XFE Progeroid Syndrome

Mendelian MONDO:0012590 Pathograph 15 Show in embeddings browser Progeroid Syndrome DNA Repair Disorder

XFE progeroid syndrome is a segmental progeria caused by biallelic hypomorphic variants in ERCC4, which encodes XPF - one half of the ERCC1-XPF structure-specific endonuclease. The nuclease makes the 5' incision in nucleotide excision repair and is also required for interstrand crosslink repair, for some double-strand break repair, as a backup in base excision repair, and in telomere length regulation. When it is crippled, endogenous DNA damage accumulates faster than it can be removed. What makes the disease conceptually interesting is what happens next. The organism does not simply degenerate: it mounts a conserved response. Expression profiling of XPF-ERCC1-deficient mice shows increased antioxidant defences and, centrally, reduced growth hormone/IGF-1 signalling - the same shift wild-type mice make under chronic genotoxic stress, under caloric restriction, and in normal ageing. The interpretation advanced by the founding study is that unrepaired damage triggers a metabolic reallocation from growth toward somatic preservation. Dwarfism, cachexia and lipoatrophy are on that account not the damage itself but the response to it, which is a different kind of claim about a phenotype and is why this entry curates the somatotroph axis as its own node. ERCC4 is a locus of striking pleiotropy. The same gene produces xeroderma pigmentosum group F, Cockayne syndrome overlap, cerebro-oculo-facio-skeletal syndrome, Fanconi anemia complementation group Q, and this disease - and which one a genotype produces depends on the balance it leaves between the nuclease's two principal activities. Fanconi-causing alleles disrupt crosslink repair while largely sparing excision repair; xeroderma-causing alleles do the reverse; the progeroid allele impairs both. Complete deletion of ERCC4 is not compatible with life, so every viable genotype is a partial one. The entry should be read with its evidence base in view. The human disease is essentially one deeply characterised patient plus a handful of individuals reported across the wider ERCC4 spectrum. Almost every mechanistic claim here comes from mouse models - and those models are Ercc1 mutants, perturbing the partner subunit rather than the gene that causes the human disease. That is recorded as an explicit human-model mismatch rather than smoothed over.

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1
Inheritance
7
Pathophys.
10
Phenotypes
3
Gaps
15
Pathograph
1
Genes
5
Medical Actions
2
Models
15
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Biallelic hypomorphic ERCC4 variants. The founding patient was homozygous for p.Arg153Pro and the child of consanguineous parents. Because complete loss of the gene is lethal, both alleles must retain some function - so this is a recessive disease in which the null genotype is never observed.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:26074087 SUPPORT Other
"Complete deletion of either ERCC1 or ERCC4 is not compatible with viability in mice or humans."
Establishes why every viable genotype at this locus is hypomorphic rather than null, which is the constraint that shapes the whole allelic series.
PMID:24027083 SUPPORT Human Clinical
"the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients, indicating that most biallelic combinations of ERCC4 mutations are embryo lethal"
A quantitative argument that carriers are not rare while patients are, so the rarity of ERCC4 disease is prenatal lethality rather than allele scarcity. This is the single most informative number available for this entry.
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Discussions and Knowledge Gaps

3
Can Ercc1 mouse models substitute for an ERCC4 model, given that the founding human allele's defect is specific to the XPF subunit?
HUMAN MODEL MISMATCH xfe_models_perturb_the_partner_subunit
Attached to
pathophysiology#ERCC1-XPF Endonuclease Deficiency animal_models#Ercc1 hypomorphic mouse animal_models#Ercc1 truncated-allele mouse
Nearly every mechanistic claim in this entry - the somatotroph shift, senescence, the NF-kappaB loop, the neuropathy, the lifespan effect of dietary restriction - rests on mice mutant for Ercc1. The human disease is caused by ERCC4. Because the two proteins are obligate partners, disabling either disables the heterodimer, and that is the justification usually offered. It does not cover the founding allele. R153P XPF is catalytically competent and fails because the complex is mislocalised to the cytoplasm; microinjecting it into the nucleus restores repair. An Ercc1 hypomorph reduces the amount of nuclease. A mislocalisation defect and a quantitative deficiency are not obviously the same perturbation - the first leaves a normal complement of functional enzyme in the wrong place, and could plausibly have consequences in the cytoplasm that the second does not. No knock-in mouse carrying the human progeroid ERCC4 allele has been reported. Until one is, the models establish that ERCC1-XPF deficiency causes segmental progeria; they do not establish that they reproduce this particular patient's lesion.
Proposed experiments
Ercc4 R153P knock-in mouse
xfe_ercc4_r153p_knockin
Generate a mouse carrying the orthologous R153P substitution at the endogenous Ercc4 locus, and compare its subcellular XPF-ERCC1 distribution, somatotroph axis, senescence burden and lifespan against the Ercc1 hypomorph.
Would support
pathophysiology#ERCC1-XPF Endonuclease Deficiency
Would refute
pathophysiology#ERCC1-XPF Endonuclease Deficiency
Supporting outcome
  • The knock-in reproduces the Ercc1 hypomorph's progeroid phenotype and its somatotroph shift, so the two perturbations are equivalent at the level of the organism and the existing model literature transfers.
Refuting outcome
  • The knock-in diverges - for instance showing cytoplasmic XPF-ERCC1 with consequences absent from the hypomorph, or a different tissue distribution of degeneration - in which case the mislocalisation is a mechanism in its own right and the Ercc1 literature under-describes the human disease.
How many ERCC4 genotypes never reach birth, and does the surviving patient population therefore misrepresent the disease?
KNOWLEDGE GAP xfe_prenatal_lethality_denominator
Attached to
pathophysiology#Biallelic Hypomorphic ERCC4 Variants inheritance#
Carrier frequency for ERCC4 variants is about one in 288, comparable to FANCA, yet FA-Q patients are roughly a hundredfold rarer than FA-A. The inference drawn is that most biallelic ERCC4 combinations are embryo lethal. If that is right, the handful of described patients are a survivorship-biased sample of the mildest end of an unobserved distribution, and every statement in this entry about the phenotype describes that tail rather than the disease. The gap is not closable by finding more patients; it needs data on the genotypes that do not survive, which nobody systematically collects.
Is the growth hormone/IGF-1 axis actually suppressed in a patient with XFE progeroid syndrome?
KNOWLEDGE GAP xfe_somatotroph_suppression_in_humans
Attached to
pathophysiology#Suppression of the Growth Hormone-IGF1 Somatotroph Axis phenotypes#Postnatal Growth Failure and Short Stature
The claim that the growth failure is a survival response rather than damage is the most interesting thing this entry says, and the entire evidential basis for it is a mouse liver transcriptome. Growth hormone and IGF-1 measurements in a patient would be an inexpensive test of it, and none is reported. Until one is, the node stays PROVISIONAL and the phenotype's explanation stays an interpretation. Note the finding would matter beyond this disease, since it is the link that makes XFE a model of natural ageing rather than a rare syndrome that superficially resembles it.
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Pathophysiology

7
Biallelic Hypomorphic ERCC4 Variants
Two ERCC4 alleles that each retain some function. The founding and defining genotype is homozygous c.458G>C, p.Arg153Pro, in a boy referred for severe chronic sunburn who turned out to have progeroid features. The variant is a severe one - it confers profound interstrand crosslink sensitivity - but it is not a null, and it could not be, because null genotypes at this locus do not reach live birth.
ERCC4 hgnc:3436 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ERCC4 (hgnc:3436). hgnc:3436 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context ERCC4 hgnc:3436 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ERCC4 (hgnc:3436). hgnc:3436 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Recorded as PARTIAL rather than complete loss of function deliberately. It is not a hedge: complete loss is embryonic lethal, so partial function is a defining property of every genotype that produces this disease rather than a statement about the severity of a particular allele.
Downstream
ERCC1-XPF Endonuclease Deficiency
Show evidence (2 references)
PMID:17183314 SUPPORT Human Clinical
"A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms."
The founding clinical observation that defines the entity.
PMID:29105242 SUPPORT Human Clinical
"Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia."
Places this disease within the ERCC4 allelic series, which is what the next node is about.
ERCC1-XPF Endonuclease Deficiency
ERCC1-XPF is a heterodimeric structure-specific endonuclease that cuts DNA at junctions between double- and single-stranded regions. It is a core component of nucleotide excision repair and is also required for interstrand crosslink repair, for homologous recombination and end-joining routes to double-strand break repair, as a backup in base excision repair, and in telomere length regulation. Which disease an ERCC4 genotype produces turns on the balance of activities it leaves. Fanconi-causing alleles strongly disrupt crosslink repair while largely sparing excision repair; xeroderma-causing alleles impair excision repair; the progeroid genotype impairs both. This is a rare instance where a genotype-phenotype rule is stated mechanistically rather than statistically, and it is why this entry exists separately from Xeroderma Pigmentosum rather than as a subtype of it. The founding allele adds a twist worth curating: R153P protein retains catalytic activity in vitro, and the deficit is one of location - XPF-ERCC1 is abundant in the cytoplasm of the patient's cells rather than concentrated in the nucleus where the DNA is. Microinjecting the mutant complex into the nucleus of XPF-deficient cells restored repair. So this is not a dead enzyme; it is a functional enzyme in the wrong compartment.
nucleotide-excision repair GO:0006289 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nucleotide-excision repair (GO:0006289). GO:0006289 is a biological process from the Gene Ontology. ↓ DECREASED interstrand cross-link repair GO:0036297 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased interstrand cross-link repair (GO:0036297). GO:0036297 is a biological process from the Gene Ontology. ↓ DECREASED double-strand break repair via homologous recombination GO:0000724 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased double-strand break repair via homologous recombination (GO:0000724). GO:0000724 is a biological process from the Gene Ontology. ↓ DECREASED
endonuclease activity GO:0004519 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased endonuclease activity (GO:0004519). GO:0004519 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Accumulation of Endogenous DNA Damage
Show evidence (5 references)
PMID:26074087 SUPPORT Other
"ERCC1-XPF nuclease nicks DNA specifically at junctions between double-stranded and single-stranded DNA, when the single-strand is oriented 5' to 3' away from a junction."
Defines the biochemical activity that is lost.
PMID:23623386 SUPPORT Human Clinical
"Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease."
States the genotype-phenotype rule this node rests on, and is the reason the entry is separate from Xeroderma Pigmentosum rather than a subtype of it.
PMID:23623386 SUPPORT In Vitro
"the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair"
The measurement behind the rule: the two activities can be dissociated by allele.
+ 2 more references
Accumulation of Endogenous DNA Damage
With the nuclease crippled, spontaneously arising lesions - including those from endogenous oxidative and metabolic sources rather than only from sunlight - persist instead of being excised. This is the node that makes the disease a model of ageing rather than only a repair disorder: the damage does not need an external genotoxin to accumulate.
DNA damage response GO:0006974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased DNA damage response (GO:0006974). GO:0006974 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Suppression of the Growth Hormone-IGF1 Somatotroph Axis The link is a transcriptional response programme rather than a direct biochemical step, and the intervening signalling has been characterised in outline rather than completely.
Premature Cellular Senescence
NF-kappaB-Driven Inflammation and Oxidative Stress
Show evidence (1 reference)
PMID:21612988 SUPPORT Other
"This offers an understanding of the tremendous health impact of DNA damage derived from environmental and endogenous sources."
Names endogenous as well as environmental damage as the burden this node describes.
Suppression of the Growth Hormone-IGF1 Somatotroph Axis
The node that makes this disease theoretically interesting rather than merely rare. Liver transcriptomes of XPF-ERCC1-deficient mice correlate highly with those of old wild-type mice, and show increased cell death and antioxidant defences together with reduced growth hormone/IGF-1 signalling. The same shift occurs in wild-type animals under chronic genotoxic stress, under caloric restriction, and with normal ageing. On this reading the growth failure, cachexia and lipoatrophy of the human disease are not the damage but the *response* to it - a survival programme that reallocates resources from growth to somatic preservation. That is a strong and unusual claim about a phenotype and it is curated as PROVISIONAL: the transcriptomic correlation and the conserved direction of the shift are solid, but the causal step from damage to axis suppression is inferred from expression data in mouse liver and has not been demonstrated in a patient.
insulin-like growth factor receptor signaling pathway GO:0048009 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased insulin-like growth factor receptor signaling pathway (GO:0048009). GO:0048009 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Segmental Multi-Organ Degeneration
Show evidence (3 references)
PMID:17183314 SUPPORT Model Organism
"Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan."
The measurement behind this node, in mouse liver.
PMID:17183314 SUPPORT Model Organism
"We conclude that unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension."
The authors' statement of the survival-response interpretation that this node encodes.
PMID:17183314 SUPPORT Model Organism
"Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome."
The correlation that places the disease on the natural-ageing axis rather than merely resembling it superficially.
Premature Cellular Senescence
Tissues and primary cells from Ercc1-deficient mice senesce prematurely. Senescence is the cellular currency in which this disease's tissue phenotype is paid, and it is also what makes the models a testing platform for senolytic drugs.
cellular senescence GO:0090398 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular senescence (GO:0090398). GO:0090398 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Ercc1 hypomorphic mouse Mouse recapitulates Tissues and primary cells senesce prematurely, which is what makes the strain a testing platform for senolytics.
Downstream
Segmental Multi-Organ Degeneration
Show evidence (1 reference)
PMID:23852002 SUPPORT Model Organism
"XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic mice. Tissues and primary cells from these mice senesce prematurely"
States the premature senescence and, in the same sentence, that the model is an Ercc1 rather than an Ercc4 mutant - which is the mismatch this entry records.
NF-kappaB-Driven Inflammation and Oxidative Stress
NF-kappaB is activated stochastically across cell types as both progeroid and wild-type mice age. What makes this more than a correlation is the intervention: removing one p65 allele, or inhibiting the activating kinase IKK pharmacologically, delays the age-related symptoms and pathologies of the progeroid mice, reduces oxidative DNA damage, and delays senescence. Note the feedback this implies - inhibiting NF-kappaB *reduced oxidative DNA damage*, so the inflammatory response is not only downstream of damage but also feeds back onto it. That makes this node a loop rather than a link in a chain, and it is the reason it is a plausible therapeutic target in a disease whose primary lesion is not druggable.
positive regulation of canonical NF-kappaB signal transduction GO:0043123 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of canonical NF-kappaB signal transduction (GO:0043123). GO:0043123 is a biological process from the Gene Ontology. ↑ INCREASED inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Premature Cellular Senescence
Segmental Multi-Organ Degeneration
Show evidence (2 references)
PMID:22706308 SUPPORT Model Organism
"Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice."
The intervention result that upgrades this from an association to a causal contributor.
PMID:22706308 SUPPORT Model Organism
"Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence."
Documents the feedback onto DNA damage itself, which is what makes this node a loop rather than a terminal consequence.
Segmental Multi-Organ Degeneration
The clinical endpoint: accelerated degeneration across many organ systems at once but not uniformly - which is what "segmental" progeria means. In the human disease this is growth failure, cachexia, lipoatrophy, microcephaly, sensory loss, photosensitivity, learning difficulty and progressive multi-organ decline. In the hypomorphic mouse it is a markedly shortened lifespan with accelerated histopathological and immunological ageing across organs, and, specifically, peripheral neuropathy indistinguishable in kind from the age-related human disease.
Animal models
Ercc1 hypomorphic mouse Mouse recapitulates Reproduces accelerated ageing across many organ systems on a compressed timetable, including a peripheral neuropathy whose onset can be timed between 8 and 20 weeks.
Ercc1 truncated-allele mouse Mouse recapitulates Median lifespan of 20 weeks against 118 for wild-type siblings, with accelerated decline in body and organ weights, histopathology and immune parameters.
Show evidence (2 references)
PMID:21612988 SUPPORT Other
"Mutations in ERCC1 or XPF cause xeroderma pigmentosum, XFE progeroid syndrome or cerebro-oculo-facio-skeletal syndrome, characterized by increased risk of cancer, accelerated aging and severe developmental abnormalities, respectively."
Assigns accelerated ageing, rather than cancer or developmental malformation, as the phenotype of this member of the series.
PMID:22953029 SUPPORT Model Organism
"Multiple signs and symptoms of aging were found to occur at an accelerated rate in the Ercc1(-/Δ7) mice as compared to wild-type controls, including a decline in weight of both whole body and various organs, numerous histopathological lesions, and immune parameters."
Gives the breadth of organ involvement that makes the phenotype segmental rather than tissue-specific.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for XFE Progeroid Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Ear 1
Sensorineural Hearing Loss FREQUENT Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301571 SUPPORT INDIRECT Human Clinical
"Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia)."
Names progressive sensorineural hearing loss among the neurologic manifestations, with a frequency for the spectrum. INDIRECT: the chapter covers the spectrum, not XFE.
Eye 1
Visual Impairment FREQUENT HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301571 SUPPORT INDIRECT Other
"corneal transplantation may improve the visual impairment resulting from severe keratitis"
Establishes visual impairment as a feature of the spectrum. INDIRECT and weak on purpose: the sentence attributes it to keratitis, which is the xeroderma mechanism, whereas the index patient's visual impairment predates any such account. Flagged in notes as a place a better source would help.
Head and Neck 1
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301571 SUPPORT INDIRECT Human Clinical
"Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia)."
Names acquired microcephaly among the neurologic manifestations of the ERCC4-containing xeroderma pigmentosum spectrum, with a frequency. INDIRECT because the chapter covers that spectrum rather than XFE specifically.
PMID:26074087 SUPPORT Human Clinical
"The patient, XP51RO, exhibited symptoms resembling premature aging, profound crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary, musculoskeletal, and hematopoietic symptoms were present."
Places neurologic involvement in the index patient for this disease specifically.
Integument 2
Cutaneous Photosensitivity VERY_FREQUENT HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous photosensitivity (HP:0000992). HP:0000992 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26074087 SUPPORT Human Clinical
"The patient, XP51RO, exhibited symptoms resembling premature aging, profound crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary, musculoskeletal, and hematopoietic symptoms were present."
Reports frequent sunburns in the index patient for this disease. Direct rather than inherited from the xeroderma spectrum.
PMID:20221251 SUPPORT INDIRECT Human Clinical
"Patients suffering from XP exhibit exquisite sun sensitivity, high incidence of skin cancer, and in some cases neurodegeneration."
Corroborates the mechanism at the class level - photosensitivity follows the nucleotide excision repair defect. INDIRECT because the sentence is about xeroderma pigmentosum patients.
Progeroid Facial Appearance VERY_FREQUENT HP:0005328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progeroid facial appearance (HP:0005328). HP:0005328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26074087 SUPPORT INDIRECT Human Clinical
"The patient, XP51RO, exhibited symptoms resembling premature aging, profound crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary, musculoskeletal, and hematopoietic symptoms were present."
Records symptoms resembling premature aging in the index patient. INDIRECT: the facial appearance specifically is not named in this sentence.
Nervous System 1
Progressive Peripheral Neuropathy FREQUENT HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:21596054 SUPPORT Model Organism
"Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals."
Gives the functional measurement and its timing.
PMID:21596054 SUPPORT Model Organism
"We conclude that Ercc1(-/Δ) mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease."
The authors' conclusion, in the model. The human items below supply the neurologic involvement; the mouse supplies the timing and the demonstration that DNA damage alone is sufficient.
PMID:26074087 SUPPORT INDIRECT Human Clinical
"The patient, XP51RO, exhibited symptoms resembling premature aging, profound crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary, musculoskeletal, and hematopoietic symptoms were present."
Records neurologic symptoms in the index patient. INDIRECT because the sentence says neurologic without specifying a peripheral neuropathy.
+ 1 more reference
Growth 1
Postnatal Growth Failure and Short Stature VERY_FREQUENT Postnatal growth retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17183314 SUPPORT Model Organism
"Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan."
Cited as the mechanistic basis for the growth phenotype, graded MODEL_ORGANISM because the axis measurement is in mice. No longer the only support: the human item below carries the phenotype.
PMID:26074087 SUPPORT Human Clinical
"The patient, XP51RO, exhibited symptoms resembling premature aging, profound crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary, musculoskeletal, and hematopoietic symptoms were present."
Human evidence for the multisystem involvement in the index patient, including the musculoskeletal features the growth phenotype belongs to.
Other 3
Cachexia VERY_FREQUENT HP:0004326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cachexia (HP:0004326). HP:0004326 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22953029 SUPPORT Model Organism
"Multiple signs and symptoms of aging were found to occur at an accelerated rate in the Ercc1(-/Δ7) mice as compared to wild-type controls, including a decline in weight of both whole body and various organs, numerous histopathological lesions, and immune parameters."
The wasting phenotype in the model. Retained alongside the human item below rather than as sole support, since MODEL_ORGANISM evidence alone is not sufficient for a human phenotype.
PMID:26074087 SUPPORT Human Clinical
"The patient, XP51RO, exhibited symptoms resembling premature aging, profound crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary, musculoskeletal, and hematopoietic symptoms were present."
Records the premature-aging presentation of the index patient, of which the wasting is part.
Lipoatrophy VERY_FREQUENT HP:0100578 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lipoatrophy (HP:0100578). HP:0100578 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26074087 SUPPORT INDIRECT Human Clinical
"The patient, XP51RO, exhibited symptoms resembling premature aging, profound crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary, musculoskeletal, and hematopoietic symptoms were present."
Records the premature-aging presentation of the index patient. INDIRECT because the sentence does not name lipoatrophy separately from that presentation.
Learning Disability FREQUENT Specific learning disability HP:0001328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Specific learning disability (HP:0001328). HP:0001328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301571 SUPPORT INDIRECT Human Clinical
"Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia)."
Names progressive cognitive impairment among the neurologic manifestations of the spectrum. INDIRECT, and note the spectrum term is cognitive impairment rather than learning disability - the two are not the same claim.
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Genetic Associations

1
ERCC4
Gene: ERCC4 hgnc:3436 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ERCC4 (hgnc:3436). hgnc:3436 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:26074087 SUPPORT Other
"However, mutations in the ERCC1 or ERCC4 genes cause a remarkable array of rare inherited human disorders. These include specific forms of xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia, XFE progeria and cerebro-oculo-facio-skeletal syndrome."
Enumerates the allelic series this gene produces.
PMID:24027083 REFUTE Human Clinical
"The frequency of ERCC4 mutation carriers does not differ between cases and controls, suggesting that ERCC4 is not a cancer susceptibility gene."
Refutes the reasonable-sounding hypothesis that a Fanconi anemia gene confers familial breast/ovarian cancer risk. Curated because the inference from "FA gene" to "cancer susceptibility gene" is one a curator would otherwise make by analogy.
💊

Medical Actions

5
Supportive and Symptomatic Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
There is no disease-modifying therapy. Management is symptomatic, plus rigorous sun protection on account of the excision repair defect. Everything below this entry is preclinical and is curated as such.
Show evidence (2 references)
PMID:20301571 SUPPORT INDIRECT Other
"Prevention of primary manifestations: Avoid sun and other UV exposure to the skin and eyes."
The one preventive measure that follows directly from the nucleotide excision repair defect. INDIRECT because the chapter is written for the xeroderma pigmentosum spectrum, of which ERCC4 is one gene.
PMID:20301571 SUPPORT INDIRECT Other
"Hearing loss may be treated with hearing aids."
A concrete symptomatic measure for one of this entry's phenotypes, rather than a statement about the source's scope.
Dietary Restriction
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
The single most effective intervention in the models, and mechanistically coherent rather than merely empirical: caloric restriction invokes the same shift from growth to preservation that the disease's own somatotroph suppression represents, so it is the intervention that most directly engages the mechanism this entry curates. In DNA repair-deficient progeroid mice it roughly doubles lifespan with systemic health benefits. Curated as preclinical. It has never been tested in a human with this disease, the patients described are already cachectic, and restricting intake in a wasting child is not a straightforward translation - which is precisely why the finding is worth recording with its context rather than as a recommendation.
Mechanism Target:
Suppression of the Growth Hormone-IGF1 Somatotroph Axis — Dietary restriction acts on the same growth-to-preservation axis that unrepaired damage engages, which is the proposed basis for its effect in these models.
Show evidence (1 reference)
PMID:39245994 SUPPORT Model Organism
"DR temporarily suppresses growth, and when applied to progeroid DNA repair-deficient mice doubles lifespan with systemic health benefits."
States both the effect and the growth-suppression mechanism this link asserts.
Show evidence (1 reference)
PMID:39245994 SUPPORT Model Organism
"Dietary restriction (DR, also known as caloric restriction) is a well-established long-term intervention recognized for its universal anti-ageing effects."
Places the intervention in context. All evidence for it in this disease is MODEL_ORGANISM; nothing here is a human result.
Senolytic Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Preclinical, and curated because the entry already asserts that the models are a senolytic testing platform - so the claim should either be evidenced or dropped. The Ercc1-deficient mouse was used as the screening system that identified HSP90 inhibitors as a senolytic class, and treating the hypomorph with one extended healthspan and reduced p16INK4a expression. Nothing has been tested in a patient with this disease, and note the circularity worth being explicit about: the model is both the discovery platform for the drug class and the system in which the class is validated.
Mechanism Target:
Premature Cellular Senescence — Senolytics clear senescent cells selectively, which is this node directly.
Show evidence (1 reference)
PMID:28871086 SUPPORT Model Organism
"Treatment of Ercc1 -/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression."
The intervention result in the model that carries this disease's lesion, including a senescence marker as readout.
Show evidence (1 reference)
PMID:28871086 SUPPORT INDIRECT Model Organism
"Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging."
Places the drug class. INDIRECT: a statement about murine ageing models generally, not about this disease.
NF-kappaB / IKK Inhibition
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Preclinical, and curated because the mechanism is a loop rather than a linear consequence: pharmacological IKK inhibition delayed age-related pathology in progeroid mice and also reduced oxidative DNA damage, meaning the intervention reaches back onto the primary lesion rather than only masking its consequences. No agent has been tested in a patient with this disease.
Mechanism Target:
NF-kappaB-Driven Inflammation and Oxidative Stress — Inhibiting the kinase that activates NF-kappaB suppresses the node directly.
Show evidence (1 reference)
PMID:22706308 SUPPORT Model Organism
"Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice."
The intervention result, by both genetic and pharmacological routes.
Show evidence (1 reference)
PMID:22706308 SUPPORT Model Organism
"IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging."
The authors' translational proposal, which is a proposal and not a result in humans.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Recurrence risk counselling, with the locus-specific complication that the same two alleles in a sibling could in principle present as a different ERCC4 disorder, and that most biallelic combinations are not viable.
Show evidence (1 reference)
PMID:24027083 SUPPORT INDIRECT Human Clinical
"the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients, indicating that most biallelic combinations of ERCC4 mutations are embryo lethal"
The carrier frequency and the embryonic lethality inference are the two facts a counselling conversation turns on. INDIRECT because the paper is a cancer susceptibility study, not a counselling study.
🌍

Environmental Factors

2
Ultraviolet radiation exposure
exposure to ultraviolet radiation ECTO:0000006 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to ultraviolet radiation (ECTO:0000006). ECTO:0000006 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
UV exposure adds helix-distorting lesions to a genome that cannot excise them. It does not cause the disease - the damage that drives the progeroid phenotype is endogenous - but it is the one exposure that is both clearly harmful and clearly avoidable, which is why sun avoidance is the entry's only preventive measure.
Show evidence (1 reference)
PMID:21612988 SUPPORT INDIRECT Other
"This offers an understanding of the tremendous health impact of DNA damage derived from environmental and endogenous sources."
Names environmental damage alongside endogenous damage as the burden. INDIRECT: it establishes that both sources matter rather than quantifying the environmental one.
Mechanism Target:
EXACERBATES Accumulation of Endogenous DNA Damage — UV-induced photoproducts are substrates for the repair pathway that is disabled, so exposure adds to the unrepaired burden.
Show evidence (1 reference)
PMID:20301571 SUPPORT INDIRECT Other
"Prevention of primary manifestations: Avoid sun and other UV exposure to the skin and eyes."
The management recommendation is the clinical expression of this mechanism. INDIRECT: it is a recommendation for the xeroderma spectrum rather than a measurement of added damage in XFE.
High dietary protein intake
Recorded because it is the mirror image of the dietary restriction entry in treatments and comes from the same experimental programme. Nearly doubling protein intake shortened lifespan in both sexes of the progeroid repair-deficient mouse, with increased markers of tissue injury, inflammation and gene-length-dependent transcriptional decline. Model evidence only, and the authors themselves frame the implication as one for nutritional guidelines in these syndromes rather than as an established human risk.
Show evidence (1 reference)
PMID:40416846 SUPPORT Model Organism
"Conversely, a near doubling of protein intake and isocaloric compensatory lowering with carbohydrates significantly shortened lifespan in both sexes."
The exposure's effect, measured in the model that carries this disease's lesion. MODEL_ORGANISM because the experiment is in mice.
Mechanism Target:
EXACERBATES Accumulation of Endogenous DNA Damage — The proposed intermediate is transcription stress: high protein intake increased gene-length-dependent transcriptional decline, which the authors read as reflecting DNA damage accumulation.
Show evidence (1 reference)
PMID:40416846 SUPPORT Model Organism
"Conversely, a near doubling of protein intake and isocaloric compensatory lowering with carbohydrates significantly shortened lifespan in both sexes."
The lifespan effect this link asserts, measured in the model that carries this disease's lesion.
🔬

Diagnosis

2
Molecular Genetic Testing of ERCC4
Sequencing ERCC4 is the diagnostic step, and interpretation is the hard part: the same gene yields four other diseases, so the variant alone does not assign the entity. In practice the diagnosis is made when a patient referred for suspected xeroderma pigmentosum turns out to have progeroid features, which is exactly how the index case was found.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29105242 SUPPORT Human Clinical
"We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome."
Shows the diagnostic route in practice - sequencing of unsolved progeroid cases - and the registry context in which such patients are found.
🐁

Animal Models

2
Ercc1 hypomorphic mouse
The workhorse model for this disease and, more broadly, one of the standard platforms in ageing research. Read the limitations carefully: the model perturbs ERCC1, the partner subunit, not ERCC4, the gene that causes the human disease.
Species
Mouse
Genotype
Ercc1(-/delta) - one null allele and one truncated allele, expressing about 10 percent of normal ERCC1-XPF
Publication
PMID:21596054
Pathograph links
Segmental Multi-Organ Degeneration recapitulates fidelity: moderate Reproduces accelerated ageing across many organ systems on a compressed timetable, including a peripheral neuropathy whose onset can be timed between 8 and 20 weeks.
Limitations: The mouse is an Ercc1 mutant and the human disease is an ERCC4 one. The two proteins are obligate partners so the heterodimer is disabled either way, but the model cannot reproduce anything specific to the ERCC4 subunit - and the founding human allele's defect is precisely subunit-specific, being a mislocalisation of catalytically intact XPF rather than a loss of nuclease. Lifespan compression also means the mouse phenotype is read out over months against a human course of years.
Readouts
Nerve conduction studies at 8 and 20 weeks
Direction: DECREASED
Interpretation: Normal at 8 weeks and significantly abnormal at 20, which times the neuropathy rather than merely reporting it.
Show evidence (1 reference)
PMID:21596054 SUPPORT Model Organism
"Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals."
The measurement behind this readout.
Show evidence (1 reference)
PMID:21596054 SUPPORT Model Organism
"We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy."
The authors' own framing of this strain as a model of XFE progeroid syndrome.
Premature Cellular Senescence recapitulates fidelity: moderate Tissues and primary cells senesce prematurely, which is what makes the strain a testing platform for senolytics.
Limitations: Same subunit caveat. In addition, senescence has not been demonstrated in tissue from a patient with this disease, so the model establishes the mechanism's existence rather than its presence in the human disease.
Show evidence (1 reference)
PMID:23852002 SUPPORT Model Organism
"XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic mice. Tissues and primary cells from these mice senesce prematurely"
Supports treating the strain as informative for the senescence node.
Ercc1 truncated-allele mouse
A second hypomorphic strain, characterised in life and post mortem specifically to establish the breadth of the progeroid phenotype rather than a single organ effect.
Species
Mouse
Genotype
Ercc1(-/delta7) - hemizygous for a single Ercc1 allele encoding a protein lacking the last seven amino acids
Publication
PMID:22953029
Pathograph links
Segmental Multi-Organ Degeneration recapitulates fidelity: moderate Median lifespan of 20 weeks against 118 for wild-type siblings, with accelerated decline in body and organ weights, histopathology and immune parameters.
Limitations: Again an Ercc1 rather than an ERCC4 model. The sixfold lifespan compression is also far more severe than the human course, so rates in this strain should not be read as a timetable for the human disease.
Readouts
Median lifespan
Direction: DECREASED
Interpretation: 20 weeks versus 118 weeks in wild-type siblings.
Show evidence (1 reference)
PMID:22953029 SUPPORT Model Organism
"Ercc1(-/Δ7) mice were much smaller and median life span was markedly reduced compared to wild-type siblings: 20 and 118 weeks, respectively."
The lifespan measurement.
Show evidence (1 reference)
PMID:22953029 SUPPORT Model Organism
"Together they define a segmental progeroid phenotype of the Ercc1(-/Δ7) mouse model."
The authors' conclusion that the phenotype is segmental progeroid, which is what this link asserts.
{ }

Source YAML

click to show 
name: XFE Progeroid Syndrome
creation_date: "2026-08-29T18:20:00Z"
category: Mendelian
description: >-
  XFE progeroid syndrome is a segmental progeria caused by biallelic hypomorphic
  variants in ERCC4, which encodes XPF - one half of the ERCC1-XPF structure-specific
  endonuclease. The nuclease makes the 5' incision in nucleotide excision repair and is
  also required for interstrand crosslink repair, for some double-strand break repair,
  as a backup in base excision repair, and in telomere length regulation. When it is
  crippled, endogenous DNA damage accumulates faster than it can be removed.

  What makes the disease conceptually interesting is what happens next. The organism
  does not simply degenerate: it mounts a conserved response. Expression profiling of
  XPF-ERCC1-deficient mice shows increased antioxidant defences and, centrally, reduced
  growth hormone/IGF-1 signalling - the same shift wild-type mice make under chronic
  genotoxic stress, under caloric restriction, and in normal ageing. The interpretation
  advanced by the founding study is that unrepaired damage triggers a metabolic
  reallocation from growth toward somatic preservation. Dwarfism, cachexia and
  lipoatrophy are on that account not the damage itself but the response to it, which
  is a different kind of claim about a phenotype and is why this entry curates the
  somatotroph axis as its own node.

  ERCC4 is a locus of striking pleiotropy. The same gene produces xeroderma pigmentosum
  group F, Cockayne syndrome overlap, cerebro-oculo-facio-skeletal syndrome, Fanconi
  anemia complementation group Q, and this disease - and which one a genotype produces
  depends on the balance it leaves between the nuclease's two principal activities.
  Fanconi-causing alleles disrupt crosslink repair while largely sparing excision
  repair; xeroderma-causing alleles do the reverse; the progeroid allele impairs both.
  Complete deletion of ERCC4 is not compatible with life, so every viable genotype is a
  partial one.

  The entry should be read with its evidence base in view. The human disease is
  essentially one deeply characterised patient plus a handful of individuals reported
  across the wider ERCC4 spectrum. Almost every mechanistic claim here comes from mouse
  models - and those models are Ercc1 mutants, perturbing the partner subunit rather
  than the gene that causes the human disease. That is recorded as an explicit
  human-model mismatch rather than smoothed over.
disease_term:
  preferred_term: XFE progeroid syndrome
  term:
    id: MONDO:0012590
    label: XFE progeroid syndrome
synonyms:
- XFEPS
- XPF-ERCC1 progeroid syndrome
- XPF-E progeroid syndrome
parents:
- Progeroid Syndrome
- DNA Repair Disorder
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic hypomorphic ERCC4 variants. The founding patient was homozygous for
    p.Arg153Pro and the child of consanguineous parents. Because complete loss of the
    gene is lethal, both alleles must retain some function - so this is a recessive
    disease in which the null genotype is never observed.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Complete deletion of either ERCC1 or ERCC4 is not compatible with viability in
      mice or humans.
    explanation: >-
      Establishes why every viable genotype at this locus is hypomorphic rather than
      null, which is the constraint that shapes the whole allelic series.
  - reference: PMID:24027083
    reference_title: Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) as familial breast/ovarian cancer susceptibility alleles.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported
      for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients,
      indicating that most biallelic combinations of ERCC4 mutations are embryo lethal
    explanation: >-
      A quantitative argument that carriers are not rare while patients are, so the
      rarity of ERCC4 disease is prenatal lethality rather than allele scarcity. This is
      the single most informative number available for this entry.
pathophysiology:
- name: Biallelic Hypomorphic ERCC4 Variants
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Two ERCC4 alleles that each retain some function. The founding and defining
    genotype is homozygous c.458G>C, p.Arg153Pro, in a boy referred for severe chronic
    sunburn who turned out to have progeroid features. The variant is a severe one - it
    confers profound interstrand crosslink sensitivity - but it is not a null, and it
    could not be, because null genotypes at this locus do not reach live birth.
  genes:
  - preferred_term: ERCC4
    term:
      id: hgnc:3436
      label: ERCC4
  genetic_context:
    genes:
    - preferred_term: ERCC4
      term:
        id: hgnc:3436
        label: ERCC4
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    notes: >-
      Recorded as PARTIAL rather than complete loss of function deliberately. It is not
      a hedge: complete loss is embryonic lethal, so partial function is a defining
      property of every genotype that produces this disease rather than a statement
      about the severity of a particular allele.
  evidence:
  - reference: PMID:17183314
    reference_title: A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A patient presented with a severe XPF mutation leading to profound crosslink
      sensitivity and dramatic progeroid symptoms.
    explanation: >-
      The founding clinical observation that defines the entity.
  - reference: PMID:29105242
    reference_title: ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid
      syndrome, Cockayne syndrome (CS), and Fanconi anemia.
    explanation: >-
      Places this disease within the ERCC4 allelic series, which is what the next node
      is about.
  downstream:
  - target: ERCC1-XPF Endonuclease Deficiency
    causal_link_type: DIRECT
- name: ERCC1-XPF Endonuclease Deficiency
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    ERCC1-XPF is a heterodimeric structure-specific endonuclease that cuts DNA at
    junctions between double- and single-stranded regions. It is a core component of
    nucleotide excision repair and is also required for interstrand crosslink repair,
    for homologous recombination and end-joining routes to double-strand break repair,
    as a backup in base excision repair, and in telomere length regulation.

    Which disease an ERCC4 genotype produces turns on the balance of activities it
    leaves. Fanconi-causing alleles strongly disrupt crosslink repair while largely
    sparing excision repair; xeroderma-causing alleles impair excision repair; the
    progeroid genotype impairs both. This is a rare instance where a genotype-phenotype
    rule is stated mechanistically rather than statistically, and it is why this entry
    exists separately from Xeroderma Pigmentosum rather than as a subtype of it.

    The founding allele adds a twist worth curating: R153P protein retains catalytic
    activity in vitro, and the deficit is one of location - XPF-ERCC1 is abundant in
    the cytoplasm of the patient's cells rather than concentrated in the nucleus where
    the DNA is. Microinjecting the mutant complex into the nucleus of XPF-deficient
    cells restored repair. So this is not a dead enzyme; it is a functional enzyme in
    the wrong compartment.
  molecular_functions:
  - preferred_term: endonuclease activity
    term:
      id: GO:0004519
      label: endonuclease activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: nucleotide-excision repair
    term:
      id: GO:0006289
      label: nucleotide-excision repair
    modifier: DECREASED
  - preferred_term: interstrand cross-link repair
    term:
      id: GO:0036297
      label: interstrand cross-link repair
    modifier: DECREASED
  - preferred_term: double-strand break repair via homologous recombination
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
    modifier: DECREASED
  evidence:
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ERCC1-XPF nuclease nicks DNA specifically at junctions between double-stranded and
      single-stranded DNA, when the single-strand is oriented 5' to 3' away from a
      junction.
    explanation: >-
      Defines the biochemical activity that is lost.
  - reference: PMID:23623386
    reference_title: Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data show that depending on the type of ERCC4 mutation and the resulting
      balance between both DNA repair activities, individuals present with one of the
      three clinically distinct disorders, highlighting the multifunctional nature of
      the XPF endonuclease in genome stability and human disease.
    explanation: >-
      States the genotype-phenotype rule this node rests on, and is the reason the entry
      is separate from Xeroderma Pigmentosum rather than a subtype of it.
  - reference: PMID:23623386
    reference_title: Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in
      DNA ICL repair without severely compromising nucleotide excision repair
    explanation: >-
      The measurement behind the rule: the two activities can be dissociated by allele.
  - reference: PMID:20221251
    reference_title: Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Surprisingly, differential immunostaining and fractionation of cells from an XFE
      progeroid patient revealed that XPF-ERCC1 is abundant in the cytoplasm.
    explanation: >-
      Locates the founding allele's defect in protein localisation rather than in
      catalysis, in cells from the index patient.
  - reference: PMID:20221251
    reference_title: Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, microinjection of XPF(R153P)-ERCC1 into the nucleus of XPF-deficient
      human cells restored nucleotide excision repair of UV-induced DNA damage.
    explanation: >-
      The rescue that proves the enzyme is competent and merely mislocalised, which is
      what makes this a trafficking defect rather than a catalytic one.
  downstream:
  - target: Accumulation of Endogenous DNA Damage
    causal_link_type: DIRECT
- name: Accumulation of Endogenous DNA Damage
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    With the nuclease crippled, spontaneously arising lesions - including those from
    endogenous oxidative and metabolic sources rather than only from sunlight - persist
    instead of being excised. This is the node that makes the disease a model of
    ageing rather than only a repair disorder: the damage does not need an external
    genotoxin to accumulate.
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:21612988
    reference_title: Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This offers an understanding of the tremendous health impact of DNA damage derived
      from environmental and endogenous sources.
    explanation: >-
      Names endogenous as well as environmental damage as the burden this node
      describes.
  downstream:
  - target: Suppression of the Growth Hormone-IGF1 Somatotroph Axis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The link is a transcriptional response programme rather than a direct biochemical
      step, and the intervening signalling has been characterised in outline rather than
      completely.
  - target: Premature Cellular Senescence
    causal_link_type: DIRECT
  - target: NF-kappaB-Driven Inflammation and Oxidative Stress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Suppression of the Growth Hormone-IGF1 Somatotroph Axis
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    The node that makes this disease theoretically interesting rather than merely rare.
    Liver transcriptomes of XPF-ERCC1-deficient mice correlate highly with those of old
    wild-type mice, and show increased cell death and antioxidant defences together
    with reduced growth hormone/IGF-1 signalling. The same shift occurs in wild-type
    animals under chronic genotoxic stress, under caloric restriction, and with normal
    ageing.

    On this reading the growth failure, cachexia and lipoatrophy of the human disease
    are not the damage but the *response* to it - a survival programme that reallocates
    resources from growth to somatic preservation. That is a strong and unusual claim
    about a phenotype and it is curated as PROVISIONAL: the transcriptomic correlation
    and the conserved direction of the shift are solid, but the causal step from damage
    to axis suppression is inferred from expression data in mouse liver and has not
    been demonstrated in a patient.
  biological_processes:
  - preferred_term: insulin-like growth factor receptor signaling pathway
    term:
      id: GO:0048009
      label: insulin-like growth factor receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:17183314
    reference_title: A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression data from XPF-ERCC1-deficient mice indicate increased cell death and
      anti-oxidant defences, a shift towards anabolism and reduced growth
      hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of
      lifespan.
    explanation: >-
      The measurement behind this node, in mouse liver.
  - reference: PMID:17183314
    reference_title: A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that unrepaired cytotoxic DNA damage induces a highly conserved
      metabolic response mediated by the IGF1/insulin pathway, which re-allocates
      resources from growth to somatic preservation and life extension.
    explanation: >-
      The authors' statement of the survival-response interpretation that this node
      encodes.
  - reference: PMID:17183314
    reference_title: A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show a highly significant correlation between the liver transcriptome of
      old mice and a mouse model of this progeroid syndrome.
    explanation: >-
      The correlation that places the disease on the natural-ageing axis rather than
      merely resembling it superficially.
  downstream:
  - target: Segmental Multi-Organ Degeneration
    causal_link_type: DIRECT
- name: Premature Cellular Senescence
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Tissues and primary cells from Ercc1-deficient mice senesce prematurely. Senescence
    is the cellular currency in which this disease's tissue phenotype is paid, and it is
    also what makes the models a testing platform for senolytic drugs.
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  evidence:
  - reference: PMID:23852002
    reference_title: Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the
      DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic
      mice. Tissues and primary cells from these mice senesce prematurely
    explanation: >-
      States the premature senescence and, in the same sentence, that the model is an
      Ercc1 rather than an Ercc4 mutant - which is the mismatch this entry records.
  downstream:
  - target: Segmental Multi-Organ Degeneration
    causal_link_type: DIRECT
- name: NF-kappaB-Driven Inflammation and Oxidative Stress
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    NF-kappaB is activated stochastically across cell types as both progeroid and
    wild-type mice age. What makes this more than a correlation is the intervention:
    removing one p65 allele, or inhibiting the activating kinase IKK pharmacologically,
    delays the age-related symptoms and pathologies of the progeroid mice, reduces
    oxidative DNA damage, and delays senescence.

    Note the feedback this implies - inhibiting NF-kappaB *reduced oxidative DNA damage*,
    so the inflammatory response is not only downstream of damage but also feeds back
    onto it. That makes this node a loop rather than a link in a chain, and it is the
    reason it is a plausible therapeutic target in a disease whose primary lesion is
    not druggable.
  biological_processes:
  - preferred_term: positive regulation of canonical NF-kappaB signal transduction
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:22706308
    reference_title: NF-κB inhibition delays DNA damage-induced senescence and aging in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a
      pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the
      age-related symptoms and pathologies of progeroid mice.
    explanation: >-
      The intervention result that upgrades this from an association to a causal
      contributor.
  - reference: PMID:22706308
    reference_title: NF-κB inhibition delays DNA damage-induced senescence and aging in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and
      delayed cellular senescence.
    explanation: >-
      Documents the feedback onto DNA damage itself, which is what makes this node a
      loop rather than a terminal consequence.
  downstream:
  - target: Premature Cellular Senescence
    causal_link_type: DIRECT
  - target: Segmental Multi-Organ Degeneration
    causal_link_type: DIRECT
- name: Segmental Multi-Organ Degeneration
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical endpoint: accelerated degeneration across many organ systems at once
    but not uniformly - which is what "segmental" progeria means. In the human disease
    this is growth failure, cachexia, lipoatrophy, microcephaly, sensory loss,
    photosensitivity, learning difficulty and progressive multi-organ decline. In the
    hypomorphic mouse it is a markedly shortened lifespan with accelerated
    histopathological and immunological ageing across organs, and, specifically,
    peripheral neuropathy indistinguishable in kind from the age-related human disease.
  evidence:
  - reference: PMID:21612988
    reference_title: Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutations in ERCC1 or XPF cause xeroderma pigmentosum, XFE progeroid syndrome or
      cerebro-oculo-facio-skeletal syndrome, characterized by increased risk of cancer,
      accelerated aging and severe developmental abnormalities, respectively.
    explanation: >-
      Assigns accelerated ageing, rather than cancer or developmental malformation, as
      the phenotype of this member of the series.
  - reference: PMID:22953029
    reference_title: Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Multiple signs and symptoms of aging were found to occur at an accelerated rate in
      the Ercc1(-/Δ7) mice as compared to wild-type controls, including a decline in
      weight of both whole body and various organs, numerous histopathological lesions,
      and immune parameters.
    explanation: >-
      Gives the breadth of organ involvement that makes the phenotype segmental rather
      than tissue-specific.
phenotypes:
- category: Growth
  name: Postnatal Growth Failure and Short Stature
  frequency: VERY_FREQUENT
  description: >-
    Normal birth weight and early milestones followed by growth arrest. In the index
    patient growth stopped and weight was lost from around age 12. On the somatotroph
    account this is the visible consequence of the growth-hormone/IGF-1 shutdown rather
    than a structural defect.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:17183314
    reference_title: A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression data from XPF-ERCC1-deficient mice indicate increased cell death and
      anti-oxidant defences, a shift towards anabolism and reduced growth
      hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of
      lifespan.
    explanation: >-
      Cited as the mechanistic basis for the growth phenotype, graded MODEL_ORGANISM
      because the axis measurement is in mice. No longer the only support: the human
      item below carries the phenotype.
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, XP51RO, exhibited symptoms resembling premature aging, profound
      crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary,
      musculoskeletal, and hematopoietic symptoms were present.
    explanation: >-
      Human evidence for the multisystem involvement in the index patient, including the
      musculoskeletal features the growth phenotype belongs to.
- category: Constitutional
  name: Cachexia
  frequency: VERY_FREQUENT
  description: >-
    Progressive loss of body mass, in the index patient beginning in the second decade
    and accompanying the growth arrest.
  phenotype_term:
    preferred_term: Cachexia
    term:
      id: HP:0004326
      label: Cachexia
  evidence:
  - reference: PMID:22953029
    reference_title: Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Multiple signs and symptoms of aging were found to occur at an accelerated rate in
      the Ercc1(-/Δ7) mice as compared to wild-type controls, including a decline in
      weight of both whole body and various organs, numerous histopathological lesions,
      and immune parameters.
    explanation: >-
      The wasting phenotype in the model. Retained alongside the human item below rather
      than as sole support, since MODEL_ORGANISM evidence alone is not sufficient for a
      human phenotype.
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, XP51RO, exhibited symptoms resembling premature aging, profound
      crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary,
      musculoskeletal, and hematopoietic symptoms were present.
    explanation: >-
      Records the premature-aging presentation of the index patient, of which the
      wasting is part.
- category: Dermatologic
  name: Cutaneous Photosensitivity
  frequency: VERY_FREQUENT
  description: >-
    Sun sensitivity from birth, which is what brought the index patient to medical
    attention and is the feature that made xeroderma pigmentosum the initial working
    diagnosis. It follows directly from the nucleotide excision repair defect.
  phenotype_term:
    preferred_term: Cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, XP51RO, exhibited symptoms resembling premature aging, profound
      crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary,
      musculoskeletal, and hematopoietic symptoms were present.
    explanation: >-
      Reports frequent sunburns in the index patient for this disease. Direct rather
      than inherited from the xeroderma spectrum.
  - reference: PMID:20221251
    reference_title: Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients suffering from XP exhibit exquisite sun sensitivity, high incidence of
      skin cancer, and in some cases neurodegeneration.
    explanation: >-
      Corroborates the mechanism at the class level - photosensitivity follows the
      nucleotide excision repair defect. INDIRECT because the sentence is about
      xeroderma pigmentosum patients.
- category: Neurologic
  name: Progressive Peripheral Neuropathy
  frequency: FREQUENT
  description: >-
    Curated because the model result is unusually clean: nerve conduction is normal in
    young adult hypomorphic mice and significantly abnormal by 20 weeks, with matching
    morphological change in the sciatic nerve appearing on the same schedule. That is a
    demonstration that DNA damage alone drives a neuropathy, on a timetable.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:21596054
    reference_title: Premature aging-related peripheral neuropathy in a mouse model of progeria.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Nerve conduction studies revealed normal nerve function in young adult (8 week)
      Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals.
    explanation: >-
      Gives the functional measurement and its timing.
  - reference: PMID:21596054
    reference_title: Premature aging-related peripheral neuropathy in a mouse model of progeria.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that Ercc1(-/Δ) mice have accelerated spontaneous peripheral
      neurodegeneration that mimics aging-related disease.
    explanation: >-
      The authors' conclusion, in the model. The human items below supply the neurologic
      involvement; the mouse supplies the timing and the demonstration that DNA damage
      alone is sufficient.
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, XP51RO, exhibited symptoms resembling premature aging, profound
      crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary,
      musculoskeletal, and hematopoietic symptoms were present.
    explanation: >-
      Records neurologic symptoms in the index patient. INDIRECT because the sentence
      says neurologic without specifying a peripheral neuropathy.
  - reference: PMID:20301571
    reference_title: Xeroderma Pigmentosum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 25% of affected individuals have neurologic manifestations (acquired
      microcephaly, diminished or absent deep tendon stretch reflexes, progressive
      sensorineural hearing loss, progressive cognitive impairment, and ataxia).
    explanation: >-
      Names diminished or absent deep tendon reflexes - the clinical signature of a
      peripheral neuropathy - in the ERCC4-containing spectrum.
- category: Neurologic
  name: Microcephaly
  frequency: FREQUENT
  description: >-
    Reported in the index patient. Recorded as a phenotype of the entry without a
    mechanistic node of its own, because whether it reflects the same somatotroph
    suppression or a separate neurodevelopmental effect of unrepaired damage is not
    established.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:20301571
    reference_title: Xeroderma Pigmentosum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 25% of affected individuals have neurologic manifestations (acquired
      microcephaly, diminished or absent deep tendon stretch reflexes, progressive
      sensorineural hearing loss, progressive cognitive impairment, and ataxia).
    explanation: >-
      Names acquired microcephaly among the neurologic manifestations of the
      ERCC4-containing xeroderma pigmentosum spectrum, with a frequency. INDIRECT
      because the chapter covers that spectrum rather than XFE specifically.
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, XP51RO, exhibited symptoms resembling premature aging, profound
      crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary,
      musculoskeletal, and hematopoietic symptoms were present.
    explanation: >-
      Places neurologic involvement in the index patient for this disease specifically.
- category: Constitutional
  name: Lipoatrophy
  frequency: VERY_FREQUENT
  description: >-
    Loss of subcutaneous fat, part of the wasted, aged appearance and, on the
    somatotroph account, another expression of the growth-to-preservation shift rather
    than a separate lesion.
  phenotype_term:
    preferred_term: Lipoatrophy
    term:
      id: HP:0100578
      label: Lipoatrophy
  evidence:
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, XP51RO, exhibited symptoms resembling premature aging, profound
      crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary,
      musculoskeletal, and hematopoietic symptoms were present.
    explanation: >-
      Records the premature-aging presentation of the index patient. INDIRECT because
      the sentence does not name lipoatrophy separately from that presentation.
- category: Craniofacial
  name: Progeroid Facial Appearance
  frequency: VERY_FREQUENT
  description: >-
    The aged, wizened, narrow face that develops from around age 10 in the index
    patient and is the feature that turned a suspected xeroderma pigmentosum referral
    into a new disease entity.
  phenotype_term:
    preferred_term: Progeroid facial appearance
    term:
      id: HP:0005328
      label: Progeroid facial appearance
  evidence:
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient, XP51RO, exhibited symptoms resembling premature aging, profound
      crosslink sensitivity, and frequent sunburns. Many neurologic, hepatobiliary,
      musculoskeletal, and hematopoietic symptoms were present.
    explanation: >-
      Records symptoms resembling premature aging in the index patient. INDIRECT: the
      facial appearance specifically is not named in this sentence.
- category: Auditory
  name: Sensorineural Hearing Loss
  frequency: FREQUENT
  description: >-
    Progressive sensorineural hearing loss, present in the index patient and one of the
    neurologic manifestations of the wider ERCC4-containing spectrum.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301571
    reference_title: Xeroderma Pigmentosum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 25% of affected individuals have neurologic manifestations (acquired
      microcephaly, diminished or absent deep tendon stretch reflexes, progressive
      sensorineural hearing loss, progressive cognitive impairment, and ataxia).
    explanation: >-
      Names progressive sensorineural hearing loss among the neurologic manifestations,
      with a frequency for the spectrum. INDIRECT: the chapter covers the spectrum, not
      XFE.
- category: Ophthalmologic
  name: Visual Impairment
  frequency: FREQUENT
  description: >-
    Visual impairment requiring correction from early childhood in the index patient.
    Distinct in origin from the ocular surface disease of classic xeroderma
    pigmentosum, which is UV-driven.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:20301571
    reference_title: Xeroderma Pigmentosum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      corneal transplantation may improve the visual impairment resulting from severe
      keratitis
    explanation: >-
      Establishes visual impairment as a feature of the spectrum. INDIRECT and weak on
      purpose: the sentence attributes it to keratitis, which is the xeroderma
      mechanism, whereas the index patient's visual impairment predates any such
      account. Flagged in notes as a place a better source would help.
- category: Neurologic
  name: Learning Disability
  frequency: FREQUENT
  description: >-
    Mild learning disability in the index patient, and progressive cognitive impairment
    in the wider spectrum.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:20301571
    reference_title: Xeroderma Pigmentosum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 25% of affected individuals have neurologic manifestations (acquired
      microcephaly, diminished or absent deep tendon stretch reflexes, progressive
      sensorineural hearing loss, progressive cognitive impairment, and ataxia).
    explanation: >-
      Names progressive cognitive impairment among the neurologic manifestations of the
      spectrum. INDIRECT, and note the spectrum term is cognitive impairment rather than
      learning disability - the two are not the same claim.
genetic:
- name: ERCC4
  gene_term:
    preferred_term: ERCC4
    term:
      id: hgnc:3436
      label: ERCC4
  relationship_type: CAUSATIVE
  notes: >-
    Also written XPF and FANCQ. One of the most phenotypically pleiotropic single genes
    in medicine: xeroderma pigmentosum group F, Cockayne syndrome overlap,
    cerebro-oculo-facio-skeletal syndrome, Fanconi anemia group Q, and this disease all
    come from ERCC4, and the discriminator is the balance of repair activities the
    genotype leaves rather than the position of the variant as such.

    Two things a curator should not conclude from the gene. It is not a familial
    breast/ovarian cancer susceptibility gene - that was tested directly in 1573 index
    cases against 854 controls and carrier frequency did not differ. And the rarity of
    patients is not the rarity of alleles: carriers are about one in 288, comparable to
    FANCA, while FA-Q patients are roughly a hundredfold rarer than FA-A, which implies
    most biallelic combinations never reach birth.
  evidence:
  - reference: PMID:26074087
    reference_title: The ERCC1 and ERCC4 (XPF) genes and gene products.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, mutations in the ERCC1 or ERCC4 genes cause a remarkable array of rare
      inherited human disorders. These include specific forms of xeroderma pigmentosum,
      Cockayne syndrome, Fanconi anemia, XFE progeria and cerebro-oculo-facio-skeletal
      syndrome.
    explanation: >-
      Enumerates the allelic series this gene produces.
  - reference: PMID:24027083
    reference_title: Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) as familial breast/ovarian cancer susceptibility alleles.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of ERCC4 mutation carriers does not differ between cases and
      controls, suggesting that ERCC4 is not a cancer susceptibility gene.
    explanation: >-
      Refutes the reasonable-sounding hypothesis that a Fanconi anemia gene confers
      familial breast/ovarian cancer risk. Curated because the inference from "FA gene"
      to "cancer susceptibility gene" is one a curator would otherwise make by analogy.
diagnosis:
- name: Molecular Genetic Testing of ERCC4
  description: >-
    Sequencing ERCC4 is the diagnostic step, and interpretation is the hard part: the
    same gene yields four other diseases, so the variant alone does not assign the
    entity. In practice the diagnosis is made when a patient referred for suspected
    xeroderma pigmentosum turns out to have progeroid features, which is exactly how the
    index case was found.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29105242
    reference_title: ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed massive parallel sequencing for 42 unsolved cases submitted to the
      International Registry of Werner Syndrome.
    explanation: >-
      Shows the diagnostic route in practice - sequencing of unsolved progeroid cases -
      and the registry context in which such patients are found.
- name: Cellular Crosslink Sensitivity Testing
  description: >-
    Patient fibroblasts show profound sensitivity to interstrand crosslinking agents, a
    functional assay that distinguishes the progeroid genotype from the xeroderma one,
    where crosslink repair is comparatively spared. Note that the founding allele is
    catalytically competent, so an assay of purified enzyme activity would be misleading
    where a cellular assay is not.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:17183314
    reference_title: A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A patient presented with a severe XPF mutation leading to profound crosslink
      sensitivity and dramatic progeroid symptoms.
    explanation: >-
      Ties the crosslink sensitivity phenotype to the progeroid presentation in the
      index patient.
treatments:
- name: Supportive and Symptomatic Management
  therapeutic_modality: OTHER
  description: >-
    There is no disease-modifying therapy. Management is symptomatic, plus rigorous sun
    protection on account of the excision repair defect. Everything below this entry is
    preclinical and is curated as such.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301571
    reference_title: Xeroderma Pigmentosum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Prevention of primary manifestations: Avoid sun and other UV exposure to the skin
      and eyes.
    explanation: >-
      The one preventive measure that follows directly from the nucleotide excision
      repair defect. INDIRECT because the chapter is written for the xeroderma
      pigmentosum spectrum, of which ERCC4 is one gene.
  - reference: PMID:20301571
    reference_title: Xeroderma Pigmentosum.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Hearing loss may be treated with hearing aids.
    explanation: >-
      A concrete symptomatic measure for one of this entry's phenotypes, rather than a
      statement about the source's scope.
- name: Dietary Restriction
  therapeutic_modality: BEHAVIORAL
  description: >-
    The single most effective intervention in the models, and mechanistically coherent
    rather than merely empirical: caloric restriction invokes the same shift from
    growth to preservation that the disease's own somatotroph suppression represents,
    so it is the intervention that most directly engages the mechanism this entry
    curates.
    In DNA repair-deficient progeroid mice it roughly doubles lifespan with systemic
    health benefits.

    Curated as preclinical. It has never been tested in a human with this disease, the
    patients described are already cachectic, and restricting intake in a wasting child
    is not a straightforward translation - which is precisely why the finding is worth
    recording with its context rather than as a recommendation.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Suppression of the Growth Hormone-IGF1 Somatotroph Axis
    description: >-
      Dietary restriction acts on the same growth-to-preservation axis that unrepaired
      damage engages, which is the proposed basis for its effect in these models.
    evidence:
    - reference: PMID:39245994
      reference_title: Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        DR temporarily suppresses growth, and when applied to progeroid DNA
        repair-deficient mice doubles lifespan with systemic health benefits.
      explanation: >-
        States both the effect and the growth-suppression mechanism this link asserts.
  evidence:
  - reference: PMID:39245994
    reference_title: Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Dietary restriction (DR, also known as caloric restriction) is a well-established
      long-term intervention recognized for its universal anti-ageing effects.
    explanation: >-
      Places the intervention in context. All evidence for it in this disease is
      MODEL_ORGANISM; nothing here is a human result.
- name: Senolytic Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Preclinical, and curated because the entry already asserts that the models are a
    senolytic testing platform - so the claim should either be evidenced or dropped.
    The Ercc1-deficient mouse was used as the screening system that identified HSP90
    inhibitors as a senolytic class, and treating the hypomorph with one extended
    healthspan and reduced p16INK4a expression. Nothing has been tested in a patient
    with this disease, and note the circularity worth being explicit about: the model
    is both the discovery platform for the drug class and the system in which the class
    is validated.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Premature Cellular Senescence
    description: >-
      Senolytics clear senescent cells selectively, which is this node directly.
    evidence:
    - reference: PMID:28871086
      reference_title: Identification of HSP90 inhibitors as a novel class of senolytics.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Treatment of Ercc1 -/∆ mice, a mouse model of a human progeroid syndrome, with
        the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several
        age-related symptoms and reduced p16INK4a expression.
      explanation: >-
        The intervention result in the model that carries this disease's lesion,
        including a senescence marker as readout.
  evidence:
  - reference: PMID:28871086
    reference_title: Identification of HSP90 inhibitors as a novel class of senolytics.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Recently, a new class of drugs termed senolytics were demonstrated to extending
      healthspan, reducing frailty and improving stem cell function in multiple murine
      models of aging.
    explanation: >-
      Places the drug class. INDIRECT: a statement about murine ageing models generally,
      not about this disease.
- name: NF-kappaB / IKK Inhibition
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Preclinical, and curated because the mechanism is a loop rather than a linear
    consequence: pharmacological IKK inhibition delayed age-related pathology in
    progeroid mice and also reduced oxidative DNA damage, meaning the intervention
    reaches back onto the primary lesion rather than only masking its consequences.
    No agent has been tested in a patient with this disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: NF-kappaB-Driven Inflammation and Oxidative Stress
    description: >-
      Inhibiting the kinase that activates NF-kappaB suppresses the node directly.
    evidence:
    - reference: PMID:22706308
      reference_title: NF-κB inhibition delays DNA damage-induced senescence and aging in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a
        pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the
        age-related symptoms and pathologies of progeroid mice.
      explanation: >-
        The intervention result, by both genetic and pharmacological routes.
  evidence:
  - reference: PMID:22706308
    reference_title: NF-κB inhibition delays DNA damage-induced senescence and aging in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide
      clinical benefit for degenerative changes associated with accelerated aging
      disorders and normal aging.
    explanation: >-
      The authors' translational proposal, which is a proposal and not a result in
      humans.
- name: Genetic Counseling
  therapeutic_modality: OTHER
  description: >-
    Recurrence risk counselling, with the locus-specific complication that the same two
    alleles in a sibling could in principle present as a different ERCC4 disorder, and
    that most biallelic combinations are not viable.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24027083
    reference_title: Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) as familial breast/ovarian cancer susceptibility alleles.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported
      for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients,
      indicating that most biallelic combinations of ERCC4 mutations are embryo lethal
    explanation: >-
      The carrier frequency and the embryonic lethality inference are the two facts a
      counselling conversation turns on. INDIRECT because the paper is a cancer
      susceptibility study, not a counselling study.
environmental:
- name: Ultraviolet radiation exposure
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  description: >-
    UV exposure adds helix-distorting lesions to a genome that cannot excise them. It
    does not cause the disease - the damage that drives the progeroid phenotype is
    endogenous - but it is the one exposure that is both clearly harmful and clearly
    avoidable, which is why sun avoidance is the entry's only preventive measure.
  influences_mechanisms:
  - target: Accumulation of Endogenous DNA Damage
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      UV-induced photoproducts are substrates for the repair pathway that is disabled,
      so exposure adds to the unrepaired burden.
    evidence:
    - reference: PMID:20301571
      reference_title: Xeroderma Pigmentosum.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        Prevention of primary manifestations: Avoid sun and other UV exposure to the
        skin and eyes.
      explanation: >-
        The management recommendation is the clinical expression of this mechanism.
        INDIRECT: it is a recommendation for the xeroderma spectrum rather than a
        measurement of added damage in XFE.
  evidence:
  - reference: PMID:21612988
    reference_title: Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      This offers an understanding of the tremendous health impact of DNA damage derived
      from environmental and endogenous sources.
    explanation: >-
      Names environmental damage alongside endogenous damage as the burden. INDIRECT:
      it establishes that both sources matter rather than quantifying the environmental
      one.
- name: High dietary protein intake
  description: >-
    Recorded because it is the mirror image of the dietary restriction entry in
    treatments and comes from the same experimental programme. Nearly doubling protein
    intake shortened lifespan in both sexes of the progeroid repair-deficient mouse,
    with increased markers of tissue injury, inflammation and gene-length-dependent
    transcriptional decline. Model evidence only, and the authors themselves frame the
    implication as one for nutritional guidelines in these syndromes rather than as an
    established human risk.
  influences_mechanisms:
  - target: Accumulation of Endogenous DNA Damage
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The proposed intermediate is transcription stress: high protein intake increased
      gene-length-dependent transcriptional decline, which the authors read as
      reflecting DNA damage accumulation.
    evidence:
    - reference: PMID:40416846
      reference_title: "High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Conversely, a near doubling of protein intake and isocaloric compensatory
        lowering with carbohydrates significantly shortened lifespan in both sexes.
      explanation: >-
        The lifespan effect this link asserts, measured in the model that carries this
        disease's lesion.
  evidence:
  - reference: PMID:40416846
    reference_title: "High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conversely, a near doubling of protein intake and isocaloric compensatory lowering
      with carbohydrates significantly shortened lifespan in both sexes.
    explanation: >-
      The exposure's effect, measured in the model that carries this disease's lesion.
      MODEL_ORGANISM because the experiment is in mice.
  review_notes: >-
    Model evidence only. Searches of PubMed for ERCC4 or ERCC1 combined with dietary
    protein, and for progeroid syndrome combined with nutrition, returned only the mouse
    programme cited here - no human exposure study exists in this disease or in any
    progeroid repair-deficiency syndrome. Recorded because the model evidence is strong
    and directly relevant to management, not because a human observation exists.
animal_models:
- name: Ercc1 hypomorphic mouse
  species: Mouse
  genotype: Ercc1(-/delta) - one null allele and one truncated allele, expressing about 10 percent of normal ERCC1-XPF
  publication: PMID:21596054
  description: >-
    The workhorse model for this disease and, more broadly, one of the standard
    platforms in ageing research. Read the limitations carefully: the model perturbs
    ERCC1, the partner subunit, not ERCC4, the gene that causes the human disease.
  modeled_mechanisms:
  - target: Segmental Multi-Organ Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces accelerated ageing across many organ systems on a compressed timetable,
      including a peripheral neuropathy whose onset can be timed between 8 and 20 weeks.
    limitations: >-
      The mouse is an Ercc1 mutant and the human disease is an ERCC4 one. The two
      proteins are obligate partners so the heterodimer is disabled either way, but the
      model cannot reproduce anything specific to the ERCC4 subunit - and the founding
      human allele's defect is precisely subunit-specific, being a mislocalisation of
      catalytically intact XPF rather than a loss of nuclease. Lifespan compression also
      means the mouse phenotype is read out over months against a human course of
      years.
    readouts:
    - name: Nerve conduction studies at 8 and 20 weeks
      target: Segmental Multi-Organ Degeneration
      direction: DECREASED
      interpretation: >-
        Normal at 8 weeks and significantly abnormal at 20, which times the neuropathy
        rather than merely reporting it.
      evidence:
      - reference: PMID:21596054
        reference_title: Premature aging-related peripheral neuropathy in a mouse model of progeria.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Nerve conduction studies revealed normal nerve function in young adult (8 week)
          Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals.
        explanation: >-
          The measurement behind this readout.
    evidence:
    - reference: PMID:21596054
      reference_title: Premature aging-related peripheral neuropathy in a mouse model of progeria.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We tested the hypothesis that a murine model of XFE progeroid syndrome, caused
        by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral
        neuropathy.
      explanation: >-
        The authors' own framing of this strain as a model of XFE progeroid syndrome.
  - target: Premature Cellular Senescence
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Tissues and primary cells senesce prematurely, which is what makes the strain a
      testing platform for senolytics.
    limitations: >-
      Same subunit caveat. In addition, senescence has not been demonstrated in tissue
      from a patient with this disease, so the model establishes the mechanism's
      existence rather than its presence in the human disease.
    evidence:
    - reference: PMID:23852002
      reference_title: Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in
        the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and
        hypomorphic mice. Tissues and primary cells from these mice senesce prematurely
      explanation: >-
        Supports treating the strain as informative for the senescence node.
- name: Ercc1 truncated-allele mouse
  species: Mouse
  genotype: Ercc1(-/delta7) - hemizygous for a single Ercc1 allele encoding a protein lacking the last seven amino acids
  publication: PMID:22953029
  description: >-
    A second hypomorphic strain, characterised in life and post mortem specifically to
    establish the breadth of the progeroid phenotype rather than a single organ effect.
  modeled_mechanisms:
  - target: Segmental Multi-Organ Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Median lifespan of 20 weeks against 118 for wild-type siblings, with accelerated
      decline in body and organ weights, histopathology and immune parameters.
    limitations: >-
      Again an Ercc1 rather than an ERCC4 model. The sixfold lifespan compression is
      also far more severe than the human course, so rates in this strain should not be
      read as a timetable for the human disease.
    readouts:
    - name: Median lifespan
      target: Segmental Multi-Organ Degeneration
      direction: DECREASED
      interpretation: >-
        20 weeks versus 118 weeks in wild-type siblings.
      evidence:
      - reference: PMID:22953029
        reference_title: Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Ercc1(-/Δ7) mice were much smaller and median life span was markedly reduced
          compared to wild-type siblings: 20 and 118 weeks, respectively.
        explanation: >-
          The lifespan measurement.
    evidence:
    - reference: PMID:22953029
      reference_title: Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together they define a segmental progeroid phenotype of the Ercc1(-/Δ7) mouse
        model.
      explanation: >-
        The authors' conclusion that the phenotype is segmental progeroid, which is what
        this link asserts.
discussions:
- discussion_id: xfe_models_perturb_the_partner_subunit
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Can Ercc1 mouse models substitute for an ERCC4 model, given that the founding human
    allele's defect is specific to the XPF subunit?
  attaches_to:
  - pathophysiology#ERCC1-XPF Endonuclease Deficiency
  - animal_models#Ercc1 hypomorphic mouse
  - animal_models#Ercc1 truncated-allele mouse
  rationale: >-
    Nearly every mechanistic claim in this entry - the somatotroph shift, senescence,
    the NF-kappaB loop, the neuropathy, the lifespan effect of dietary restriction -
    rests on mice mutant for Ercc1. The human disease is caused by ERCC4. Because the
    two proteins are obligate partners, disabling either disables the heterodimer, and
    that is the justification usually offered.

    It does not cover the founding allele. R153P XPF is catalytically competent and
    fails because the complex is mislocalised to the cytoplasm; microinjecting it into
    the nucleus restores repair. An Ercc1 hypomorph reduces the amount of nuclease. A
    mislocalisation defect and a quantitative deficiency are not obviously the same
    perturbation - the first leaves a normal complement of functional enzyme in the
    wrong place, and could plausibly have consequences in the cytoplasm that the second
    does not. No knock-in mouse carrying the human progeroid ERCC4 allele has been
    reported. Until one is, the models establish that ERCC1-XPF deficiency causes
    segmental progeria; they do not establish that they reproduce this particular
    patient's lesion.
  proposed_experiments:
  - experiment_id: xfe_ercc4_r153p_knockin
    name: Ercc4 R153P knock-in mouse
    description: >-
      Generate a mouse carrying the orthologous R153P substitution at the endogenous
      Ercc4 locus, and compare its subcellular XPF-ERCC1 distribution, somatotroph axis,
      senescence burden and lifespan against the Ercc1 hypomorph.
    would_support:
    - pathophysiology#ERCC1-XPF Endonuclease Deficiency
    supporting_outcome:
    - >-
      The knock-in reproduces the Ercc1 hypomorph's progeroid phenotype and its
      somatotroph shift, so the two perturbations are equivalent at the level of the
      organism and the existing model literature transfers.
    would_refute:
    - pathophysiology#ERCC1-XPF Endonuclease Deficiency
    refuting_outcome:
    - >-
      The knock-in diverges - for instance showing cytoplasmic XPF-ERCC1 with
      consequences absent from the hypomorph, or a different tissue distribution of
      degeneration - in which case the mislocalisation is a mechanism in its own right
      and the Ercc1 literature under-describes the human disease.
- discussion_id: xfe_prenatal_lethality_denominator
  kind: KNOWLEDGE_GAP
  prompt: >-
    How many ERCC4 genotypes never reach birth, and does the surviving patient
    population therefore misrepresent the disease?
  attaches_to:
  - pathophysiology#Biallelic Hypomorphic ERCC4 Variants
  - inheritance#
  rationale: >-
    Carrier frequency for ERCC4 variants is about one in 288, comparable to FANCA, yet
    FA-Q patients are roughly a hundredfold rarer than FA-A. The inference drawn is that
    most biallelic ERCC4 combinations are embryo lethal. If that is right, the handful
    of described patients are a survivorship-biased sample of the mildest end of an
    unobserved distribution, and every statement in this entry about the phenotype
    describes that tail rather than the disease. The gap is not closable by finding more
    patients; it needs data on the genotypes that do not survive, which nobody
    systematically collects.
- discussion_id: xfe_somatotroph_suppression_in_humans
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the growth hormone/IGF-1 axis actually suppressed in a patient with XFE progeroid
    syndrome?
  attaches_to:
  - pathophysiology#Suppression of the Growth Hormone-IGF1 Somatotroph Axis
  - phenotypes#Postnatal Growth Failure and Short Stature
  rationale: >-
    The claim that the growth failure is a survival response rather than damage is the
    most interesting thing this entry says, and the entire evidential basis for it is a
    mouse liver transcriptome. Growth hormone and IGF-1 measurements in a patient would
    be an inexpensive test of it, and none is reported. Until one is, the node stays
    PROVISIONAL and the phenotype's explanation stays an interpretation. Note the
    finding would matter beyond this disease, since it is the link that makes XFE a
    model of natural ageing rather than a rare syndrome that superficially resembles it.
references:
- reference: PMID:20301571
  title: Xeroderma Pigmentosum.
  tags:
  - GeneReviews
- reference: PMID:17183314
  title: A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
- reference: PMID:26074087
  title: The ERCC1 and ERCC4 (XPF) genes and gene products.
- reference: PMID:20221251
  title: Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients.
- reference: PMID:23623386
  title: Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.
- reference: PMID:24027083
  title: Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) as familial breast/ovarian cancer susceptibility alleles.
- reference: PMID:29105242
  title: ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.
- reference: PMID:21612988
  title: Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.
- reference: PMID:22953029
  title: "Broad segmental progeroid changes in short-lived Ercc1(-/\u03947) mice."
- reference: PMID:21596054
  title: Premature aging-related peripheral neuropathy in a mouse model of progeria.
- reference: PMID:23852002
  title: Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress.
- reference: PMID:22706308
  title: "NF-\u03baB inhibition delays DNA damage-induced senescence and aging in mice."
- reference: PMID:28871086
  title: Identification of HSP90 inhibitors as a novel class of senolytics.
- reference: PMID:39245994
  title: Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.
- reference: PMID:40416846
  title: "High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice."
notes: >-
  Lump/split decision. Curated as its own Disease entry rather than as a subtype of
  Xeroderma Pigmentosum, which already carries XP-F (MONDO:0010215) as a has_subtypes
  entry on the same gene. The reason is mechanistic and is stated in the literature
  rather than assumed: the ERCC4 disorders are separated by the balance of repair
  activities a genotype leaves, and the progeroid genotype impairs both nucleotide
  excision and interstrand crosslink repair while the xeroderma genotypes impair
  excision repair alone. The resulting pathographs differ in kind - a cancer-prone
  syndrome versus an accelerated-ageing one - not in degree. XFE also holds its own
  MONDO and OMIM identity. COFS_Syndrome, the third ERCC4-adjacent entry in this KB,
  is likewise separate.

  Evidence base and its limits, stated plainly, because they are unusually severe here.
  The human disease is essentially one deeply characterised patient. There is no cohort,
  no natural history, no prevalence estimate and no trial, so this entry carries no
  prevalence block and no clinical_trials block. Almost every mechanistic and phenotypic
  claim is graded MODEL_ORGANISM, and per this KB's evidence policy model-organism
  evidence is not sufficient support for a human phenotype on its own - so the
  phenotypes here should be read as reported in the index case and mechanistically
  supported in mice, not as independently established. Two items are weaker still and
  are flagged rather than dressed up: the microcephaly and supportive-care items cite a
  review for its scope because no quotable sentence naming the finding was available in
  the cached abstract. Those are the first places a future curator should improve.

  A claim this entry got wrong on the first pass, corrected in review and left here as
  the record. The original note asserted that the founding case report's clinical
  description of patient XP51RO was not quotable, because the paper is a Nature letter
  whose abstract compresses the case to one sentence - and concluded from that premise
  that several human phenotypes had to rest on mouse evidence. The first half is true of
  PMID:17183314. The conclusion was not, because PMID:26074087 - a reference this same
  curation added, cached as full text - carries a dedicated XP51RO paragraph naming the
  premature-aging presentation, the crosslink sensitivity, the frequent sunburns, and
  neurologic, hepatobiliary, musculoskeletal and hematopoietic involvement. The
  phenotypes have been reworked against it and now carry human evidence. The lesson
  worth keeping is procedural rather than biological: a structural-gap claim is a claim
  about the cache, and it should be checked against the cache rather than inferred from
  the shape of one paper.

  What remains genuinely thin, and is not the same thing: the XP51RO paragraph is a
  summary, so it names organ systems rather than individual findings. Several phenotypes
  are therefore INDIRECT on it - the sentence says "premature aging" where the entry
  says lipoatrophy, and "neurologic" where the entry says peripheral neuropathy. The
  visual impairment item is the weakest in the entry and is flagged in place: the only
  quotable sentence attributes visual impairment to keratitis, which is the xeroderma
  mechanism, whereas the index patient needed correction from age six.

  Two review suggestions that could not be actioned, recorded so they are not retried.
  OMIM #610965 identifies this disease and is stated in the description, but there is no
  place to put it: the DiseaseMappings class carries icd10cm_mappings, icd11f_mappings,
  mondo_mappings and ncit_mappings and no OMIM slot, so the identifier cannot be made
  machine-readable in the current schema. And three organ-specific Ercc1 models -
  Purkinje-cell, striated-muscle cardiomyopathy, retinal/RPE - were left out
  deliberately rather than overlooked: the two whole-organism strains already establish
  the segmental phenotype and carry the subunit caveat this entry is built around, and
  adding three more Ercc1 models would multiply the same mismatch rather than address
  it. A curator adding organ-specific phenotype nodes should reach for them then.

  Named-entity-confusion check. Three traps. ERCC4 is not ERCC1: they encode the two
  subunits of one nuclease, every mouse model in this entry mutates ERCC1, and the human
  disease is ERCC4 - a distinction the entry's first discussion is entirely about.
  ERCC4, XPF and FANCQ are three names for the same gene. And "XFE" abbreviates
  XPF-ERCC1, not a complementation group letter, so it does not belong in the XP-A
  through XP-V series despite looking as though it might.
📚

References & Deep Research

References

15
PMID:20301571
Xeroderma Pigmentosum.
No top-level findings curated for this source.
PMID:17183314
A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis.
No top-level findings curated for this source.
PMID:26074087
The ERCC1 and ERCC4 (XPF) genes and gene products.
No top-level findings curated for this source.
PMID:20221251
Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients.
No top-level findings curated for this source.
PMID:23623386
Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia.
No top-level findings curated for this source.
PMID:24027083
Evaluation of rare variants in the new fanconi anemia gene ERCC4 (FANCQ) as familial breast/ovarian cancer susceptibility alleles.
No top-level findings curated for this source.
PMID:29105242
ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.
No top-level findings curated for this source.
PMID:21612988
Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease.
No top-level findings curated for this source.
PMID:22953029
Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice.
No top-level findings curated for this source.
PMID:21596054
Premature aging-related peripheral neuropathy in a mouse model of progeria.
No top-level findings curated for this source.
PMID:23852002
Identification of microRNAs dysregulated in cellular senescence driven by endogenous genotoxic stress.
No top-level findings curated for this source.
PMID:22706308
NF-κB inhibition delays DNA damage-induced senescence and aging in mice.
No top-level findings curated for this source.
PMID:28871086
Identification of HSP90 inhibitors as a novel class of senolytics.
No top-level findings curated for this source.
PMID:39245994
Improved health by combining dietary restriction and promoting muscle growth in DNA repair-deficient progeroid mice.
No top-level findings curated for this source.
PMID:40416846
High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice.
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
XFE Progeroid Syndrome — Comprehensive Disease Characteristics Report
openscientist-autonomous 24 citations 2026-08-29T16:47:11.318556

XFE Progeroid Syndrome — Comprehensive Disease Characteristics Report

Disease: XFE Progeroid Syndrome (XFEPS) Category: Mendelian, autosomal recessive Primary gene: ERCC4 (XPF) MONDO: MONDO:0012590 · OMIM: #610965 · Disease Ontology: DOID:0060590

Summary

XFE progeroid syndrome is an ultra-rare, autosomal-recessive segmental progeria (accelerated multi-system aging disorder) caused by biallelic hypomorphic (partial loss-of-function) mutations in ERCC4, the gene encoding the XPF subunit of the ERCC1–XPF structure-specific endonuclease. This nuclease is essential for nucleotide excision repair (NER), DNA interstrand-crosslink (ICL) repair, and aspects of double-strand-break repair. When its activity is crippled, endogenous DNA damage accumulates faster than it can be removed, and the organism mounts a highly conserved "survival" response — suppression of the growth-hormone/IGF-1 (somatotroph) axis, cellular senescence, NF-κB–driven inflammation, and oxidative stress — that reallocates resources from growth toward somatic preservation. The clinical result is dwarfism, cachexia, lipoatrophy, microcephaly, an "old, bird-like" facies, sensory (hearing/vision) impairment, learning disability, sun-sensitivity, progressive neurodegeneration, and premature failure of multiple organs, with death in early life.

XFE sits at the severe end of the ERCC4 allelic spectrum, which also includes xeroderma pigmentosum complementation group F (XP-F), XP with Cockayne-syndrome overlap (XPCS-complex), cerebro-oculo-facio-skeletal syndrome (COFS), and Fanconi anemia group Q (FA-Q). The specific disorder that emerges from a given genotype depends on the balance between XPF's two principal DNA-repair activities (NER versus ICL repair) that a mutation preserves or destroys. The defining human case — patient XP51RO, a consanguineous Afghan boy homozygous for ERCC4 c.458G>C (p.Arg153Pro; R153P) — retains catalytic activity in vitro but mislocalizes XPF-ERCC1 to the cytoplasm, reducing nuclear repair.

There is no curative therapy. The disease is understood almost entirely through the founding case report and a rich set of Ercc1-deficient mouse models (whole-body hypomorphs, knockouts, and tissue-specific deletions) that faithfully recapitulate the segmental progeroid phenotype and have become a premier platform for aging research. Interventions that slow the phenotype in these models — most robustly dietary/caloric restriction (roughly doubling lifespan) and senolytics, plus NF-κB/IKK inhibition, nicotinamide riboside, and mesenchymal-stem-cell-derived extracellular vesicles — define the leading translational directions.

Key Findings

F001 — XFE is caused by biallelic loss-of-function mutations in ERCC4 (XPF)

XFE progeroid syndrome arises from biallelic severe/hypomorphic mutations in ERCC4, which encodes one subunit of the ERCC1–XPF structure-specific endonuclease. The founding patient carried the homozygous missense allele p.Arg153Pro (R153P), producing profound DNA interstrand-crosslink sensitivity and dramatic progeroid symptoms: "A patient presented with a severe XPF mutation leading to profound crosslink sensitivity and dramatic progeroid symptoms" (PMID: 17183314). ERCC4/ERCC1 is an allelic locus for a striking array of disorders — "mutations in the ERCC1 or ERCC4 genes cause a remarkable array of rare inherited human disorders … xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia, XFE progeria and cerebro-oculo-facio-skeletal syndrome" (PMID: 26074087). Missense XPF mutations can cause XP or "XPF-ERCC1 (XFE) progeroid syndrome, a disease of accelerated aging" (PMID: 20221251). Identifiers: OMIM #610965; ERCC4 OMIM 133520; HGNC:3436.

F002 — Mechanism: unrepaired DNA damage suppresses the GH/IGF1 somatotroph axis

In XPF-ERCC1-deficient mice, the response to accumulating damage is a systemic, conserved survival program. "Expression data from XPF-ERCC1-deficient mice indicate increased cell death and anti-oxidant defences, a shift towards anabolism and reduced growth hormone/insulin-like growth factor 1 (IGF1) signalling, a known regulator of lifespan" (PMID: 17183314). The mechanistic conclusion is that "unrepaired cytotoxic DNA damage induces a highly conserved metabolic response mediated by the IGF1/insulin pathway, which re-allocates resources from growth to somatic preservation and life extension" (PMID: 17183314). The same shifts occur in wild-type mice under chronic genotoxic stress, caloric restriction, or aging — placing XFE squarely on the natural-aging axis.

F003 — ERCC1-XPF is a structure-specific endonuclease essential for NER, ICL and some DSB repair

ERCC1–XPF is a heterodimeric endonuclease that "nicks DNA specifically at junctions between double-stranded and single-stranded DNA, when the single-strand is oriented 5' to 3' away from a junction" (PMID: 26074087). It performs the 5′ incision in NER and also acts in ICL repair, homologous recombination/end-joining, base-excision-repair backup, and telomere-length regulation, interacting with XPA, RPA, SLX4 and TRF2. The gene is essential: "Complete deletion of either ERCC1 or ERCC4 is not compatible with viability in mice or humans" (PMID: 26074087) — so XFE arises only from partial-function alleles. Notably, the R153P progeroid mutation retains catalysis but mislocalizes the complex: "differential immunostaining and fractionation of cells from an XFE progeroid patient revealed that XPF-ERCC1 is abundant in the cytoplasm" (PMID: 20221251).

F004 — Ercc1-deficient mice recapitulate XFE as a broad segmental progeria

Hypomorphic Ercc1(-/Δ7) mice model the disease across organ systems: "Ercc1(-/Δ7) mice were much smaller and median life span was markedly reduced compared to wild-type siblings: 20 and 118 weeks, respectively. Multiple signs and symptoms of aging were found to occur at an accelerated rate" and "Together they define a segmental progeroid phenotype of the Ercc1(-/Δ7) mouse model" (PMID: 22953029). Complementary models show premature peripheral neuropathy — "Ercc1(-/Δ) mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease" (PMID: 21596054) — and tissue-specific cardiomyopathy: "we deleted the DNA repair gene Ercc1 specifically in striated muscle" (PMID: 36734200), plus retinal/RPE degeneration and Purkinje-cell loss.

F005 — Senescence/SASP are core drivers; dietary restriction and senolytics are candidate interventions

"XFE progeroid syndrome, a disease of accelerated aging caused by deficiency in the DNA repair endonuclease XPF-ERCC1, is modeled by Ercc1 knockout and hypomorphic mice. Tissues and primary cells from these mice senesce prematurely" (PMID: 23852002). Dietary restriction, "when applied to progeroid DNA repair-deficient mice doubles lifespan with systemic health benefits" (PMID: 39245994). Senolytics are a validated strategy: "a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging" (PMID: 28871086). Conversely, "High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice" (PMID: 40416846).

F006 — Allelic spectrum, extreme rarity, and embryonic lethality of most biallelic combinations

"Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia" (PMID: 29105242). The disease's extreme rarity is explained by lethality: "the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients, indicating that most biallelic combinations of ERCC4 mutations are embryo lethal" (PMID: 24027083). Only a handful of patients exist across the entire spectrum; e.g., a case was assigned "as the third individual of complementation group FA-Q" (PMID: 29325523). ERCC4 is not a familial breast/ovarian cancer susceptibility gene (PMID: 24027083).

F007 — Genotype–phenotype: NER-vs-ICL activity balance determines XP vs FA vs XFE

"depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease" (PMID: 23623386). Specifically, "the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair" (PMID: 23623386). XP-causing mutations impair NER; XFE (severe, e.g., R153P) profoundly impairs both, producing accelerated aging.

F008 — NF-κB inflammation and oxidative stress are downstream effectors; IKK/NF-κB inhibition is protective

"Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice" and "inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence" (PMID: 22706308). XFE cells also show a distinctive nuclear-morphology abnormality: "we found that XFE nuclei were larger and significantly more elongated than control nuclei" (PMID: 22127259) — distinguishing them from the small round nuclei of Hutchinson-Gilford progeria.

F009 — XFE is a multisystem segmental progeria

"Mutations in ERCC1 or XPF cause xeroderma pigmentosum, XFE progeroid syndrome or cerebro-oculo-facio-skeletal syndrome, characterized by increased risk of cancer, accelerated aging and severe developmental abnormalities, respectively" (PMID: 21612988). The founding patient presented in the second decade with dwarfism, microcephaly, cachexia and progressive multi-organ decline (PMID: 17183314). Model and human data implicate peripheral neuropathy, Purkinje-cell/CNS neurodegeneration, sensorineural involvement, retinal/RPE degeneration (systemic "depletion of expression of the DNA repair enzyme ERCC1-XPF", PMID: 39604117), sarcopenia, cardiomyopathy, renal/hepatic dysfunction, osteopenia, anemia and immunosenescence.

F010 — Molecular profiling: XFE-model liver transcriptome overlaps the natural-aging transcriptome

"Here we show a highly significant correlation between the liver transcriptome of old mice and a mouse model of this progeroid syndrome" (PMID: 17183314). The XFE model also shows accelerated epigenetic age: "The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair" (PMID: 38140713), and a senescence-associated microRNA signature: "the miRNA expression regulator Dicer is significantly downregulated in tissues of old mice and late passage cells compared to young controls" (PMID: 23852002).

F011 — Verified disease identifiers and OMIM clinical synopsis

Authoritative cross-references (OMIM, MalaCards, Disease Ontology): OMIM #610965 (XFEPS); Phenotypic Series PS176670; ERCC4 133520 at 16p13.12; MONDO:0012590; DOID:0060590; MedGen C1970416; MeSH C567043/D049914; GARD 10628. No dedicated Orphanet ORPHA code (grouped under "Progeroid syndrome") and no dedicated ICD-10 code. The OMIM clinical synopsis describes aged, bird-like facies, lipoatrophy, dwarfism, cachexia and microcephaly, with sun-sensitivity from birth, learning disabilities, hearing loss and visual impairment.

F012 — Founding patient XP51RO and the defining ERCC4 c.458G>C (p.Arg153Pro) mutation

The index case was a 15-year-old Afghan boy of consanguineous parents, referred for severe chronic sunburn but showing progeroid features. He had normal birth weight and early milestones, congenital sun-sensitivity, mild learning disability, hearing loss, and visual impairment requiring correction from age 6. By ~age 10 he had an "old, wizened" narrow face; from ~age 12 he lost weight and stopped growing, with progressive decline and frequent dizziness. cDNA sequencing of his fibroblasts revealed a homozygous G→C transversion at ERCC4 position 458 (c.458G>C), substituting proline for the conserved arginine at residue 153 (p.Arg153Pro/R153P) (PMID: 17183314).

1. Disease Information

Overview. XFE progeroid syndrome is a DNA-repair-deficiency disorder producing accelerated, segmental aging. "XFE" denotes XPF-ERCC1. It was first described in 2006 in a patient who presented with features suggestive of xeroderma pigmentosum but with dramatic progeroid symptoms, establishing a new disease entity (PMID: 17183314).

Key identifiers.

Resource Identifier
OMIM (phenotype) #610965 (XFE PROGEROID SYNDROME; XFEPS)
OMIM Phenotypic Series PS176670
OMIM (gene) 133520 (ERCC4)
MONDO MONDO:0012590
Disease Ontology DOID:0060590
MedGen C1970416
MeSH C567043 / D049914
GARD 10628
HGNC (gene) HGNC:3436
Cytoband 16p13.12
Orphanet No dedicated ORPHA code (grouped under "Progeroid syndrome")
ICD-10 No dedicated code

Synonyms / alternative names: XFEPS; XPF-ERCC1 progeroid syndrome; XPF-E progeroid syndrome. The causal gene is variously written ERCC4, XPF, or FANCQ.

Data provenance. Knowledge derives from a very small number of individual clinical case reports (most importantly patient XP51RO) combined with aggregated model-organism data and mechanistic in vitro studies.

2. Etiology

Primary cause — genetic. XFE is caused by biallelic loss-of-function mutations in ERCC4 (XPF) (F001). The founding patient was homozygous for the severe p.Arg153Pro allele, which confers profound DNA interstrand-crosslink sensitivity (PMID: 17183314). ERCC4/ERCC1 is an allelic locus for XP-F, Cockayne syndrome, Fanconi anemia (FANCQ), COFS, and XFE (PMID: 26074087).

Genetic risk factors. The disorder is monogenic and fully determined by the two ERCC4 alleles inherited; there are no susceptibility loci beyond the causal gene. Because the gene is essential (F003), only hypomorphic combinations retaining residual activity are compatible with live birth. Consanguinity is a major contributing circumstance — the index patient was born to consanguineous parents (F012) — raising the probability of homozygosity for rare recessive alleles.

Environmental risk / modifying factors. No environmental factor causes XFE, but exposures that increase genotoxic burden worsen it. UV radiation is clinically relevant because of the NER defect (congenital sun-sensitivity). In models, high dietary protein accelerates the phenotype (PMID: 40416846, F005).

Protective factors. In models, dietary/caloric restriction is strongly protective, roughly doubling lifespan and providing systemic and neuroprotective benefits (PMID: 39245994; PMID: 36760711). No protective human modifier alleles are identified given the disease's rarity.

Gene–environment interaction. The core mechanism is itself a gene–environment interaction: the inherited repair defect determines how much endogenous and exogenous DNA damage persists, and the systemic IGF-1/insulin response is the same program invoked by wild-type animals under chronic genotoxic stress or caloric restriction (PMID: 17183314, F002).

3. Phenotypes

XFE is a multisystem segmental progeria. Phenotypes derive from the index case, the OMIM clinical synopsis (F009, F011, F012) and model data. Onset is typically first-to-second decade with congenital sun-sensitivity; the course is progressive.

Phenotype Type Onset / course Suggested HPO term
Postnatal growth failure / dwarfism Physical/growth Normal birth weight; growth arrest ~age 12; progressive HP:0008897 / HP:0004322
Cachexia / progressive weight loss Physical Adolescence; progressive HP:0004326
Loss of subcutaneous fat (lipoatrophy) Physical Childhood–adolescence HP:0003758
Microcephaly Physical/CNS Congenital/childhood HP:0000252
"Aged, bird-like," wizened facies Physical ~age 10; progressive HP:0011451
Cutaneous photosensitivity / severe sunburn Skin From birth HP:0000992
Sensorineural hearing loss Sensory Childhood HP:0000407
Visual impairment (correction from ~age 6) Sensory Childhood HP:0000505
Learning disability / mild intellectual disability Neurobehavioral Childhood HP:0001328 / HP:0001256
Peripheral neuropathy Nervous Model: abnormal nerve conduction by 20 wk HP:0009830
Cerebellar/Purkinje-cell neurodegeneration Nervous Progressive (model) HP:0002073
Retinal / RPE degeneration (AMD-like) Sensory Progressive (model) HP:0000546
Sarcopenia / muscle wasting Musculoskeletal Progressive HP:0003202
Dilated cardiomyopathy Cardiovascular Model (muscle-specific deletion) HP:0001644
Osteopenia Skeletal Progressive HP:0000938
Anemia Hematologic Progressive HP:0001903
Renal / hepatic dysfunction Renal/hepatic Progressive HP:0000083 / HP:0001392

Severity and QoL. The disorder is severe and life-limiting, with profound impact on growth, mobility, sensory function, cognition and independence, culminating in early death. Reliable percentage frequencies cannot be given because only a handful of patients have been described. Cellular hallmark: profound sensitivity to interstrand-crosslinking agents (e.g., mitomycin C) and UV, with abnormally enlarged, elongated nuclei (PMID: 22127259, F008).

4. Genetic / Molecular Information

Causal gene. ERCC4 (XPF; FANCQ), OMIM 133520, HGNC:3436, at 16p13.12 (F001, F011). It encodes the catalytic XPF subunit of the ERCC1–XPF endonuclease.

Defining pathogenic variant. ERCC4 c.458G>C, a G→C transversion → p.Arg153Pro (R153P) (F012). Found homozygous in patient XP51RO. Classification: pathogenic; type: missense; origin: germline, homozygous by descent.

Functional consequence. R153P retains catalytic activity in vitro but causes cytoplasmic mislocalization of XPF-ERCC1, depleting nuclear repair capacity (PMID: 20221251, F003) — a hypomorphic loss of function in situ.

Allelic spectrum and genotype–phenotype (PMID: 23623386, F007):

Disorder Repair activity most affected Cardinal features
Xeroderma pigmentosum (XP-F) NER / UV-lesion repair Sun-sensitivity, skin-cancer predisposition
XPCS-complex NER (persistent factor retention) XP + Cockayne overlap, neurodevelopmental
COFS Severe developmental repair loss Cerebro-oculo-facio-skeletal malformation
Fanconi anemia (FA-Q) ICL repair (NER relatively spared) Bone-marrow failure, crosslinker sensitivity
XFE progeroid Both NER and ICL (severe, e.g., R153P) Accelerated multi-organ aging

Allele frequency & rarity. ERCC4 carrier frequency ~1 in 288 (Spanish cohort), similar to FANCA, yet most biallelic combinations are embryo-lethal (PMID: 24027083, F006). ERCC4 is not a breast/ovarian cancer susceptibility gene.

Modifier genes / epigenetics. No specific human modifier genes established. XFE-model tissues show accelerated DNA-methylation age (PMID: 38140713) and a senescence-associated microRNA signature with Dicer downregulation (PMID: 23852002) (F010).

Chromosomal abnormalities. None; XFE is a single-gene point-mutation disorder.

5. Environmental Information

XFE is fundamentally genetic; environmental factors modulate rather than cause it. UV radiation is directly relevant (NER defect → congenital photosensitivity). Interstrand-crosslinking agents (mitomycin C, cisplatin) are extreme cellular stressors (ICL-repair defect). Dietary composition is the best-characterized modifier: high protein accelerates aging (PMID: 40416846); caloric restriction is protective. No infectious agent is involved.

6. Mechanism / Pathophysiology

Causal chain.

Biallelic hypomorphic ERCC4 (XPF) mutation
│
▼
ERCC1–XPF endonuclease dysfunction / cytoplasmic mislocalization (R153P)
│
▼
Failure of NER + interstrand-crosslink repair (± DSB/HR repair)
│
▼
Accumulation of unrepaired endogenous DNA damage
│
├──► Conserved survival response: ↓ GH/IGF-1–insulin signaling
│        (resource re-allocation growth → somatic preservation)
├──► Cellular senescence + SASP (p16 induction)
├──► NF-κB activation → chronic inflammation + oxidative stress
│
▼
Multi-organ accelerated aging → clinical XFE → early death

Molecular pathways. The central node is the IGF-1/insulin axis: unrepaired damage "induces a highly conserved metabolic response mediated by the IGF1/insulin pathway" (PMID: 17183314, F002). Downstream, NF-κB signaling is stochastically activated; IKK inhibition delays pathology (PMID: 22706308, F008).

Protein dysfunction. ERCC1–XPF is a structure-specific endonuclease performing the 5′ NER incision and functioning in ICL/DSB repair and telomere regulation (F003). The R153P defect is chiefly subcellular mislocalization rather than loss of catalysis.

Cellular processes. Premature cellular senescence with SASP is a core driver (PMID: 23852002, F005), accompanied by apoptosis, anti-oxidant induction and an anabolic shift.

Metabolic changes. The liver transcriptome shifts toward anabolism with reduced GH/IGF-1 signaling (PMID: 17183314); DR-responsive metabolomic sarcopenia signatures are documented (PMID: 38689513).

Tissue-damage mechanisms. Oxidative stress and NF-κB inflammation injure tissues; both are reduced by NF-κB inhibition (PMID: 22706308). Immunosenescence contributes systemically.

Molecular profiling (model-based). Transcriptomic overlap with natural aging (PMID: 17183314); accelerated DNAm age (PMID: 38140713); senescence miRNA/Dicer signature (PMID: 23852002); DR-responsive metabolomics (PMID: 38689513).

Suggested ontology terms. GO BP: NER (GO:0006289), ICL repair (GO:0036297), DSB repair (GO:0006302), cellular senescence (GO:0090398), IGF receptor signaling (GO:0048009), NF-κB signaling (GO:0038061). GO CC: nucleus (GO:0005634), NER complex (GO:0000109). CL: fibroblast (CL:0000057), Purkinje cell (CL:0000121), hepatocyte (CL:0000182), RPE cell (CL:0002586). CHEBI: mitomycin C (CHEBI:27504), cisplatin (CHEBI:27899).

7. Anatomical Structures Affected

Organ / system level (primary): skin (UBERON:0002097), CNS/PNS (UBERON:0001017 / UBERON:0000010), skeletal muscle (UBERON:0001134), liver (UBERON:0002107), kidney (UBERON:0002113), eye/retina (UBERON:0000970 / UBERON:0000966), inner ear/cochlea (UBERON:0001844), bone (UBERON:0002481), and the GH/IGF-1 endocrine axis. Secondary: cardiac muscle (PMID: 36734200), hematopoietic system (anemia), immune system (immunosenescence).

Body systems: nervous, musculoskeletal, integumentary, cardiovascular, renal/hepatic, sensory, endocrine, hematopoietic/immune.

Tissue / cell level: connective-tissue fibroblasts (diagnostic cell type), Purkinje cells (CL:0000121; PMID: 36760711), peripheral neurons (PMID: 21596054), retinal pigment epithelium (PMID: 39604117), cardiomyocytes, hepatocytes.

Subcellular level: the nucleus (site of DNA repair) is central; R153P shifts ERCC1–XPF to the cytoplasm (F003); nuclei are enlarged/elongated (F008); mitochondria/oxidative-stress machinery involved downstream.

Localization / lateralization: manifestations are systemic and bilateral/symmetric, consistent with a cell-autonomous genome-maintenance defect.

8. Temporal Development

Onset. Congenital sun-sensitivity from birth; normal birth weight and early milestones. Progeroid features emerged in the first-to-second decade — aged facies by ~age 10; growth arrest and weight loss from ~age 12 (F012). Pattern: chronic, insidious, progressive.

Progression. Relentlessly progressive with multi-organ decline over a few years; no spontaneous remission; chronic and life-limiting.

Critical periods. Model data indicate windows during which dietary restriction confers maximal neuroprotection and lifespan extension; peripheral-nerve and Purkinje-cell degeneration have measurable onset points defining preclinical intervention timing.

9. Inheritance and Population

Inheritance. Autosomal recessive; index case homozygous by consanguineous descent (F012). Penetrance appears complete for biallelic hypomorphic genotypes; expressivity variable across the spectrum. No anticipation (not a repeat-expansion disorder). Consanguinity is a strong contributing circumstance.

Carrier frequency / rarity. ~1 in 288 carriers, but most biallelic combinations are embryo-lethal, so viable XFE is extraordinarily rare — only a handful of reported patients worldwide (PMID: 24027083, F006).

Epidemiology. Prevalence and incidence are not formally established (ultra-rare; no dedicated Orphanet estimate). No reliable sex ratio or geographic clustering given case scarcity; founder/consanguinity effects concentrate recessive alleles in specific families. The index case was of Afghan ancestry. Sex ratio expected ~1:1 (autosomal); age distribution pediatric/adolescent.

10. Diagnostics

Clinical recognition. Suspect XFE in a child with combined XP-like photosensitivity and progeroid features (growth failure, lipoatrophy, aged facies, sensory/cognitive impairment).

Cellular / laboratory tests. - Crosslinker hypersensitivity assay — profound sensitivity of patient fibroblasts to mitomycin C and UV (F009). - Immunostaining / fractionation — cytoplasmic mislocalization of XPF-ERCC1 in R153P (PMID: 20221251). - Nuclear-morphology analysis — enlarged, elongated nuclei distinguishing XFE from HGPS (PMID: 22127259, F008).

Genetic testing (definitive). Molecular sequencing of ERCC4 — WES/WGS or targeted single-gene/panel testing (DNA-repair/progeria panels). The index diagnosis used cDNA sequencing of patient fibroblasts (c.458G>C; p.Arg153Pro) (F012). Chromosomal microarray, karyotype, FISH, mtDNA and repeat-expansion testing are not applicable.

Clinical criteria / differential diagnosis. No formal consensus criteria. Differentials: Werner, Cockayne, Hutchinson-Gilford progeria, trichothiodystrophy, and allelic ERCC4 disorders (XP-F, XPCS-complex, COFS, FA-Q). The International Registry of Werner Syndrome has been used to find atypical ERCC4 cases (F006). Distinguishing features: crosslinker hypersensitivity, XPF cytoplasmic mislocalization, enlarged/elongated nuclei.

Screening. No population screening warranted; cascade carrier testing within families and preconception counseling in consanguineous unions are relevant.

11. Outcome / Prognosis

Survival. Prognosis is poor; the founding patient died young after progressive multi-organ decline (F009, F012). No cohort-level survival statistics exist; life expectancy is markedly reduced.

Morbidity / function. Severe disability from growth failure, cachexia/sarcopenia, neurodegeneration, sensory loss, cognitive impairment and organ decline. QoL is heavily impacted across physical, sensory and cognitive domains.

Complications. Cardiomyopathy, anemia, osteopenia, immunosenescence with heightened infection susceptibility.

Prognostic factors. Residual XPF activity (position on the allelic spectrum) predicts severity: the more severely both NER and ICL repair are impaired, the more progeroid the outcome (F007). Model biomarkers (DNAm age, senescence/SASP burden) track biological aging.

12. Treatment

No curative therapy exists. Management is supportive and symptomatic: photoprotection, nutritional support for cachexia, hearing/vision aids, physical/occupational therapy, and treatment of organ-specific complications. Avoidance of DNA-crosslinking/genotoxic agents is prudent given cellular hypersensitivity (a pharmacogenomic caveat: crosslinking chemotherapeutics are contraindicated/highly toxic).

Interventions validated in XFE (Ercc1) mouse models — leading translational leads (F005):

Intervention Effect in model Evidence
Dietary / caloric restriction ~Doubles lifespan (≈20→40 wk); systemic + strong neuroprotection PMID: 39245994; PMID: 36760711
Senolytics (e.g., HSP90 inhibitors) Reduce senescent-cell/SASP burden; extend healthspan PMID: 28871086
NF-κB / IKK inhibition Delays age-related pathology; reduces oxidative damage & senescence PMID: 22706308
Nicotinamide riboside Extends health/lifespan PMID: 36313181
MSC-derived extracellular vesicles Reduce senescence; extend healthspan PMID: 33728821
Avoid high dietary protein High protein shortens lifespan, accelerates aging PMID: 40416846

Suggested NCIT terms: Dietary/Caloric Restriction, Senolytic Agent, Supportive Care (NCIT:C133426), Physical Therapy (NCIT:C15342). All disease-modifying options remain experimental/preclinical for human XFE; no approved targeted or gene therapy exists.

13. Prevention

Primary prevention rests on reproductive genetics: genetic counseling for consanguineous couples and carrier families, carrier/cascade testing of ERCC4, and preimplantation or prenatal genetic diagnosis where a pathogenic variant is known. Secondary prevention in a diagnosed child centers on strict photoprotection and early management of complications. Tertiary prevention targets slowing progression — the model-validated strategies (dietary restriction, senolytics) are candidate approaches. Immunization/public-health/environmental interventions are not disease-specific; no vaccine or chemoprophylaxis applies.

14. Other Species / Natural Disease

Taxonomy & orthologs. The disease is studied in Mus musculus (NCBI:txid10090) via the orthologous Ercc1 and Ercc4 genes; human genes are ERCC4 (NCBI Gene 2072) and ERCC1 (NCBI Gene 2067). No naturally occurring companion-animal or wildlife counterpart of XFE is established in OMIA; the disease is essentially known from humans and engineered mouse models. Evolutionary conservation is high — the ERCC1–XPF repair function and the IGF-1/insulin survival response are deeply conserved, which is why the mouse recapitulates the human syndrome (PMID: 17183314). There is no zoonotic or transmissible component.

15. Model Organisms

Mouse models are the cornerstone of XFE research (F004).

Model Type Key phenotype Evidence
Ercc1(-/Δ7) whole-body hypomorph Compound hemizygous Small; median lifespan ~20 wk vs ~118 wk WT; multi-organ histopathology — segmental progeria PMID: 22953029
Ercc1(-/Δ) Hypomorph Accelerated spontaneous peripheral neurodegeneration PMID: 21596054
Purkinje-cell-specific Ercc1 KO/hypomorph Conditional Cell-intrinsic Purkinje-cell neurodegeneration; DR protective (25–40% retention) PMID: 36760711
Striated-muscle-specific Ercc1 deletion Conditional Dilated cardiomyopathy PMID: 36734200
Systemic ERCC1-XPF depletion Genetic Retinal/RPE degeneration (AMD-like) PMID: 39604117
Ercc1 primary cells / fibroblasts In vitro Premature senescence, SASP, senolytic-screening platform PMID: 23852002; PMID: 28871086

Phenotype recapitulation. The Ercc1 mouse liver transcriptome correlates highly with naturally aged liver, and the animals display accelerated DNAm age — strong evidence of a true accelerated-aging program (F010). Limitations: mice do not fully capture human cognitive/craniofacial features or exact human lifespan scale, and most models use Ercc1 hypomorphs rather than the human ERCC4 R153P allele. Applications: premier platform for anti-aging/senotherapeutic testing, dietary modulation, and organ-specific genotoxic-aging mechanisms. Resources: MGI (Ercc1, Ercc4), IMSR.

Mechanistic Model / Interpretation

XFE is best understood as a genome-maintenance failure that trips a conserved aging program. A hypomorphic ERCC4 genotype (prototypically R153P, which mislocalizes ERCC1–XPF to the cytoplasm) leaves NER and ICL repair unable to keep pace with endogenous DNA damage. The organism responds exactly as wild-type animals do under severe chronic genotoxic stress: it suppresses the GH/IGF-1 somatotroph axis, halting growth and redirecting resources to somatic maintenance. In parallel, damaged cells enter senescence (SASP, p16), and stochastic NF-κB activation propagates inflammation and oxidative stress. These downstream effectors injure organ after organ, producing the segmental progeroid phenotype.

The position on the ERCC4 allelic spectrum is set upstream by which repair activity a mutation destroys (NER → XP; ICL → FA; both, severely → XFE), while the downstream aging effectors are shared with normal aging. This dual structure explains two therapeutic logics that both work in models: interventions that reduce the damage/stress load (dietary restriction; avoiding high protein and genotoxins) and interventions that blunt downstream effectors (senolytics, NF-κB/IKK inhibition, NAD⁺ precursors).

UPSTREAM (genotype-specific)          DOWNSTREAM (shared with aging)
ERCC4 mutation ─► repair-activity ──► DNA damage load ─► [senescence/SASP]
 balance (NER/ICL)                     ─► [NF-κB inflammation]
     │                                 ─► [oxidative stress]
     ▼                                 ─► [↓GH/IGF-1]
     XP / FA / XFE                                     │
                                               ▼
                                 multi-organ accelerated aging

Evidence Base

PMID Contribution Supports
17183314 Founding case (R153P); GH/IGF-1 suppression; liver–aging transcriptome correlation F001, F002, F009, F010, F012
26074087 ERCC1/ERCC4 gene-product review; endonuclease activity; essentiality F001, F003
20221251 XPF missense → XFE "accelerated aging"; cytoplasmic mislocalization F001, F003
22953029 Ercc1(-/Δ7) segmental progeroid model; lifespan 20 vs 118 wk F004
21596054 Premature peripheral neuropathy in model F004, F009
36734200 Muscle-specific Ercc1 deletion → cardiomyopathy F004
23852002 Premature senescence; senescence miRNA/Dicer signature F005, F010
39245994 Dietary restriction doubles lifespan F005
28871086 Senolytics (HSP90 inhibitors) extend healthspan F005
40416846 High protein shortens lifespan / accelerates aging F005
24027083 Carrier freq ~1/288; embryonic lethality; not a breast-cancer gene F006
23623386 NER vs ICL balance determines XP/FA/XFE; ERCC4 → Fanconi anemia F007
22706308 NF-κB/IKK inhibition delays aging; reduces oxidative stress/senescence F008
22127259 Enlarged/elongated XFE nuclei (diagnostic) F008
21612988 ERCC1/XPF disorder classification (XP/XFE/COFS) F009
39604117 Systemic ERCC1-XPF depletion → retinal/RPE degeneration F009
38140713 Accelerated DNAm (Horvath-clock) age in Ercc1 mice F010
36760711 Purkinje-cell model; DR cell-intrinsic neuroprotection F004, F005
29105242 ERCC4 variants across segmental progeroid syndromes F006
29325523 "third individual of complementation group FA-Q" — rarity F006
36313181 Nicotinamide riboside as anti-aging compound in model F005
33728821 MSC-EVs reduce senescence, extend healthspan F005
38689513 DR-responsive metabolomic sarcopenia signatures F010

Contradicting / nuancing evidence. PMID: 20798040 found that telomeric sister-chromatid-exchange–driven premature senescence contributes to Werner and Bloom syndromes but not XFE, indicating that XFE's accelerated senescence arises through a different (non-telomere-recombination) route — consistent with the primary-DNA-damage model rather than a telomere-instability model. Separately, R153P refutes a simple "dead enzyme" model: the defect is mislocalization, not loss of intrinsic catalysis (PMID: 20221251).

Limitations and Knowledge Gaps

  • Extreme rarity: human data rest largely on a single well-characterized index case (XP51RO) plus scattered ERCC4-spectrum reports; there are no epidemiologic prevalence/incidence figures, survival curves, or sex-ratio data.
  • Model-vs-human gap: most mechanistic and therapeutic evidence comes from Ercc1 mouse hypomorphs, not the human ERCC4 R153P allele; translation of dietary restriction, senolytics, NF-κB inhibition, NAD⁺ precursors, and MSC-EVs to human XFE is unproven.
  • No formal diagnostic criteria or clinical guidelines exist; diagnosis is ad hoc (crosslinker sensitivity + XPF mislocalization + ERCC4 sequencing).
  • No approved disease-modifying therapy; all leads are preclinical.
  • Phenotype frequencies cannot be quantified as percentages because the patient population is too small.
  • Human penetrance/expressivity are inferred from allelic disorders rather than measured in XFE cohorts.

Proposed Follow-up Experiments / Actions

  1. Establish an international XFE/ERCC4 patient registry (leveraging the Werner Syndrome and Fanconi anemia registries) to aggregate natural-history, survival, and genotype–phenotype data.
  2. Generate patient-specific iPSC and knock-in R153P models (mouse and organoid) to test whether the human allele reproduces the Ercc1 hypomorph phenotype and to screen therapeutics on the exact human genotype.
  3. Test the model-validated interventions (dietary restriction, HSP90-inhibitor/senolytic combinations, IKK/NF-κB inhibitors, nicotinamide riboside) head-to-head and in combination in R153P knock-in models, with DNAm-age and SASP-burden readouts as biomarkers.
  4. Develop diagnostic standardization: validate the enlarged/elongated-nucleus morphometric assay and XPF-mislocalization immunostaining as adjunct diagnostics alongside ERCC4 sequencing.
  5. Correct mislocalization directly: since R153P retains catalysis but is cytoplasmically mislocalized, test small molecules/chaperones or gene-corrective approaches that restore nuclear import of ERCC1–XPF.
  6. Deep multi-omic phenotyping (single-cell transcriptomics, proteomics, metabolomics) of affected organs in models to map cell-type-specific vulnerability (Purkinje cells, RPE, cardiomyocytes) and identify tractable nodes.
  7. Formalize reproductive-prevention pathways: carrier-screening and preconception counseling protocols for consanguineous families with known ERCC4 variants.

Report compiled from 12 confirmed findings and 38 reviewed papers over 5 investigation iterations. Evidence source types span human clinical case reports, mouse model-organism studies, in vitro cellular assays, and computational/transcriptomic analyses, as annotated per finding.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 24
On topic 22
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 49
Resolved 48
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 15
Terms named correctly 0
Terms named as a different term 14
Terms whose name is worth a second look 1

Terms the report names something else

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

  • MONDO:0012590 (3 mentions) - the report calls it "MONDO"; MONDO calls it XFE progeroid syndrome
  • DOID:0060590 (3 mentions) - the report calls it "Disease Ontology"; DOID calls it XFE progeroid syndrome
  • HP:0004326 (1 mention) - the report calls it "Adolescence; progressive"; HP calls it Cachexia
  • HP:0003758 (1 mention) - the report calls it "Childhood–adolescence"; HP calls it Reduced subcutaneous adipose tissue
  • HP:0000252 (1 mention) - the report calls it "Congenital/childhood"; HP calls it Microcephaly
  • HP:0011451 (1 mention) - the report calls it "~age 10; progressive"; HP calls it Primary microcephaly
  • HP:0000407 (1 mention) - the report calls it "Childhood"; HP calls it Sensorineural hearing impairment
  • HP:0000505 (1 mention) - the report calls it "Childhood"; HP calls it Visual impairment
  • HP:0009830 (1 mention) - the report calls it "Model: abnormal nerve conduction by 20 wk"; HP calls it Peripheral neuropathy
  • HP:0000546 (1 mention) - the report calls it "Progressive (model)"; HP calls it Retinal degeneration
  • HP:0003202 (1 mention) - the report calls it "Progressive"; HP calls it Skeletal muscle atrophy
  • HP:0001644 (1 mention) - the report calls it "Model (muscle-specific deletion)"; HP calls it Dilated cardiomyopathy
  • HP:0000938 (1 mention) - the report calls it "Progressive"; HP calls it Osteopenia
  • HP:0001903 (1 mention) - the report calls it "Progressive"; HP calls it Anemia

Terms whose name is worth a second look

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

  • HP:0002073 (1 mention) - the report calls it "Progressive (model)"; HP calls it Progressive cerebellar ataxia, and lists "Progressive ataxia" among its other names