenotype plus an associated late-maturation block.

Show evidence (1 reference)

PMID:18621876 SUPPORT DIRECT Model Organism

"The Lbr(GT/GT) granulocytes lack a mature segmented nucleus and have a block in late maturation."

The measured nuclear and maturation phenotype.

Staphylococcus aureus killing

Direction: UNCHANGED

Interpretation: A real negative result, and the one that matters clinically: the nuclear phenotype is present and bacterial killing is not measurably impaired. It is the strongest available support for the trait being functionally benign, and it is contradicted by another mouse study - see the knowledge gap.

Show evidence (1 reference)

PMID:18621876 SUPPORT DIRECT Model Organism

"Despite these changes in nuclear morphology, the innate granulocyte immune function in the killing of Staphylococcus aureus bacteria appears to be intact."

Recorded as UNCHANGED because the measurement was made and found equal, which is a different claim from not having been made.

Show evidence (1 reference)

PMID:18621876 SUPPORT DIRECT Model Organism

"Our findings indicate that the Lbr(GT/GT) mice are a model for Pelger-Huët anomaly and that Lbr, under transcriptional regulation of C/EBPepsilon, is necessary for morphological but not necessarily functional granulocyte maturation."

The authors' own claim that this is a model for the disorder, with their hedge - "not necessarily" - preserved.

{ }

Source YAML

click to show

name: Pelger-Huet Anomaly
creation_date: "2026-09-10T00:00:00Z"
category: Mendelian
description: >-
  Pelger-Huet anomaly is an autosomal dominant trait in which blood granulocytes fail to
  segment their nuclei. Neutrophils that should carry three to five lobes instead show two
  lobes joined by a thin filament - the "pince-nez" form - or a single unsegmented nucleus,
  and the chromatin inside them is unusually coarse. The cause is heterozygous
  loss-of-function variation in LBR, encoding the lamin B receptor, an inner nuclear
  membrane protein whose nucleoplasmic N-terminal domain tethers heterochromatin to the
  nuclear periphery. What makes the anomaly unusual mechanistically is that the phenotype
  tracks protein dose rather than any qualitative change: heterozygous cells carry reduced
  LBR and give hypolobulated nuclei, cells with two mutant alleles carry only traces and
  give frankly ovoid nuclei, and the relationship was shown to be dose-dependent in the
  same experiment that identified the gene. So the entry is a haploinsufficiency, not a
  dominant-negative one, and the "dominant" in autosomal dominant describes the pedigree
  rather than the allele's behaviour.

  The clinical point of the entry is almost entirely diagnostic rather than therapeutic.
  Carriers are healthy - neutrophil migration, phagocytosis and killing are not
  meaningfully impaired, and the trait is usually found incidentally on a blood film. Its
  importance is that the same morphology is acquired in myelodysplastic syndromes, acute
  leukaemia, severe infection and as a drug reaction, where it is called pseudo-Pelger-Huet
  anomaly and is a marker of dysplasia. Mistaking the inherited trait for the acquired one
  can precipitate a bone marrow biopsy and a haematological work-up in a well person;
  mistaking the acquired one for the inherited trait can delay a diagnosis of MDS.

  LBR carries a second, unrelated function in its transmembrane segments - the
  3-beta-hydroxysterol delta-14-reductase step of post-squalene cholesterol synthesis - and
  the allelic series at this locus separates the two. Alleles that reduce LBR protein level
  give this anomaly; alleles that abolish the reductase activity give the prenatally lethal
  Greenberg dysplasia, which is curated separately. The separation is not clean in the
  direction one would assume: a homozygous missense allele has been reported that produces a
  non-lethal skeletal dysplasia with no Pelger-Huet anomaly at all, so the nuclear-shape
  phenotype is not an obligate accompaniment of biallelic LBR disease.
synonyms:
- PHA
- Pelger-Huet nuclear anomaly
- Pelger anomaly
- Pelger-Huet nuclear hypolobulation
disease_term:
  preferred_term: Pelger-Huet anomaly
  term:
    id: MONDO:0008214
    label: Pelger-Huet anomaly
parents:
- Laminopathy
- Leukocyte Disorder
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: >-
      The encounter is haematological: the anomaly is found on a blood film, and the
      question it raises is whether the dysplastic-looking neutrophils are inherited or
      are a marker of myelodysplasia.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian autosomal dominant trait with a gene-dosage mechanism, and the
      counselling question for a carrier couple is the biallelic state.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008214
      label: Pelger-Huet anomaly
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The dismech entry and the MONDO class denote the same entity: the LBR-related
      inherited granulocyte nuclear hypolobulation trait. The other LBR phenotypes
      (Greenberg dysplasia, the mild biallelic anadysplasia-like spondylometaphyseal
      dysplasia, the reported non-lethal skeletal dysplasia without Pelger-Huet anomaly)
      are discussed here as an allelic series but are not part of this class.
references:
- reference: PMID:12118250
  title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
- reference: PMID:14617022
  title: "Lamin B-receptor mutations in Pelger-Huët anomaly."
- reference: PMID:17245605
  title: "The granulocyte nucleus and lamin B receptor: avoiding the ovoid."
- reference: PMID:19468205
  title: "Pelger-Huët anomaly: a critical review of the literature."
- reference: PMID:21327094
  title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
- reference: PMID:22338047
  title: "Understanding and recognizing the Pelger-Huët anomaly."
- reference: PMID:27830109
  title: "Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism."
- reference: PMID:28858257
  title: "Lamin B Receptor: Interplay between Structure, Function and Localization."
- reference: PMID:32827848
  title: "A homozygous variant in the Lamin B receptor gene LBR results in a non-lethal skeletal dysplasia without Pelger-Huët anomaly."
- reference: PMID:12490533
  title: "Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huët anomaly."
- reference: PMID:17403717
  title: "HEM dysplasia and ichthyosis are likely laminopathies and not due to 3beta-hydroxysterol Delta14-reductase deficiency."
- reference: PMID:18550262
  title: "Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses."
- reference: PMID:18621876
  title: "The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils."
- reference: PMID:30564248
  title: "The Neutrophil Nucleus: An Important Influence on Neutrophil Migration and Function."
- reference: PMID:35650273
  title: Genetic architecture of band neutrophil fraction in Iceland.
- reference: PMID:37347778
  title: "Autosomal recessive hyposegmentation of granulocytes in Australian Shepherd Dogs indicates a role for LMBR1L in myeloid leukocytes."
- reference: PMID:42622427
  title: "A homozygous lamin B receptor variant resulting in Pelger-Huët anomaly without skeletal dysplasia."
- reference: PMID:22140257
  title: "Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis."
- reference: PMID:26634137
  title: "Case of acquired or pseudo-Pelger-Huët anomaly."
- reference: PMID:27684937
  title: "Image analysis of neutrophil nuclear morphology: Learning about phenotypic range and its reliable analysis from patients with pelger-Huët-anomaly and treated with colchicine."
- reference: PMID:29369590
  title: "[Population frequency and age of mutation G5741→A in gene NBAS which is a cause of SOPH syndrome in Sakha (Yakutia) Republic]."
- reference: PMID:32694168
  title: "TMEM147 interacts with lamin B receptor, regulates its localization and levels, and affects cholesterol homeostasis."
- reference: PMID:36044892
  title: "Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly."
has_subtypes:
- name: Heterozygous PHA
  display_name: Heterozygous Pelger-Huet anomaly (the classic trait)
  description: >-
    One LBR loss-of-function allele. Neutrophil nuclei are hypolobulated with coarse
    chromatin, and the carrier is otherwise healthy. This is what is meant by
    "Pelger-Huet anomaly" without qualification, and it is the state ascertained on blood
    films.
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin."
    explanation: States the morphology that defines the heterozygous trait.
- name: Homozygous PHA
  display_name: Homozygous Pelger-Huet anomaly (ovoid nuclei with systemic features)
  description: >-
    Two LBR loss-of-function alleles, with only trace amounts of the protein. Granulocyte
    nuclei are frankly ovoid rather than merely hypolobulated, and the reported
    individuals also carry developmental delay, epilepsy and skeletal abnormalities in
    varying degree - so the biallelic state is not simply a more marked version of the
    same benign trait. This is a distinct band of the LBR allelic series from Greenberg
    dysplasia, which is prenatally lethal and is curated separately.
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying
      degrees of developmental delay, epilepsy and skeletal abnormalities.
    explanation: >-
      Establishes both the nuclear morphology and the extra-haematological features of the
      biallelic state. Note the authors' own hedge - "presumed homozygous" - which is why
      this entry does not treat the systemic features as fully established.
  - reference: PMID:42622427
    reference_title: "A homozygous lamin B receptor variant resulting in Pelger-Huët anomaly without skeletal dysplasia."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Already in 1981, a homozygous Pelger-Huët proband with ovoid neutrophil nuclei but
      without special clinical symptoms has been reported.
    explanation: >-
      Recorded as REFUTE against treating the systemic features as an obligate part of the
      biallelic state. A molecularly re-analysed homozygous proband had the ovoid nuclei
      and no clinical symptoms, so the developmental delay, epilepsy and skeletal
      abnormalities of the other report are not a necessary consequence of two mutant
      alleles. This is the strongest reason the entry keeps its hedge.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    No reliable numeric estimate is curated here. Published figures rest on blood-film
    ascertainment, and the review literature says explicitly that the anomaly is often
    missed, so any denominator drawn from routine haematology under-counts by an unknown
    factor. Founder effects are described in specific populations, which makes a single
    worldwide rate misleading in any case.
  evidence:
  - reference: PMID:19468205
    reference_title: "Pelger-Huët anomaly: a critical review of the literature."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to its asymptomatic nature or lack of observer familiarity, PHA is often overlooked."
    explanation: >-
      Supports the ascertainment caveat rather than a rate. Quoted as the reason no
      numeric prevalence is asserted, so the inference step from "often overlooked" to
      "published rates under-count" is why this is marked INDIRECT.
  - reference: PMID:35650273
    reference_title: Genetic architecture of band neutrophil fraction in Iceland.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To search for sequence variants affecting nuclear morphology of granulocytes, we
      performed a genome-wide association study using band neutrophil fraction from 88,101
      Icelanders.
    explanation: >-
      The one population-scale measurement available, and the reason this entry can say the
      LBR locus effect on nuclear morphology is not confined to rare pedigrees. It does not
      give a prevalence for the anomaly itself - band neutrophil fraction is a quantitative
      proxy, not a diagnosis - which is why it is INDIRECT and why no rate is asserted.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 16.7
  notes: >-
    The published figure, roughly 1 in 6,000, carried as a second record rather than in
    place of the one above. It is stated in a case report as background rather than
    measured there, and it rests on the same blood-film ascertainment the first record's
    caveat is about, so it should be read as the number the literature repeats rather than
    as an established rate. Recording it is still better than omitting it: a reader looking
    for the figure will otherwise conclude the entry did not find one.
  evidence:
  - reference: PMID:26634137
    reference_title: "Case of acquired or pseudo-Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pelger-Huët anomaly (PHA) is a rare benign autosomal-dominant anomaly with an
      incidence of ∼1 in 6000.
    explanation: >-
      States the figure directly. Note the source calls it an incidence while describing a
      lifelong congenital trait, so it is curated as a point prevalence; the wording is
      preserved in the quote rather than corrected.
pathophysiology:
- name: LBR Loss-of-Function Allele
  biological_scale: MOLECULAR
  description: >-
    A heterozygous germline loss-of-function variant in LBR. The mutational spectrum
    reported with the anomaly is dominated by alleles that destroy or truncate the
    transcript rather than by missense alleles acting on a specific residue, which is the
    first hint that the mechanism is one of protein quantity.
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    gene:
      preferred_term: LBR
      term:
        id: hgnc:6518
        label: LBR
    description: >-
      Splice-site, frameshift and nonsense alleles account for the originally reported
      families; missense alleles are also described. The biallelic state, curated here as
      the Homozygous PHA subtype, gives ovoid nuclei rather than a qualitatively different
      disease.
  cellular_components:
  - preferred_term: inner nuclear membrane
    term:
      id: GO:0005637
      label: nuclear inner membrane
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor."
    explanation: >-
      Identifies LBR as the causal gene and gives the mutational classes - all
      loss-of-function - found in the mapping families.
  - reference: PMID:14617022
    reference_title: "Lamin B-receptor mutations in Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The LBR gene (LBR) was also sequenced from a single English man with Pelger-Huët
      anomaly and a heterozygous C-->G mutation was found in codon 569 of exon 14,
      predicted to cause a proline-->arginine.
    explanation: >-
      Independent replication in a separate family, and the one that extends the spectrum
      to missense alleles.
  downstream:
  - target: Reduced Lamin B Receptor Protein Level
    description: >-
      A single null allele is not compensated: heterozygous cells carry measurably less
      LBR protein than controls.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12118250
      reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced
        expression of the lamin B receptor, and cells homozygous with respect to PHA
        contain only trace amounts of it.
      explanation: >-
        Measures the protein level directly in patient-derived cells of both genotypes,
        which is what makes this a dosage lesion rather than an inferred one.
- name: Reduced Lamin B Receptor Protein Level
  biological_scale: MOLECULAR
  description: >-
    The quantity of lamin B receptor at the inner nuclear membrane falls below the level
    the differentiating granulocyte needs. This node, not the allele, is what the
    phenotype tracks: nuclear shape and chromatin distribution vary with LBR dose across
    the wild-type, heterozygous and biallelic states, so the same lesion at two doses
    gives hypolobulation and then frank ovoid nuclei.
  cellular_components:
  - preferred_term: inner nuclear membrane
    term:
      id: GO:0005637
      label: nuclear inner membrane
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner."
    explanation: >-
      The dose-response is the substantive claim of this node, and it is what rules out a
      dominant-negative reading of the dominant pedigree.
  - reference: PMID:22338047
    reference_title: "Understanding and recognizing the Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "PHA is caused by a decreased amount of the lamin B receptor (LBR)."
    explanation: >-
      An independent review states the mechanism as a quantity defect. Graded OTHER
      because it is a review's summary statement rather than a reported experiment.
  downstream:
  - target: Heterochromatin Redistribution in the Granulocyte Nucleus
    description: >-
      LBR's nucleoplasmic N-terminal domain is what holds heterochromatin against the
      nuclear periphery. With less of the protein, that peripheral tethering is lost and
      heterochromatin redistributes, which is seen on the film as the coarse chromatin.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28858257
      reference_title: "Lamin B Receptor: Interplay between Structure, Function and Localization."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Its N-terminal domain tethers heterochromatin to the nuclear periphery, thus
        contributing to the shape of interphase nuclear architecture, while its
        transmembrane domains exhibit sterol reductase activity.
      explanation: >-
        Establishes the tethering function that this edge depends on. Marked INDIRECT
        because it states what the domain does in general, and the step to "therefore less
        LBR redistributes heterochromatin in granulocytes" is an inference.
    - reference: PMID:21327094
      reference_title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In humans, a genetic deficiency of LBR produces Pelger-Huët anomaly, resulting in
        blood neutrophils that exhibit hypolobulated nuclei with redistributed
        heterochromatin.
      explanation: >-
        States the redistribution as an observed feature of the human neutrophils, tying
        the LBR deficiency to the chromatin change rather than only to the shape change.
  - target: Failure of Granulocyte Nuclear Lobulation
    description: >-
      LBR is required for the granulocyte nucleus to depart from the ovoid default shape
      of other cell types. The requirement is not merely correlative: reducing LBR is
      sufficient to keep the nucleus ovoid through induced granulopoiesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17245605
      reference_title: "The granulocyte nucleus and lamin B receptor: avoiding the ovoid."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      snippet: "Recent studies have demonstrated that lamin B receptor (LBR) is necessary for the non-ovoid shape."
      explanation: States the necessity relation this edge asserts.
    - reference: PMID:17245605
      reference_title: "The granulocyte nucleus and lamin B receptor: avoiding the ovoid."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A single dominant mutation in humans leads to neutrophils with hypolobulated
        nuclei (Pelger-Huet anomaly); homozygosity leads to ovoid granulocyte nuclei.
      explanation: >-
        Gives the two-step dose relation in human genotypes, which is the specific form
        this edge takes.
- name: Heterochromatin Redistribution in the Granulocyte Nucleus
  biological_scale: CELLULAR
  description: >-
    Heterochromatin that would sit against the inner nuclear membrane is released into the
    nuclear interior. On a stained film this is the "coarse", clumped chromatin that
    accompanies the shape change, and it is a separate observable from lobe count.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: heterochromatin organization
    modifier: DECREASED
    term:
      id: GO:0070828
      label: heterochromatin organization
  cellular_components:
  - preferred_term: heterochromatin
    term:
      id: GO:0000792
      label: heterochromatin
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pelger-Huët anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes."
    explanation: >-
      Names chromatin organization as a defining abnormality alongside nuclear shape, so
      the two are curated as separate nodes rather than one.
  downstream:
  - target: Failure of Granulocyte Nuclear Lobulation
    description: >-
      Whether the chromatin change causes the shape change, or the two are parallel
      consequences of losing LBR, is not settled - see the knowledge gap recorded in
      discussions. The edge is drawn because the two are consistently reported together
      and heterochromatin tethering is the structural function LBR is losing, but it is
      the weakest link in this pathograph.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21327094
      reference_title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
      supports: NO_EVIDENCE
      evidence_source: IN_VITRO
      snippet: "The exact mechanisms of this nuclear shape change and of heterochromatin redistribution remain largely unknown."
      explanation: >-
        Recorded as NO_EVIDENCE deliberately. The cited paper does not establish the
        direction of this edge; it states that the mechanism is unknown, which is the
        honest status of the link and the reason it is typed INDIRECT.
- name: Failure of Granulocyte Nuclear Lobulation
  biological_scale: CELLULAR
  description: >-
    The maturing granulocyte nucleus does not undergo the segmentation that normally
    converts it from a round to a multi-lobed shape. In the heterozygous state it stops at
    two lobes joined by a filament; with essentially no LBR it stays ovoid. The lobulated
    shape is thought to serve deformability during migration through tight tissue spaces,
    which is why the failure is a plausible candidate for functional consequence - and
    why the absence of one in carriers is itself worth recording.

    Why a ubiquitously expressed nuclear-envelope protein produces a granulocyte-restricted
    phenotype is answered at this node rather than upstream: LBR is transcriptionally
    upregulated by C/EBPepsilon during terminal granulopoiesis, against a reciprocal
    downregulation of lamins, so the granulocyte is the lineage that depends on a rising
    LBR level at exactly the point where a halved gene dosage cannot supply it. That
    reading is what the HL-60 knockdown's lineage-specificity readout probes: macrophage
    forms induced from the same knockdown cells were indistinguishable from the parent.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  biological_processes:
  - preferred_term: granulocyte differentiation
    term:
      id: GO:0030851
      label: granulocyte differentiation
  evidence:
  - reference: PMID:21327094
    reference_title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      During in vitro granulopoiesis induced with retinoic acid, the LBR knockdown cells
      retain an ovoid shaped nucleus with reduced levels of lamin A/C; while, the parent
      cells develop highly lobulated nuclei.
    explanation: >-
      An isogenic knockdown reproduces the failure of lobulation during granulopoiesis,
      which is the strongest available evidence that reduced LBR is sufficient for this
      node rather than merely associated with it. The clause about lamin A/C is the
      reciprocal half of the envelope remodelling described above.
  - reference: PMID:18621876
    reference_title: "The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We identified C/EBPepsilon binding sites within the Lbr promoter and used EMSAs and
      luciferase assays to show that Lbr is transcriptionally regulated by C/EBPepsilon.
    explanation: >-
      The transcriptional link that makes the lineage restriction of this node explicable
      rather than merely observed. INDIRECT: it establishes the regulation, and the step
      from there to "which is why the defect is granulocyte-specific" is an inference.
  - reference: PMID:18550262
    reference_title: "Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      LBR expression is increased during neutrophil differentiation, while the expression
      of certain lamins is downregulated
    explanation: >-
      The reciprocal remodelling itself, stated as established background. Graded OTHER
      because the sentence reviews prior HL-60 work rather than reporting this paper's own
      experiment.
  - reference: PMID:17245605
    reference_title: "The granulocyte nucleus and lamin B receptor: avoiding the ovoid."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "This deformable nucleus enhances rapid migration."
    explanation: >-
      Supplies the functional rationale for why nuclear lobulation exists at all. Marked
      INDIRECT: it is a statement about normal physiology, from which the significance of
      the failure follows by inference rather than by measurement in carriers.
  downstream:
  - target: Hyposegmentation of Neutrophil Nuclei
    description: >-
      The failure of lobulation is what is seen on the blood film as the bilobed
      "pince-nez" neutrophil, and it is the observation the diagnosis rests on.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19468205
      reference_title: "Pelger-Huët anomaly: a critical review of the literature."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pelger-Huët anomaly (PHA), an autosomal dominant haematological trait is
        characterised by neutrophil nuclear hypolobulation and modified chromatin
        distribution.
      explanation: Ties the cellular failure to the reported clinical morphology.
  - target: Coarse Granulocyte Nuclear Chromatin
    description: >-
      The second film finding, reported alongside hypolobulation rather than as a
      consequence of it.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:14617022
      reference_title: "Lamin B-receptor mutations in Pelger-Huët anomaly."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pelger-Huët anomaly is an inherited abnormality of neutrophils, characterized by
        reduced nuclear segmentation and an apparently looser chromatin structure.
      explanation: >-
        Reports the two film findings together. Note the authors' hedge, "apparently
        looser", which is preserved rather than smoothed into a firmer claim.
- name: Reduced LBR Sterol C14-Reductase Activity
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    LBR's transmembrane segments carry the 3-beta-hydroxysterol delta-14-reductase step of
    post-squalene cholesterol synthesis, and a variant that lowers LBR level or stability
    lowers that activity too. Whether this arm contributes to the granulocyte nuclear
    phenotype, or is simply the arm that produces the skeletal end of the allelic series,
    is unresolved - which is why the node is marked HYPOTHETICAL and carries no downstream
    edge to the nuclear nodes. It is recorded because one authoritative review places
    Pelger-Huet anomaly on the cholesterol-synthesis side, against the reading that the
    trait is a pure heterochromatin-tethering defect.
  molecular_functions:
  - preferred_term: 3-beta-hydroxysterol delta-14-reductase activity
    modifier: DECREASED
    term:
      id: GO:0050613
      label: Delta14-sterol reductase activity
  evidence:
  - reference: PMID:27830109
    reference_title: "Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The study furthermore determined that disease-associated LBR point mutations reduce
      sterol C14 reductase activity by decreasing the affinity of LBR for the reducing
      agent NADPH.
    explanation: >-
      Gives a mechanism by which disease alleles lower the enzymatic activity. INDIRECT
      because the assayed alleles are described as disease-associated for the LBR
      disorders as a class, and the quote does not separate the Pelger-Huet alleles from
      the Greenberg ones.
  - reference: PMID:27830109
    reference_title: "Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, two disease-associated LBR truncation mutants were found to be highly
      unstable at the protein level and are rapidly turned over by a novel nuclear
      membrane-based protein quality control pathway.
    explanation: >-
      Supplies a route from a truncating allele to reduced protein quantity, which is the
      node above. INDIRECT for the same reason - the alleles are not separated by
      phenotype in the quoted sentence.
phenotypes:
- category: Cellular
  name: Hyposegmentation of Neutrophil Nuclei
  description: >-
    Neutrophil nuclei carry fewer lobes than normal - characteristically two, joined by a
    thin chromatin filament. This is the defining and usually the only finding.
  phenotype_term:
    preferred_term: Hyposegmentation of neutrophil nuclei
    term:
      id: HP:0011447
      label: Hyposegmentation of neutrophil nuclei
  evidence:
  - reference: PMID:19468205
    reference_title: "Pelger-Huët anomaly: a critical review of the literature."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pelger-Huët anomaly (PHA), an autosomal dominant haematological trait is
      characterised by neutrophil nuclear hypolobulation and modified chromatin
      distribution.
    explanation: Names hypolobulation as the defining feature of the trait.
- category: Cellular
  name: Coarse Granulocyte Nuclear Chromatin
  description: >-
    Chromatin in the granulocyte nucleus appears coarse and clumped. No HP term is bound:
    the HPO has no class for granulocyte nuclear chromatin texture, and binding a generic
    neutrophil-morphology parent would assert less than the free-text name already says.
  phenotype_term:
    preferred_term: Coarse granulocyte nuclear chromatin
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin."
    explanation: Reports the chromatin finding in affected heterozygotes.
- category: Cellular
  name: Ovoid Granulocyte Nuclei
  subtype: Homozygous PHA
  description: >-
    With essentially no LBR the granulocyte nucleus does not segment at all and retains the
    ovoid shape typical of other cell types. Curated as a distinct phenotype from
    hyposegmentation rather than as its severe grade, because it marks the biallelic
    genotype.
  phenotype_term:
    preferred_term: Ovoid granulocyte nuclei
  evidence:
  - reference: PMID:17245605
    reference_title: "The granulocyte nucleus and lamin B receptor: avoiding the ovoid."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A single dominant mutation in humans leads to neutrophils with hypolobulated nuclei
      (Pelger-Huet anomaly); homozygosity leads to ovoid granulocyte nuclei.
    explanation: Assigns the ovoid morphology specifically to the biallelic genotype.
- category: Neurologic
  name: Global Developmental Delay
  subtype: Homozygous PHA
  description: >-
    Reported in presumed-homozygous individuals, in varying degree. Not a feature of the
    heterozygous trait.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying
      degrees of developmental delay, epilepsy and skeletal abnormalities.
    explanation: >-
      Reports the feature in the biallelic state, with the authors' own "presumed"
      qualifier on the genotype call preserved.
- category: Neurologic
  name: Seizure
  subtype: Homozygous PHA
  description: Epilepsy reported in presumed-homozygous individuals. Not a feature of carriers.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying
      degrees of developmental delay, epilepsy and skeletal abnormalities.
    explanation: Same sentence; epilepsy is one of the listed biallelic features.
- category: Skeletal
  name: Skeletal Abnormalities
  subtype: Homozygous PHA
  description: >-
    Skeletal abnormalities reported in presumed-homozygous individuals, the third feature in
    the same clause that supplies the developmental delay and epilepsy rows above. The
    binding stays at the system level because the source says only "skeletal abnormalities"
    and names no specific bone finding; binding something narrower would assert a
    granularity the sentence does not carry. Not a feature of carriers.
  phenotype_term:
    preferred_term: Skeletal abnormalities
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying
      degrees of developmental delay, epilepsy and skeletal abnormalities.
    explanation: >-
      Same sentence and same "presumed" genotype qualifier; skeletal abnormalities is the
      third listed biallelic feature.
genetic:
- name: LBR
  gene_term:
    preferred_term: LBR
    term:
      id: hgnc:6518
      label: LBR
  relationship_type: CAUSATIVE
  review_notes: >-
    Lamin B receptor. An integral protein of the inner nuclear membrane with a
    nucleoplasmic N-terminal domain that tethers heterochromatin to the nuclear periphery
    and eight transmembrane segments that carry sterol C14-reductase activity. Pelger-Huet
    anomaly is the heterozygous loss-of-function phenotype at this locus; Greenberg
    dysplasia is the biallelic enzyme-null phenotype and is a separate dismech entry.
  evidence:
  - reference: PMID:12118250
    reference_title: "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly)."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor."
    explanation: Establishes the gene-disease relationship in the mapping families.
  - reference: PMID:28858257
    reference_title: "Lamin B Receptor: Interplay between Structure, Function and Localization."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane,
      containing a hydrophilic N-terminal end protruding into the nucleoplasm, eight
      hydrophobic segments that span the membrane and a short, nucleoplasmic C-terminal
      tail.
    explanation: Describes the protein architecture the two functional domains sit in.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Transmitted as an autosomal dominant trait. The label describes the pedigree, not the
    allele's mode of action: the underlying lesion is haploinsufficiency, and the
    biallelic state is both viable and more severe, which a true dominant-negative would
    not predict in this form.
  evidence:
  - reference: PMID:19468205
    reference_title: "Pelger-Huët anomaly: a critical review of the literature."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pelger-Huët anomaly (PHA), an autosomal dominant haematological trait is characterised by neutrophil nuclear hypolobulation and modified chromatin distribution."
    explanation: States the inheritance mode.
diagnosis:
- name: Peripheral Blood Film Morphology
  description: >-
    The anomaly is a morphological diagnosis made on a stained peripheral blood film, and
    it is usually incidental. The finding affects all granulocytes but is most easily seen
    in neutrophils. Because the same morphology is acquired in myelodysplasia and other
    states, recognising it should prompt the question of which it is, not a conclusion.
  evidence:
  - reference: PMID:22338047
    reference_title: "Understanding and recognizing the Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "The Pelger-Huët anomaly (PHA) is a recognized morphologic variant affecting all granulocytes but is most evident in polymorphonuclear neutrophils (PMNs)."
    explanation: Establishes what is examined and in which cells the finding is clearest.
- name: LBR Sequencing
  description: >-
    Sequencing LBR confirms the inherited trait and is what separates it from an acquired
    pseudo-Pelger-Huet picture when the film alone cannot.
  evidence:
  - reference: PMID:22338047
    reference_title: "Understanding and recognizing the Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Recognition of PHA morphologic features serves as a marker for mutations in the LBR gene."
    explanation: Ties the morphological finding to the confirmatory genetic test.
- name: Spurious Band-Form Count on the Automated Differential
  description: >-
    The one consequence the anomaly reliably has. Hyposegmented neutrophils are counted as
    band forms, so an untroubled carrier's differential shows a marked left shift with a
    normal total white cell count - a picture that reads as bacterial infection and can
    trigger an infection work-up, or, in the acquired mimic, as myelodysplasia. The hazard
    is iatrogenic rather than a feature of the disease, which is why it is curated here as
    a diagnostic pitfall and not as clinical burden: nothing happens to the patient because
    of their neutrophils, only because of what is inferred from them. The remedy is the
    blood-film entry above.
  evidence:
  - reference: PMID:26634137
    reference_title: "Case of acquired or pseudo-Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It does not cause neutrophilia, but it can cause a false increase in band forms.
    explanation: >-
      States the artifact and, in the same sentence, what distinguishes it from real
      infection: the band fraction moves and the total count does not.
  - reference: PMID:26634137
    reference_title: "Case of acquired or pseudo-Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presented case showed that we should think of PHA\PPHA in any case with normal
      total WBC count and significant shift to the lift with no apparent explanation.
    explanation: >-
      The authors' own diagnostic rule, curated separately because it is a recommendation
      rather than a description of the artifact. Quoted with the source's typo for "left"
      intact, as a snippet never corrects what it quotes.
differential_diagnoses:
- name: Pseudo-Pelger-Huet anomaly
  description: >-
    Acquired hyposegmentation of neutrophil nuclei, seen in myelodysplastic syndromes,
    acute leukaemia, severe infection and as a drug effect. Morphologically it can be
    indistinguishable from the inherited trait on a single film, which is the whole
    clinical problem: here the finding is a marker of dysplasia and demands a
    haematological work-up, whereas in the inherited trait it demands nothing.
  distinguishing_features:
  - Acquired rather than lifelong, so an earlier normal film settles it where one exists
  - Typically affects a proportion of neutrophils rather than nearly all of them
  - Accompanied by other dysplastic features and by cytopenias
  - No LBR germline variant, and no affected first-degree relatives
  evidence:
  - reference: PMID:22338047
    reference_title: "Understanding and recognizing the Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: "Guidance is given for distinguishing PHA from other hematologic disorders in which granulocytes may show similar changes."
    explanation: >-
      Confirms that other haematological disorders produce a similar granulocyte
      appearance and that the distinction is a recognised diagnostic task.
- name: Greenberg dysplasia
  description: >-
    The other end of the LBR allelic series: biallelic alleles that abolish sterol
    C14-reductase activity give a prenatally lethal skeletal dysplasia. It is not a severe
    form of this anomaly and is curated as a separate dismech entry.
  distinguishing_features:
  - Prenatally lethal, presenting as fetal hydrops with markedly short limbs
  - Driven by loss of the enzymatic function rather than by reduced protein quantity
  - Biallelic; obligate carriers are healthy apart from the Pelger-Huet trait
  evidence:
  - reference: PMID:27830109
    reference_title: "Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      Lamin B Receptor (LBR) is an inner nuclear membrane protein associated with the rare
      human diseases Pelger-Huët anomaly and Greenberg skeletal dysplasia.
    explanation: Establishes the two as distinct diseases of the same gene.
- name: Non-LBR hyposegmentation of granulocytes in animals
  description: >-
    Hyposegmented granulocytes occur in domestic animals and are often called Pelger-Huet
    anomaly by analogy. That analogy should not be assumed to extend to the gene. In
    Australian Shepherd Dogs with an autosomal recessive hyposegmentation phenotype,
    linkage analysis excluded LBR and implicated LMBR1L instead. The row is here because a
    veterinary report of "Pelger-Huet anomaly" is not evidence about LBR, and a curator
    reaching for cross-species support should check which gene was actually mapped.
  distinguishing_features:
  - LBR excluded by linkage in the reported canine phenotype
  - Autosomal recessive with stillbirth in the affected litter, unlike the benign human heterozygous trait
  evidence:
  - reference: PMID:37347778
    reference_title: "Autosomal recessive hyposegmentation of granulocytes in Australian Shepherd Dogs indicates a role for LMBR1L in myeloid leukocytes."
    supports: REFUTE
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      HG phenotypes have also been described in domestic animals and homology to human PHA
      has been claimed in the literature.
    explanation: >-
      Recorded as REFUTE against the assumption that animal hyposegmentation phenotypes are
      LBR-related. The sentence states the claim that the paper then goes on to test, and
      the study's own finding excludes LBR for this breed.
- name: LBR-related non-lethal skeletal dysplasia
  description: >-
    A biallelic LBR missense genotype reported in two adult sisters with a skeletal
    dysplasia milder than Greenberg dysplasia and, importantly, no Pelger-Huet anomaly at
    all. This matters to the present entry as a negative result: it shows the nuclear
    phenotype is not an obligate accompaniment of biallelic LBR disease, so a normal blood
    film does not exclude an LBR disorder.
  distinguishing_features:
  - Skeletal dysplasia with short stature and short limbs, surviving to adulthood
  - Blood film explicitly normal for Pelger-Huet anomaly despite two mutant alleles
  evidence:
  - reference: PMID:32827848
    reference_title: "A homozygous variant in the Lamin B receptor gene LBR results in a non-lethal skeletal dysplasia without Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report provides additional evidence of variability for Lamin B receptor-related disorders associated with a non-lethal skeletal dysplasia without Pelger-Huët anomaly."
    explanation: >-
      Documents a biallelic LBR genotype without the nuclear phenotype, which is the
      dissociation this row exists to record.
- name: SOPH syndrome (NBAS)
  description: >-
    Short stature with optic nerve atrophy and Pelger-Huet anomaly, an autosomal recessive
    syndrome caused by the NBAS founder variant G5741A (R1914H) and first described in
    Yakuts, where heterozygous carriage averages 13 per 1000. The neutrophil finding is part
    of the named phenotype, so a film alone does not separate it from the isolated trait -
    but everything around the film does, and the carrier frequency means ancestry is a real
    prior rather than a curiosity.
  distinguishing_features:
  - Autosomal recessive, so parents are unaffected where the isolated trait is dominant
  - Proportionate postnatal short stature and optic nerve atrophy, neither a feature of the isolated trait
  - Facial dysmorphism, micromelia of hands and feet, lax skin
  - NBAS rather than LBR on sequencing
  - Sakha (Yakut) ancestry raises the prior substantially
  evidence:
  - reference: PMID:29369590
    reference_title: "[Population frequency and age of mutation G5741→A in gene NBAS which is a cause of SOPH syndrome in Sakha (Yakutia) Republic]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SOPH syndrome (Short stature with Optic nerve atrophy and Pelger–Huët anomaly
      syndrome, OMIM#614800) is an autosomal recessive hereditary disease characterized by
      the following main clinical symptoms: postnatal hypoplasia, proportionately short
      stature, facial dysmorphism, micromelia of feet and hands, limp and loose skin, optic
      nerve atrophy, and Pelger–Huët anomaly of neutrophils.
    explanation: >-
      Establishes the syndrome, its inheritance and the fact that the neutrophil anomaly is
      one of its defining features, which is what makes it a differential rather than an
      unrelated disorder.
  - reference: PMID:29369590
    reference_title: "[Population frequency and age of mutation G5741→A in gene NBAS which is a cause of SOPH syndrome in Sakha (Yakutia) Republic]."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of heterozygous carriers of mutation G5741→A (R1914H) in gene NBAS was
      found, which averaged 13 per 1000 healthy Yakuts.
    explanation: >-
      Curated as its own item because the carrier frequency is a separate claim from the
      phenotype, and it is the part that makes ancestry diagnostically useful here.
- name: TMEM147-related syndromic pseudo-Pelger-Huet anomaly
  description: >-
    Biallelic loss of function in TMEM147, which anchors LBR to the inner nuclear membrane,
    causes moderate to profound intellectual disability with coarse facies and abnormal
    nuclear segmentation in about a fifth of neutrophils. Mechanistically this is the
    closest of the differentials to the entry itself: it reaches the same nuclear phenotype
    by removing LBR's anchor rather than LBR, which is why it produces a partial rather than
    a near-universal neutrophil picture.
  distinguishing_features:
  - Autosomal recessive, and syndromic rather than isolated
  - Moderate to profound intellectual disability, behavioural problems, coarse facies
  - Roughly 20 per cent of neutrophils affected rather than nearly all
  - TMEM147 rather than LBR on sequencing, with LBR itself intact
  evidence:
  - reference: PMID:36044892
    reference_title: "Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal nuclear segmentation and chromatin compaction were also observed in
      approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët
      anomaly.
    explanation: >-
      States the neutrophil finding and its partial penetrance across the cell population,
      which is the feature that separates it from the isolated trait on a film.
  - reference: PMID:32694168
    reference_title: "TMEM147 interacts with lamin B receptor, regulates its localization and levels, and affects cholesterol homeostasis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Silencing of TMEM147 drastically reduces the level of lamin B receptor (LBR) at the
      inner nuclear membrane and results in mistargeting of LBR to the ER.
    explanation: >-
      The mechanistic link, and the reason this differential converges on the same node as
      the entry rather than mimicking it coincidentally: losing TMEM147 lowers LBR where it
      has to act. INDIRECT on two counts - it is HeLa silencing rather than the patient
      genotype, and the step to the neutrophil phenotype in affected individuals is an
      inference.
animal_models:
- name: Ichthyosis (ic) mouse
  species: Mouse
  genotype: Lbr(ic/ic), Lbr(icJ/icJ), Lbr(ic4J/ic4J) - nonsense and frameshift alleles
  publication: PMID:12490533
  description: >-
    The classical mouse counterpart, and a case where the mouse locus was known long before
    the gene. Mice homozygous at the ichthyosis locus have a blood phenotype like
    Pelger-Huet anomaly, and the causal mutations were shown to lie in Lbr. Note the mouse
    is homozygous where the human trait is heterozygous, and carries extra features -
    alopecia, variable syndactyly, hydrocephalus - that the human heterozygous trait does
    not.
  modeled_mechanisms:
  - target: Failure of Granulocyte Nuclear Lobulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the granulocyte nuclear phenotype from an Lbr lesion, in vivo and across
      three independent alleles.
    limitations: >-
      Homozygous, where the defining human trait is heterozygous, so the model corresponds
      to the Homozygous PHA subtype rather than to the common presentation. It also carries
      alopecia, syndactyly and hydrocephalus, which are not features of the human
      heterozygous trait, so the model is not phenotypically clean.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The extra murine features (alopecia, syndactyly, hydrocephalus) have no counterpart
        in human heterozygous Pelger-Huet anomaly, so the allele's consequences are not
        equivalent across species.
    - divergence_type: POPULATION_MISMATCH
      materiality: INVALIDATING
      description: >-
        The model is homozygous and the human trait this entry is named for is
        heterozygous. For a dosage-dependent phenotype that is the difference between the
        two bands of the allelic series, not a matter of degree.
    readouts:
    - name: Granulocyte nuclear morphology
      target: Failure of Granulocyte Nuclear Lobulation
      direction: ALTERED
      interpretation: A blood phenotype resembling the human anomaly.
      evidence:
      - reference: PMID:12490533
        reference_title: "Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huët anomaly."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a
          blood phenotype similar to PHA, and develop other phenotypic abnormalities,
          including alopecia, variable expression of syndactyly and hydrocephalus.
        explanation: >-
          States both the resemblance and the divergence in one sentence, which is why it is
          quoted whole rather than trimmed to the supportive clause.
  evidence:
  - reference: PMID:12490533
    reference_title: "Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huët anomaly."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In this study, we identified one nonsense (815ins) and two frameshift mutations
      (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three
      independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus.
    explanation: >-
      Establishes that the mouse locus is Lbr, across three independent alleles, which is
      what makes this a model of the same gene rather than a phenocopy.
- name: Lbr gene-trap mouse
  species: Mouse
  genotype: Lbr(GT/GT)
  publication: PMID:18621876
  description: >-
    A gene-trap insertion at Lbr, described by its authors as a model for Pelger-Huet
    anomaly. Its interest here is not the nuclear phenotype, which is expected, but the
    functional result: the granulocytes look immature and kill bacteria normally. The same
    study also places Lbr downstream of C/EBP-epsilon, which links this entry to the
    transcriptional program of granulocyte maturation.
  modeled_mechanisms:
  - target: Failure of Granulocyte Nuclear Lobulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Granulocytes lack a mature segmented nucleus and show a block in late maturation.
    limitations: >-
      Homozygous gene-trap, against a heterozygous human trait. A gene trap may leave
      residual transcript, so the effective dose is not necessarily null, and the study does
      not quantify it.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: INVALIDATING
      description: >-
        Homozygous model, heterozygous human trait, in a phenotype that tracks protein dose.
    readouts:
    - name: Granulocyte nuclear segmentation and maturation
      target: Failure of Granulocyte Nuclear Lobulation
      direction: ALTERED
      interpretation: The nuclear phenotype plus an associated late-maturation block.
      evidence:
      - reference: PMID:18621876
        reference_title: "The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The Lbr(GT/GT) granulocytes lack a mature segmented nucleus and have a block in
          late maturation.
        explanation: The measured nuclear and maturation phenotype.
    - name: Staphylococcus aureus killing
      target: Failure of Granulocyte Nuclear Lobulation
      direction: UNCHANGED
      interpretation: >-
        A real negative result, and the one that matters clinically: the nuclear phenotype
        is present and bacterial killing is not measurably impaired. It is the strongest
        available support for the trait being functionally benign, and it is contradicted by
        another mouse study - see the knowledge gap.
      evidence:
      - reference: PMID:18621876
        reference_title: "The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Despite these changes in nuclear morphology, the innate granulocyte immune function
          in the killing of Staphylococcus aureus bacteria appears to be intact.
        explanation: >-
          Recorded as UNCHANGED because the measurement was made and found equal, which is a
          different claim from not having been made.
  evidence:
  - reference: PMID:18621876
    reference_title: "The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings indicate that the Lbr(GT/GT) mice are a model for Pelger-Huët anomaly and
      that Lbr, under transcriptional regulation of C/EBPepsilon, is necessary for
      morphological but not necessarily functional granulocyte maturation.
    explanation: >-
      The authors' own claim that this is a model for the disorder, with their hedge - "not
      necessarily" - preserved.
experimental_models:
- name: LBR-knockdown HL-60 subline
  experimental_model_type: CELL_LINE
  description: >-
    A stable LBR-knockdown subline of the human promyelocytic HL-60 line, differentiated
    down the granulocyte lineage with retinoic acid. It is the closest thing to an
    isogenic in vitro model of the anomaly: the same genetic background with and without
    LBR, taken through granulopoiesis, so the nuclear phenotype can be attributed to LBR
    dose rather than to line-to-line variation.
  publication: PMID:21327094
  modeled_mechanisms:
  - target: Failure of Granulocyte Nuclear Lobulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Knockdown cells retain an ovoid nucleus through retinoic-acid-induced granulopoiesis
      while the parent line lobulates, reproducing the biallelic end of the human
      phenotype.
    limitations: >-
      HL-60 is a leukaemia-derived line carrying its own karyotypic abnormalities, and
      retinoic-acid-induced granulopoiesis in culture is not marrow granulopoiesis.
      Knockdown gives a graded reduction rather than the defined one- or two-allele human
      genotypes, so the model reproduces the ovoid extreme rather than the heterozygous
      hypolobulation that defines the trait clinically.
    readouts:
    - name: Nuclear shape after retinoic-acid-induced granulopoiesis
      target: Failure of Granulocyte Nuclear Lobulation
      direction: ALTERED
      interpretation: >-
        Ovoid rather than lobulated nuclei in the knockdown line is the structural
        correlate of this node.
      evidence:
      - reference: PMID:21327094
        reference_title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        snippet: >-
          During in vitro granulopoiesis induced with retinoic acid, the LBR knockdown
          cells retain an ovoid shaped nucleus with reduced levels of lamin A/C; while,
          the parent cells develop highly lobulated nuclei.
        explanation: Reports the measurement and its direction against an isogenic control.
    - name: Nuclear shape after phorbol-ester-induced macrophage differentiation
      target: Failure of Granulocyte Nuclear Lobulation
      direction: UNCHANGED
      interpretation: >-
        A real negative result, and the one that gives the model its specificity: losing
        LBR does not disturb nuclear shape down the macrophage lineage, so the defect is
        specific to granulopoiesis rather than a general nuclear-morphology artefact of
        the knockdown.
      evidence:
      - reference: PMID:21327094
        reference_title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        snippet: >-
          In contrast, macrophage forms induced in LBR knockdown cells by in vitro
          treatment with phorbol ester were indistinguishable from the parent cells,
          judged by both nuclear shape and attached cell morphology.
        explanation: >-
          Reports the lineage-specificity control. Recorded as UNCHANGED because the
          measurement was made and found equal, which is different from not having been
          made.
  evidence:
  - reference: PMID:21327094
    reference_title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      As a tool to facilitate analysis of these mechanisms, a stable LBR knockdown subline
      of HL-60 cells was established.
    explanation: >-
      States that the line was built for the purpose of studying this mechanism, which is
      what makes it informative for the node rather than incidentally relevant.
discussions:
- discussion_id: lbr_domain_attribution
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Heterochromatin Redistribution in the Granulocyte Nucleus
  - pathophysiology#Reduced LBR Sterol C14-Reductase Activity
  prompt: >-
    Does Pelger-Huet anomaly arise from loss of LBR's heterochromatin-tethering function,
    from loss of its sterol C14-reductase function, or from neither individually?
  rationale: >-
    Three positions are defended in the literature and they are not reconcilable by
    emphasis.

    The structural reading is that less LBR means less heterochromatin tethered at the
    nuclear periphery and therefore no lobulation. It is the intuitive one, and the
    quantitative human dose-response result cited below is what it is usually taken to
    rest on: across 26 subjects carrying zero to three wild-type LBR alleles, about 65 per
    cent of the variance in nuclear segmentation tracks allele count. Note that this
    establishes dose-dependence on LBR quantity, not which of LBR's two domains does the
    work - so on its own it is equally consistent with the third position below.

    The metabolic reading is that the mutations causing both Pelger-Huet anomaly and
    Greenberg dysplasia lie in the transmembrane segments and act through cholesterol
    synthesis, and that no harmful mutation of the anchoring function has been reported at
    all.

    Against the metabolic reading there is a direct mouse experiment, and it is the
    strongest single piece of evidence here. DHCR14 encodes a second sterol
    delta-14-reductase, so LBR is not the only one. Disrupting Dhcr14 in mice produces
    essentially normal animals, Lbr-null mice do not resemble the Dhcr14 mutants, and no
    sterol abnormalities were detected in liver or kidney of either. On that basis the
    authors argue these disorders are laminopathies rather than inborn errors of
    cholesterol synthesis. Note this cuts against the metabolic account for the LBR
    disorders as a class, which includes Greenberg dysplasia, where a separate line of
    yeast-complementation evidence supports the enzymatic reading - so the contradiction is
    live rather than settled.

    A third possibility, consistent with the truncation-instability finding, is that the
    operative variable is total LBR protein quantity and neither domain function is
    separately causal for the nuclear phenotype.

    One experiment does bear on the domain question directly, and it favours the metabolic
    reading: in the EML ic/ic line, expressing the C-terminal sterol reductase domain alone
    rescued nuclear lobulation as well as growth arrest, lipid production and the
    respiratory burst. Two things keep this from settling the argument. It is a cultured
    myeloid line rather than an animal or a patient, so it inherits the in-vitro caveat
    recorded on the same system elsewhere in this entry; and a domain that is sufficient in
    a rescue construct is not thereby the domain whose loss causes the human disease, since
    an over-expressed fragment can restore a phenotype by a route the endogenous protein
    does not take.

    The distinction is not academic: it determines whether the anomaly belongs with the
    laminopathies or with the inborn errors of sterol metabolism, and this entry lists both
    as parents rather than choosing.
  evidence:
  - reference: PMID:28858257
    reference_title: "Lamin B Receptor: Interplay between Structure, Function and Localization."
    supports: REFUTE
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      Mutations within the transmembrane segments result in defects in cholesterol
      synthesis and are associated with diseases such as the Pelger-Huët anomaly and
      Greenberg skeletal dysplasia, whereas no such harmful mutations related to the
      anchoring properties of LBR have been reported so far.
    explanation: >-
      Recorded as REFUTE against the heterochromatin-tethering account of this disease.
      The sentence asserts that no disease-causing mutation of the anchoring function has
      been reported, which cuts directly against the reading that lost tethering is what
      produces the anomaly.
  - reference: PMID:21327094
    reference_title: "An in vitro model for Pelger-Huët anomaly: stable knockdown of lamin B receptor in HL-60 cells."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "The exact mechanisms of this nuclear shape change and of heterochromatin redistribution remain largely unknown."
    explanation: >-
      An explicit statement from within the field that the mechanism is open, which is the
      claim this knowledge gap makes.
  - reference: PMID:27684937
    reference_title: "Image analysis of neutrophil nuclear morphology: Learning about phenotypic range and its reliable analysis from patients with pelger-Huët-anomaly and treated with colchicine."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 65% of the observed phenotypic variance was explainable by the number of
      LBR wild type alleles.
    explanation: >-
      The quantitative human dose-response measurement the structural reading is usually
      taken to rest on, and the strongest human support for treating LBR protein quantity as
      the operative variable. INDIRECT because allele count is a proxy for protein level and
      because the result says nothing about which domain is responsible.
  - reference: PMID:27684937
    reference_title: "Image analysis of neutrophil nuclear morphology: Learning about phenotypic range and its reliable analysis from patients with pelger-Huët-anomaly and treated with colchicine."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gene-dosage effect followed a non-additive, hysteresis-like characteristic with
      lower and upper plateaus.
    explanation: >-
      Curated as its own item because the shape of the dose-response is a separate claim
      from its magnitude, and a non-additive response with plateaus is the detail that makes
      the heterozygous phenotype compatible with a quantity-threshold account.
  - reference: PMID:22140257
    reference_title: "Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Expression of just the C-terminal sterol reductase domain of Lbr in ic/ic cells also
      improved each of these phenotypes.
    explanation: >-
      The domain-swap rescue, and the one experiment here that separates the two functions
      rather than arguing from mutation location. Recorded as supporting the metabolic
      reading. INDIRECT on two counts: sufficiency of an expressed fragment does not
      establish that loss of that domain causes the human disease, and the system is the
      same EML line whose in-vitro status is recorded elsewhere in this entry.
  - reference: PMID:17403717
    reference_title: "HEM dysplasia and ichthyosis are likely laminopathies and not due to 3beta-hydroxysterol Delta14-reductase deficiency."
    supports: REFUTE
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lbr(-/-), Dhcr14(Delta4-7/Delta4-7) and Lbr(+/-):Dhcr14(Delta4-7/Delta4-7) mutant mice
      have distinct physical and biochemical phenotypes.
    explanation: >-
      Recorded as REFUTE against the metabolic account. If the LBR phenotype were a sterol
      delta-14-reductase deficiency, disrupting the other delta-14-reductase should
      phenocopy it, and it does not. The title states the authors' conclusion outright.
  - reference: PMID:17403717
    reference_title: "HEM dysplasia and ichthyosis are likely laminopathies and not due to 3beta-hydroxysterol Delta14-reductase deficiency."
    supports: REFUTE
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Neither of these mutants resembles the ichthyosis mouse and biochemically, no sterol
      abnormalities were detected in either liver or kidney tissue.
    explanation: >-
      The negative biochemical result. A sterol-synthesis disorder that produces no
      detectable sterol abnormality in the tissues examined is a hard claim to sustain, and
      this is why the gap treats the metabolic reading as contested rather than as the
      accepted account.
- discussion_id: lobulation_function_without_burden
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Hyposegmentation of Neutrophil Nuclei
  prompt: >-
    If the lobulated granulocyte nucleus exists to make the cell deformable enough to
    migrate through tight tissue spaces, why are Pelger-Huet carriers not measurably more
    susceptible to infection?
  rationale: >-
    The functional rationale for nuclear lobulation is migration through constricted
    spaces, and the anomaly abolishes lobulation in essentially every granulocyte for life.
    The trait is nonetheless described as asymptomatic.

    Two murine studies have asked the question directly and they disagree. A gene-trap Lbr
    mouse whose granulocytes lack a segmented nucleus kills Staphylococcus aureus normally,
    and its authors conclude LBR is needed for morphological but not functional granulocyte
    maturation. Neutrophils derived from the ichthyosis allele, by contrast, show abnormal
    chemotaxis and a deficient respiratory burst.

    The sharpest asymmetry between them is not the allele but the system. The gene-trap
    result is measured in granulocytes taken from a living animal; the ichthyosis result is
    measured in an EML progenitor cell line derived from an ic/ic mouse and induced to
    mature in culture, with no in vivo arm. A cultured line induced to a neutrophil-like
    state is not obliged to reproduce the proliferative and respiratory-burst competence of
    a marrow-matured cell, so a candidate adjudication does exist and is not the one this
    entry previously implied: repeat the chemotaxis and respiratory-burst assays on
    primary granulocytes from the same animal. Different alleles and different assays remain
    confounded on top of that.

    The human question is untouched either way, and the source itself says why. Both
    experiments are homozygous, and the human trait called asymptomatic is the heterozygous
    one, where far more LBR remains - the same paper notes that every prior human PHA
    functional study used heterozygous neutrophils. Carriers are ascertained incidentally,
    so no cohort has been assembled to look for a mild susceptibility with adequate power.
    This entry records the absence of an infection-susceptibility clinical burden as a claim
    about the literature rather than about the biology. It is a separate claim from the
    diagnostic hazard, which is documented and is curated in diagnosis:.
  evidence:
  - reference: PMID:17245605
    reference_title: "The granulocyte nucleus and lamin B receptor: avoiding the ovoid."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "This deformable nucleus enhances rapid migration."
    explanation: >-
      States the functional claim that makes the absence of a clinical phenotype
      surprising. INDIRECT: it describes normal physiology, and the tension with the
      asymptomatic trait is an inference from it.
  - reference: PMID:18550262
    reference_title: "Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      All of these studies were performed with neutrophils heterozygous for the PHA
      mutation, which is not surprising since homozygous forms of PHA are most commonly
      fatal due to associated skeletal abnormalities
    explanation: >-
      Sharpens the gap rather than closing it: it says the human functional literature is
      entirely heterozygous, and names the reason it cannot easily be otherwise. Graded
      OTHER because this sentence is the paper's review of prior work, not a result of its
      own experiment, which is graded IN_VITRO where it is cited.
  - reference: PMID:19468205
    reference_title: "Pelger-Huët anomaly: a critical review of the literature."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to its asymptomatic nature or lack of observer familiarity, PHA is often overlooked."
    explanation: >-
      States the asymptomatic nature, and simultaneously names the ascertainment problem
      that would hide a mild susceptibility.
  - reference: PMID:18621876
    reference_title: "The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Despite these changes in nuclear morphology, the innate granulocyte immune function in
      the killing of Staphylococcus aureus bacteria appears to be intact.
    explanation: >-
      Supports the asymptomatic reading: nuclear shape and bacterial killing come apart in
      this model. INDIRECT because it is a homozygous mouse and the human trait in question
      is heterozygous. Note the authors' own hedge, "appears to be intact".
  - reference: PMID:18550262
    reference_title: "Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses."
    supports: REFUTE
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The ic/ic neutrophils also displayed abnormal chemotaxis, supporting the notion that
      nuclear segmentation augments neutrophil extravasation.
    explanation: >-
      Recorded as REFUTE against the asymptomatic reading, and now on the reported result
      rather than on the title. LBR-null neutrophils show a functional deficit, which is the
      opposite conclusion to the gene-trap study above. Graded IN_VITRO because every result
      in this paper comes from an EML progenitor cell line derived from an ic/ic mouse and
      induced to mature: there is no in vivo arm, which is also the axis on which it differs
      most from the gene-trap study.
  - reference: PMID:30564248
    reference_title: "The Neutrophil Nucleus: An Important Influence on Neutrophil Migration and Function."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Neutrophil nuclear morphology has historically been used in haematology for neutrophil
      identification and characterisation, but its exact role in neutrophil function has
      remained enigmatic.
    explanation: >-
      A review saying plainly that the question this gap asks is open in the general case,
      not merely for this disorder.
notes: >-
  Lump/split decision: DISEASE. MONDO:0008214 names one entity with one conserved
  pathograph - heterozygous LBR loss of function, reduced LBR protein, failure of
  granulocyte nuclear lobulation - and the stub is retired accordingly. The biallelic
  state is curated as a has_subtypes entry rather than a separate disease, because it is
  the same lesion at a different dose and the reported systemic features rest on
  genotypes the source itself calls "presumed homozygous". Greenberg dysplasia is a
  separate MONDO class and a separate dismech entry; it is not folded in here.

  On whether a benign trait belongs in a disease knowledge base: it does, and the reason
  is the differential rather than the biology. The morphology this entry describes is
  also the acquired marker of myelodysplasia, and the cost of confusing the two runs in
  both directions - an unnecessary marrow biopsy in a well carrier, or a missed MDS. A
  pathograph that says where the inherited finding comes from is what lets that
  distinction be made on grounds other than pattern recognition.

  No treatments section. Not an omission: there is no treatment, and none is indicated,
  because the heterozygous trait causes no impairment to treat. Recording an empty
  supportive-care row would assert more clinical content than exists.

  No clinical_burden section, but that absence now covers one claim rather than two, and
  the distinction is worth stating because the first version of this entry ran them
  together. The claim it does cover is infection susceptibility: no measurable
  susceptibility has been demonstrated, "asymptomatic" rests on incidental ascertainment,
  and no assembled cohort has tested it - see the second knowledge gap in discussions.

  The claim it does not cover is the diagnostic hazard, which is real, documented and now
  curated as a diagnosis entry: hyposegmented neutrophils are counted as band forms, so a
  well carrier's differential shows a marked left shift with a normal white cell count and
  can trigger an infection work-up or a suspicion of myelodysplasia. That belongs in
  diagnosis rather than clinical_burden because it is a hazard of being examined, not a
  consequence of the biology - nothing happens to the patient because of their neutrophils,
  only because of what is inferred from them.

  Two mouse models are curated and both carry a POPULATION_MISMATCH divergence marked
  INVALIDATING rather than QUALIFYING. That is deliberate. Both are homozygous and the
  trait this entry is named for is heterozygous, and since the phenotype tracks LBR protein
  dose, the difference between one and two mutant alleles is the difference between the two
  bands of the allelic series rather than a matter of degree. Any functional conclusion
  drawn from those mice applies to the Homozygous PHA subtype, not to the common trait.

  A note on how the entry was assembled. The deep-research run fetches references into
  references_cache/ as part of its own citation validation, and a first draft cited nine of
  the twenty-eight it produced. Review of a sibling PR in the same batch (#11619) flagged
  that pattern, and reading the rest before pushing changed this entry rather than padding
  it: a homozygous proband reported without clinical symptoms now refutes the systemic
  features of the biallelic state, a mouse cross-breeding experiment now argues against the
  cholesterol-synthesis account of the disorder class, and the second knowledge gap turned
  out to have two published answers that contradict each other. None of that was visible
  from the nine references the first draft used.

  The deep-research report is committed alongside the entry under research/. It is
  on-target, naming LBR throughout. Reference selection and every snippet here were
  nonetheless taken from the fetched reference cache rather than from the report.

📚

References & Deep Research

References

PMID:12118250

Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly).