GAPO Syndrome

Mendelian MONDO:0009263 Pathograph 16 Show in embeddings browser autosomal recessive disease ectodermal dysplasia syndrome rare disease

GAPO syndrome is the autosomal recessive disorder named for its four cardinal features — growth retardation, alopecia, pseudoanodontia and optic atrophy — caused by biallelic loss of ANTXR1, a matrix-interacting adhesion molecule better known as anthrax toxin receptor 1. Around 30 to 35 cases have been reported worldwide, which makes it one of the rarest recessive conditions, and its craniofacial appearance is distinctive enough that it is recognised clinically before it is confirmed genetically. The unifying lesion is a generalised defect in extracellular-matrix homeostasis. Reported ANTXR1 alleles are nonsense changes predicted to trigger nonsense-mediated decay, a splice change encoding a truncated protein with a 118-residue neopeptide at its C terminus, and frameshift and missense variants. Cultured skin fibroblasts from patients show a disordered actin cytoskeleton, and Antxr1-mutant mice reproduce both the dental abnormalities and the extracellular-matrix accumulation — which is the argument that the matrix is where the four features converge rather than being four independent consequences of one gene. That argument is strong for the dental and connective-tissue features and weaker for the ocular ones, and this entry types its causal edges accordingly. Pseudoanodontia is the clearest instance: the teeth are formed but do not erupt, which is what the name means and what a matrix-clearance defect would predict. For the optic atrophy a route is proposed and it is mechanical, matrix and thickened dura compressing the nerve, but it does not fit what is observed. The eponymous ocular feature was scored positive in one of the six patients of the cohort curated here and is described in the ophthalmologic literature as not consistent, while glaucoma, which the acronym does not mention, was present in four of the same six.

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1
Mappings
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Inheritance
3
Pathophys.
28
Phenotypes
4
Gaps
16
Pathograph
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Genes
4
Variants
1
Models
4
References
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Deep Research
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Mappings

MONDO
MONDO:0009263 GAPO syndrome
skos:exactMatch MONDO
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic ANTXR1 variants are required, and every reported genotype has been homozygous — four ethnically unrelated individuals in the founding report, and five individuals from three Turkish kindreds in the exome study that followed. The pattern was recognised as autosomal recessive from pedigrees long before the gene was found.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:23602711 SUPPORT Human Clinical
"We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations"
The founding genetic result: four unrelated individuals, all homozygous, which is what establishes the recessive requirement rather than a founder effect. The quote stops before the variant list because the reference validator strips bracketed spans before matching and each variant carries a bracketed protein change; the alleles themselves are recorded under genetic[].variants.
PMID:27587992 SUPPORT BACKGROUND Human Clinical
"Recently, gene alterations in the ANTXR1 gene have been reported to be causative of this disorder, and an autosomal recessive pattern has been observed."
Independent confirmation of the inheritance pattern. Stated as established background in this case report rather than derived here.
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Discussions and Knowledge Gaps

4
Why does a generalised matrix defect produce a specific and reproducible craniofacial pattern rather than diffuse thickening?
KNOWLEDGE GAP gapo_craniofacial_gestalt
Attached to
phenotypes#Relative macrocephaly phenotypes#Depressed nasal bridge phenotypes#Long philtrum phenotypes#Micrognathia phenotypes#Low-set ears
Eleven craniofacial features are positive in all six patients of the cohort curated here, which is the reason the disorder is recognisable on sight. Two of them, the thickened eyelids and the thick lips, have a stated intermediate: subcutaneous accumulation increasing with age. The rest do not. Relative macrocephaly, a depressed nasal bridge, a long philtrum, micrognathia and low-set ears are proportions and positions, not thicknesses, and nothing located explains how unresorbed matrix produces them. They are left with no incoming edge rather than attached to the accumulation node, because a generalised accumulation predicts diffuse thickening and does not predict a reproducible pattern. Two possibilities are open and are not distinguished anywhere: that the matrix defect acts during craniofacial morphogenesis, where timing and site would make a pattern out of a generalised lesion, or that ANTXR1 has a developmental role separate from matrix turnover. The Antxr1 knock-out mouse is reported at the cranial sutures but no craniofacial morphometry is reported for it.
Does optic nerve compression by accumulated matrix account for the ocular feature, given that it was present in only one of six patients?
KNOWLEDGE GAP gapo_optic_atrophy_mechanism
Attached to
phenotypes#Optic atrophy
There is a stated account, and it is mechanical: matrix accumulating around the optic nerve, with thickening of the surrounding dura, compresses it. The gap is not that nobody has proposed a route. It is that the proposed route does not fit the two things that are actually observed. A compressive lesion produced by matrix that accumulates with age predicts a deficit that is progressive, which matches, but it also predicts a deficit that is close to universal in a disorder whose matrix defect is generalised, and optic atrophy was scored positive in one of six patients here and is described in the ophthalmologic literature as not a consistent feature. Glaucoma, which is not in the acronym, was more frequent in the same cohort. Either the compression is modified by something not identified, or some of what has been called optic atrophy in this syndrome is a different optic neuropathy, or the acronym has fixed attention on the wrong ocular feature. Nothing located distinguishes those.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"It is concluded that optic nerve pathologies are observed potentially secondary to physical compression of the optic nerve by the accumulation of extracellular matrix and thickening of the dura matter surrounding the optic nerve"
The proposed route, which the earlier version of this gap incorrectly said did not exist. It is quoted here so the gap is visibly about the fit of the proposal rather than about its absence.
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic findings"
The observation the proposal has to accommodate: in this cohort glaucoma was present in four of six patients and keratopathy in three, while optic atrophy was present in one. A generalised matrix defect compressing the optic nerve does not obviously predict that ordering.
Does the c.1435-12A>G splice allele behave as a null, or does its 118-residue neopeptide add an effect of its own?
KNOWLEDGE GAP gapo_neopeptide_allele
Attached to
genetic#ANTXR1
The nonsense alleles are predicted to abolish the protein through nonsense-mediated decay, and the splice allele is predicted to produce a truncated protein carrying a novel C-terminal peptide, which is a different molecular event. The functional answer is partly in hand and narrows the question rather than leaving it open: all three of the originally reported alleles, the splice allele included, were confirmed to behave as null alleles in patient fibroblasts, and immunohistochemistry on patient fibroblast lines showed complete loss of the ANTXR1 isoform. What remains is narrower and is an assay question. An antibody raised against the normal isoform reporting its loss does not establish that no truncated neopeptide-bearing species is made, only that the isoform it detects is gone, and a species that is functionally null for adhesion could still do something else. With about 30 reported patients that distinction will not emerge from clinical correlation.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Interestingly, all of them produce null alleles as confirmed by functional studies with fibroblasts obtained from GAPO patients."
The functional result that answers the first half of the question: the alleles were not only predicted to be null, they were confirmed null in patient cells. This is the sentence the earlier version of this rationale contradicted.
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"immunohistochemical studies performed on skin fibroblast cell lines obtained from GAPO syndrome patients demonstrated complete loss of the ANTXR1 isoform and remarkable alterations in the actin cytoskeletal network in affected fibroblasts"
The immunohistochemical half. It reports loss of the ANTXR1 isoform, which is why the residual question in this gap is about what the antibody could have detected rather than about whether the allele is functionally null.
Is the alopecia a consequence of matrix accumulation in the dermis, or a separate developmental effect of ANTXR1 loss on the hair follicle?
KNOWLEDGE GAP gapo_alopecia_route
Attached to
phenotypes#Alopecia
Alopecia with rarefaction of eyebrows and eyelashes is an ectodermal pattern, and the syndrome is classified among the ectodermal dysplasias for that reason, yet the proposed mechanism is mesenchymal. Hair follicle development depends on epithelial-mesenchymal signalling, so a dermal matrix defect could produce it, and one located source does put the matrix in the right place: in the Antxr1 knock-out mouse the extracellular-matrix excess is localised to the skin at the basal aspects of the hair follicles specifically, among several other tissues. That is a localisation, not a demonstration. No source reports whether that mouse loses hair, no source tests whether removing the peri-follicular matrix excess rescues anything, and the alternative that ANTXR1 has a follicle-intrinsic role is not excluded. The gap is therefore about the step from peri-follicular matrix accumulation to hair loss, not about whether anyone has looked at the follicle.
Show evidence (1 reference)
PMID:25045128 SUPPORT BACKGROUND Model Organism
"In an Antxr1 knock-out mouse model a mild to moderate increase of extracellular matrix (especially collagen) has been observed in many tissues including: the skin (basal aspects of the hair follicles), endometrium, ovaries, periosteum of femurs and vertebra, cranial sutures of the skull, and the..."
The localisation. Among the tissues listed for the knock-out mouse, the skin entry is qualified as the basal aspects of the hair follicles, which is the peri-follicular compartment this gap is about. The same sentence carries the periodontal ligament finding that underpins the dental edge, so it is one observation supporting two very differently typed edges.
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Pathophysiology

3
ANTXR1 Loss of Function
Biallelic ANTXR1 variants remove or truncate a matrix-interacting protein that works as an adhesion molecule. The reported alleles are mechanistically varied: nonsense changes predicted to trigger nonsense-mediated decay and so abolish the protein, and a splice change that theoretically encodes a truncated protein carrying a 118-residue neopeptide at its C terminus. Whether the neopeptide allele behaves as a plain null or has an additional effect is not resolved.
ANTXR1 hgnc:21014 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANTXR1 (hgnc:21014). hgnc:21014 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Actin Cytoskeletal Disorganisation ANTXR1 links the extracellular matrix to the cytoskeleton, so patient fibroblasts show a disordered actin microfilament pattern.
Extracellular Matrix Accumulation The founding study's conclusion is that ANTXR1 loss produces a generalized defect in extracellular-matrix homeostasis, with accumulation as the observed consequence.
Show evidence (2 references)
PMID:23602711 SUPPORT Human Clinical
"The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss of ANTXR1."
The molecular consequence of the nonsense alleles. "Predictably" is the source's word — this is an inference from the variant class, not a measurement.
PMID:27587992 SUPPORT BACKGROUND Human Clinical
"This gene encodes a matrix-interacting protein that works as an adhesion molecule."
The protein's function, which is what makes the matrix the site of the lesion.
Actin Cytoskeletal Disorganisation
Cultured skin fibroblasts from GAPO patients show an aberrant pattern of actin microfilament organisation. This is the cellular observation that connects the loss of an adhesion molecule to a failure of matrix handling, since matrix turnover depends on cells being able to engage and remodel it.
skin fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skin fibroblast, annotated with fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Extracellular Matrix Accumulation The inference from disordered cytoskeleton to matrix accumulation is the founding study's, and is described in a later paper as strongly suggested rather than demonstrated. The intervening steps are not identified.
Extracellular Matrix Accumulation
Unresorbed extracellular matrix accumulates in connective tissue. This is the node the syndrome's coherence rests on: it is what the Antxr1-mutant mouse shows alongside the dental phenotype, and it is offered as the explanation for the involvement of cardiovascular, skeletal, cerebrovascular, pulmonary and auditory systems in reported patients — all of which are connective-tissue territories.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Animal models
Antxr1 mutant Mouse Mouse recapitulates Shows extracellular-matrix accumulation together with the dental phenotype, which is the pairing the human matrix hypothesis rests on.
Downstream
Eruption failure Teeth that have formed cannot erupt through connective tissue that is not being cleared. This is the feature the matrix hypothesis explains best, and the one the mouse reproduces.
Growth delay
Alopecia
Thickened eyelids Subcutaneous accumulation increasing with age is what the source reports coarsening the face, and the eyelid is the thinnest subcutaneous compartment in it. The intermediate is named, which is the accumulation itself; what is not established is why the eyelid is affected in every patient when other subcutaneous sites are not scored at all.
Thick lips The same accumulation, at the other soft-tissue site the cohort table scores. Eyelids and lips are both positive in all six patients, which is what a generalised subcutaneous process predicts and what a patterning defect would not.
Delayed closure of the anterior fontanel The knock-out mouse shows matrix excess specifically at the cranial sutures, which is the named intermediate between the matrix node and a fontanel that closes late. The mouse is not reported to have a patent fontanel, so this edge rests on the site of the lesion rather than on a reproduced phenotype.
Optic atrophy A route is proposed, and it is a mechanical one: matrix accumulating around the optic nerve, together with thickening of the surrounding dura, physically compresses it. That names the intermediate, which is why this edge is typed with known intermediates rather than unknown ones. What the proposal does not do is explain the course or the frequency, since a compressive lesion that accumulates with age fits a progressive deficit but not a feature absent in most patients.
Show evidence (1 reference)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Patients with GAPO syndrome demonstrate abnormalities of the cardiovascular"
The opening of this source's summary of multi-system involvement, which it goes on to attribute to connective tissue. The quote is short because the full sentence interleaves per-system citation markers that the reference validator strips before matching; the systems listed are cardiovascular, skeletal, cerebrovascular, pulmonary and auditory, and this entry's description carries them.
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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 GAPO 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

28
Breast 1
Breast and nipple hypoplasia VERY_FREQUENT Breast hypoplasia HP:0003187 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Breast and nipple hypoplasia, annotated with Breast hypoplasia (HP:0003187). HP:0003187 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Breast and nipple hypoplasia | + | + | + | + | n.d. | n.d. |"
Table I: four of four assessed.
Cardiovascular 2
Dilated cardiomyopathy OCCASIONAL HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19206158 SUPPORT Human Clinical
The primary case report behind the review's mention. No snippet is given because PubMed holds no abstract for this record, so there is no body text to quote; quoting the title would be quoting a claim rather than a finding. The reference is recorded so the phenotype is traceable to its source, and a curator who obtains the full text can add the quote.
Pulmonary hypertension OCCASIONAL Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypertension, annotated with Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Pulmonary involvement is one of the life-span reducing visceral manifestations present in patients with GAPO syndrome and reported in a GAPO patient who had pulmonary hypertension that lead to death at the age of 17 months"
Both the finding and its consequence in one sentence, which is why this phenotype carries a frequency band from the literature rather than from the cohort table.
Digestive 1
Umbilical hernia FREQUENT HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Umblical hernia | + | + | + | − | n.d. | n.d. |"
Table I: three positive, one negative, two not done. The row label carries the source's own misspelling and is quoted as printed.
Ear 3
Low-set ears VERY_FREQUENT HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Low set and protruding ears | + | + | + | + | + | + |"
Table I: six of six for the combined row. The row does not distinguish the two components, so both phenotypes carry the same frequency and the same source.
Protruding ears VERY_FREQUENT HP:0000411 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protruding ears, annotated with Protruding ear (HP:0000411). HP:0000411 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Low set and protruding ears | + | + | + | + | + | + |"
Table I: six of six.
Bilateral sensorineural deafness OCCASIONAL Bilateral sensorineural hearing impairment HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural deafness, annotated with Bilateral sensorineural hearing impairment (HP:0008619). HP:0008619 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"The other occasional findings of GAPO syndrome published in the literature are bilateral sensorineural deafness"
The first item in the source's list of occasional findings, quoted up to the citation marker that follows it.
Eye 5
Optic atrophy OCCASIONAL HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive optic atrophy, annotated with Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"GAPO syndrome (OMIM#230740) is the acronym for growth retardation, alopecia, pseudoanodontia, and optic atrophy."
Optic atrophy as the fourth letter of the acronym. This establishes that the feature is named, and nothing more; it is not evidence of how often it is present, which is a different question and is answered by the two items below.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"As Ilker et al. noted that optic atrophy is not a consistent feature of this disorder, we also detected optic atrophy in only one of our cases."
The frequency, stated twice in one sentence: the ophthalmologic literature does not find optic atrophy consistent, and this cohort found it in one of six. That is what sets the band on this phenotype, against the acronym rather than with it.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Optic atrophy | n.d. | − | + | n.d. | − | − |"
Table I, the optic atrophy row across the six patients: one plus, three minus and two not done. It is the only row in the table where the majority of scored patients are negative, and it is the eponymous feature.
+ 1 more reference
Hypertelorism VERY_FREQUENT HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype."
Hypertelorism among the craniofacial features that make the phenotype recognisable. Like the frontal bossing sentence it carries no denominator, so the band rests on the two items below.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Hypertelorism | + | + | + | + | + | + |"
Table I: six of six.
Glaucoma FREQUENT HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic findings"
Names glaucoma in four patients by identifier, and classes it among the uncommon ophthalmic findings. The count and the classification are both the source's.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Glaucoma | + | − | − | + | + | + |"
Table I: four positive, two negative, none not-done. This is the most completely scored ophthalmic row in the table.
Keratopathy FREQUENT Abnormal cornea morphology HP:0000481 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratopathy, annotated with Abnormal cornea morphology (HP:0000481). HP:0000481 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic findings"
Names keratopathy in three patients by identifier.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Keratopathy | + | − | − | + | − | + |"
Table I: three of six.
Hypermyelinated retinal nerve fibers OCCASIONAL HP:0007922 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelinated retinal nerve fiber layer, annotated with Hypermyelinated retinal nerve fibers (HP:0007922). HP:0007922 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic findings"
Names myelinated retinal nerve fiber in two patients by identifier.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Myelinated nerve fiber layer | − | + | + | − | n.d. | n.d. |"
Table I: two positive, two negative, two not done.
Head and Neck 13
Eruption failure VERY_FREQUENT HP:0000706 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pseudoanodontia, annotated with Eruption failure (HP:0000706). HP:0000706 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23602711 SUPPORT Human Clinical
"The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified."
Pseudoanodontia as a defining feature.
PMID:23602711 SUPPORT Model Organism
"GAPO syndrome's major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation."
The mouse recapitulation of the dental phenotype, quoted as a separate evidence item because it is model evidence for the same feature.
Frontal bossing VERY_FREQUENT HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype."
Frontal bossing among the craniofacial features that make the phenotype clinically recognisable. This sentence gives no denominator, which is why it is not on its own the source of the frequency band; the two items below are.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Frontal bossing | + | + | + | + | + | + |"
Table I: six of six.
Thick lips VERY_FREQUENT Thick vermilion border HP:0012471 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thick, full lips, annotated with Thick vermilion border (HP:0012471). HP:0012471 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype."
Thickened lips among the craniofacial features. This sentence names eyelids and lips together, which is what the earlier single phenotype followed; the cohort table scores them as separate rows, so they are now two phenotypes and each cites this sentence for its own half.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Thick, full lips | + | + | + | + | + | + |"
Table I: six of six. This row is why the band is VERY_FREQUENT rather than the FREQUENT the phenotype carried when it was split out of the combined eyelids-and-lips entry.
Relative macrocephaly VERY_FREQUENT HP:0004482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Relative macrocephaly (HP:0004482). HP:0004482 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Relative macrocephaly | + | + | + | + | + | + |"
Table I: six of six.
Thickened eyelids VERY_FREQUENT Palpebral thickening HP:0030939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thickened eyelids, annotated with Palpebral thickening (HP:0030939). HP:0030939 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Thickened eyelids | + | + | + | + | + | + |"
Table I: six of six.
Sparse eyebrows VERY_FREQUENT HP:0045075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse eyebrows, annotated with Sparse eyebrow (HP:0045075). HP:0045075 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Sparse eyebrows and eyelashes | + | + | + | + | + | + |"
Table I: six of six.
Sparse eyelashes VERY_FREQUENT HP:0000653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse eyelashes (HP:0000653). HP:0000653 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Sparse eyebrows and eyelashes | + | + | + | + | + | + |"
Table I: six of six.
Depressed nasal bridge VERY_FREQUENT HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Depressed nasal bridge | + | + | + | + | + | + |"
Table I: six of six.
Short nose VERY_FREQUENT HP:0003196 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short nose (HP:0003196). HP:0003196 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Plagiocephaly, frontal bossing, hypertelorism, depressed nasal bridge, short nose, long philtrum, anteverted nares, thick lips and micrognathia are the typical craniofacial findings of GAPO syndrome"
The typical-findings sentence from this source's introduction, which lists short nose and anteverted nares among the features that make the disorder recognisable.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Short nose, anteverted nares | + | + | + | + | + | − |"
Table I: five of six. The negative is BAB5349, the 37-year-old, which raises but does not settle the question of whether the nasal feature is modified by the facial coarsening this source reports as increasing with age.
Anteverted nares VERY_FREQUENT HP:0000463 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteverted nares (HP:0000463). HP:0000463 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Plagiocephaly, frontal bossing, hypertelorism, depressed nasal bridge, short nose, long philtrum, anteverted nares, thick lips and micrognathia are the typical craniofacial findings of GAPO syndrome"
Named in the typical-findings sentence.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Short nose, anteverted nares | + | + | + | + | + | − |"
Table I: five of six.
Long philtrum VERY_FREQUENT HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Long philtrum | + | + | + | + | + | + |"
Table I: six of six.
Micrognathia VERY_FREQUENT HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"The common craniofacial findings in all patients are alopecia, relative macrocephaly, frontal bossing, low set and protruding ears, hypertelorism, thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long philtrum, thick lips and micrognathia (Fig. 1)."
The common-findings sentence, which states these features as present in all patients in the cohort and is the source of the VERY_FREQUENT band on each of them.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Micrognathia | + | + | + | + | + | + |"
Table I: six of six.
Delayed closure of the anterior fontanel VERY_FREQUENT Delayed cranial suture closure HP:0000270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed closure of the anterior fontanel, annotated with Delayed cranial suture closure (HP:0000270). HP:0000270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Delayed closure of anterior fontanel | + | + | + | + | n.d. | n.d. |"
Table I: positive in four of four assessed, not done in the two oldest patients.
Integument 1
Alopecia VERY_FREQUENT HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype."
Alopecia with the associated rarefaction of eyebrows and lashes, in the source's description of the recognisable phenotype.
Musculoskeletal 1
Delayed bone age VERY_FREQUENT Delayed skeletal maturation HP:0002750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed bone age, annotated with Delayed skeletal maturation (HP:0002750). HP:0002750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"| Delayed bone age | + | + | + | + | + | + |"
Table I: six of six.
Growth 1
Growth delay VERY_FREQUENT HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23602711 SUPPORT Human Clinical
"The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified."
Growth retardation as a defining feature. The VERY_FREQUENT band reflects that the feature is part of the disease definition, not a published denominator — there is none for a disorder with about 30 reported cases.
🧬

Genetic Associations

1
ANTXR1
Gene: ANTXR1 hgnc:21014 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANTXR1 (hgnc:21014). hgnc:21014 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:23602711 SUPPORT Human Clinical
"The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus."
The distinctive consequence of the splice allele. "Theoretically" is the source's word and the protein was not measured.
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"Exome sequencing analysis identified three novel homozygous mutations including; one frame-shift (c.1220_1221insT; p.Ala408Cysfs*2), one splice site (c.411A>G; p.Gln137Gln), and one non-synonymous (c.1150G>A; p.Gly384Ser) mutation in the ANTXR1 gene."
Three further alleles, expanding the spectrum beyond nonsense variants.
PMID:27587992 SUPPORT Human Clinical
"This mutation produces the substitution of a glutamine in position 137 for a leucine (c.410A>T, p.Q137L)."
A missense allele in two homozygous siblings.
Variants (4)
c.262C>T (p.Arg88*) and c.505C>T (p.Arg169*)
Homozygous nonsense variants in the founding cohort, predicted to trigger nonsense-mediated mRNA decay and so to abolish the protein.
c.1435-12A>G (p.Gly479Phefs*119)
A splicing variant that theoretically encodes a truncated ANTXR1 carrying a neopeptide of 118 unique amino acids at its C terminus.
c.1220_1221insT (p.Ala408Cysfs*2), c.411A>G (p.Gln137Gln), c.1150G>A (p.Gly384Ser)
Three novel homozygous variants — frameshift, splice site and non-synonymous — found by whole exome sequencing in three Turkish kindreds.
c.410A>T (p.Q137L)
A missense variant found homozygous in two siblings.
📈

Progression

2
Progressive course of the ocular and hair features
Two of the four cardinal features are described as progressive rather than congenital and static: the visual impairment and, in the acronym's original framing, the optic atrophy. The growth retardation and the failure of tooth eruption are established early. Reported patients have normal intellectual development.
Show evidence (2 references)
PMID:23602711 SUPPORT Human Clinical
"The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified."
Names the visual impairment as progressive. Note this source says "progressive visual impairment" where others say "progressive optic atrophy"; the difference is discussed in this entry's notes.
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"All reported individuals have normal intellectual development and the vast majority demonstrates no remarkable biochemical or endocrinologic abnormalities."
The negative findings, which matter for counselling and for distinguishing GAPO from syndromes it resembles facially.
Visceral involvement and premature death
GAPO is not a disorder of appearance alone and its published course includes death in childhood and in adult life from visceral causes. One patient in the cohort curated here died at 37 of central apnoea and respiratory insufficiency, and a separately reported patient died at 17 months of pulmonary hypertension. Pulmonary involvement is named as one of the life-span reducing manifestations. Nothing located establishes a survival distribution, and with roughly 30 published cases nothing is likely to; these are two reported deaths, recorded as such.
Show evidence (2 references)
PMID:25045128 SUPPORT PRIMARY RESULT Human Clinical
"Clinical follow up of our families revealed that patient BAB5349 died at age 37 due to central apnea and respiratory insufficiency."
The death in the cohort, with its age and its cause. BAB5349 is the oldest patient in the table and the only one in whom the disorder's late course is observed at all.
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"Pulmonary involvement is one of the life-span reducing visceral manifestations present in patients with GAPO syndrome and reported in a GAPO patient who had pulmonary hypertension that lead to death at the age of 17 months"
The second death, from the wider literature, and the source's own characterisation of pulmonary involvement as life-span reducing. The two deaths are 35 years apart in age, which is why no phase in this entry claims a typical course.
📊

Prevalence

1
Cases reported worldwide
Cases In Literature Ultra Rare
Roughly 30 to 35 cases in the world literature, depending on the review. Two sources in this entry give slightly different counts a couple of years apart — about 35 in 2014 and about 30 in 2016 — which is the ordinary noise of counting case reports rather than a discrepancy worth resolving. No population prevalence has been published.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Human Clinical
"About 35 cases have been reported, making it among one of the rarest recessive conditions."
The published case count and the source's own characterisation of the rarity.
PMID:27587992 SUPPORT BACKGROUND Human Clinical
"To date, only 30 cases have been described worldwide."
An independent count from two years later, quoted so the imprecision in the literature is visible rather than averaged away.
🐁

Animal Models

1
Antxr1 mutant Mouse
The Antxr1-mutant mouse reproduces the dental abnormalities and the extracellular-matrix accumulation. It is the evidence that makes the matrix hypothesis more than an interpretation of a fibroblast stain, because it shows the two features arising together from the same lesion in an animal.
Species
Mouse
Genotype
Antxr1 mutant
Publication
PMID:23602711
Pathograph links
Extracellular Matrix Accumulation recapitulates fidelity: moderate observes: tissue Shows extracellular-matrix accumulation together with the dental phenotype, which is the pairing the human matrix hypothesis rests on.
Limitations: The tissues assessed are enumerated and the ocular system is not among them. The knock-out shows a mild to moderate matrix increase in skin at the basal aspects of the hair follicles, endometrium, ovaries, periosteum of femur and vertebra, cranial sutures, and the periodontal ligament of the incisors, where it produces misalignment and dental dysplasia. Two limits follow. The increase is graded mild to moderate, against a human phenotype severe enough to prevent tooth eruption entirely and to coarsen the face with age. And nothing reports an optic nerve, a retinal or a hair-loss finding in the mouse, so the model speaks to the dental and connective-tissue arm and is silent on the two human features this entry types as least well explained.
Divergences from the human mechanism
boundary omission qualifying
The enumerated tissues cover skin, reproductive tract, bone, cranial sutures and periodontal ligament. Neither the optic nerve nor hair loss appears, so the two human features with the weakest mechanistic account in this entry are also the two the model does not report on.
species mismatch qualifying
The mouse matrix increase is graded mild to moderate. The human phenotype it is offered as a model of prevents tooth eruption outright, so the same lesion is producing quantitatively different tissue consequences in the two species.
Show evidence (2 references)
PMID:25045128 SUPPORT BACKGROUND Model Organism
"In an Antxr1 knock-out mouse model a mild to moderate increase of extracellular matrix (especially collagen) has been observed in many tissues including: the skin (basal aspects of the hair follicles), endometrium, ovaries, periosteum of femurs and vertebra, cranial sutures of the skull, and the..."
The tissue-by-tissue enumeration, which is what the limitations field now records. The periodontal ligament clause is the mechanistic core of the dental edge: matrix excess in the ligament produces misalignment and dental dysplasia in the mouse.
+ 1 more reference
{ }

Source YAML

click to show 
name: GAPO Syndrome
creation_date: "2026-09-17T15:30:00Z"
description: >-
  GAPO syndrome is the autosomal recessive disorder named for its four cardinal
  features — growth retardation, alopecia, pseudoanodontia and optic atrophy —
  caused by biallelic loss of ANTXR1, a matrix-interacting adhesion molecule better
  known as anthrax toxin receptor 1. Around 30 to 35 cases have been reported
  worldwide, which makes it one of the rarest recessive conditions, and its
  craniofacial appearance is distinctive enough that it is recognised clinically
  before it is confirmed genetically.

  The unifying lesion is a generalised defect in extracellular-matrix homeostasis.
  Reported ANTXR1 alleles are nonsense changes predicted to trigger
  nonsense-mediated decay, a splice change encoding a truncated protein with a
  118-residue neopeptide at its C terminus, and frameshift and missense variants.
  Cultured skin fibroblasts from patients show a disordered actin cytoskeleton, and
  Antxr1-mutant mice reproduce both the dental abnormalities and the
  extracellular-matrix accumulation — which is the argument that the matrix is where
  the four features converge rather than being four independent consequences of one
  gene.

  That argument is strong for the dental and connective-tissue features and weaker for
  the ocular ones, and this entry types its causal edges accordingly. Pseudoanodontia is
  the clearest instance: the teeth are formed but do not erupt, which is what the name
  means and what a matrix-clearance defect would predict. For the optic atrophy a route
  is proposed and it is mechanical, matrix and thickened dura compressing the nerve, but
  it does not fit what is observed. The eponymous ocular feature was scored positive in
  one of the six patients of the cohort curated here and is described in the
  ophthalmologic literature as not consistent, while glaucoma, which the acronym does
  not mention, was present in four of the same six.
synonyms:
- growth retardation-alopecia-pseudoanodontia-optic atrophy syndrome
- GAPO
- anthrax toxin receptor 1 deficiency
category: Mendelian
disease_term:
  preferred_term: GAPO syndrome
  term:
    id: MONDO:0009263
    label: GAPO syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009263
      label: GAPO syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- autosomal recessive disease
- ectodermal dysplasia syndrome
- rare disease
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic ANTXR1 variants are required, and every reported genotype has been
    homozygous — four ethnically unrelated individuals in the founding report, and
    five individuals from three Turkish kindreds in the exome study that followed.
    The pattern was recognised as autosomal recessive from pedigrees long before the
    gene was found.
  evidence:
  - reference: PMID:23602711
    reference_title: Mutations in ANTXR1 cause GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied four ethnically unrelated affected individuals and identified
      homozygous nonsense mutations
    explanation: >-
      The founding genetic result: four unrelated individuals, all homozygous, which is
      what establishes the recessive requirement rather than a founder effect. The
      quote stops before the variant list because the reference validator strips
      bracketed spans before matching and each variant carries a bracketed protein
      change; the alleles themselves are recorded under genetic[].variants.
  - reference: PMID:27587992
    reference_title: "New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, gene alterations in the ANTXR1 gene have been reported to be
      causative of this disorder, and an autosomal recessive pattern has been observed.
    explanation: >-
      Independent confirmation of the inheritance pattern. Stated as established
      background in this case report rather than derived here.
    quote_role: BACKGROUND
prevalence:
- population: Cases reported worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Roughly 30 to 35 cases in the world literature, depending on the review. Two
    sources in this entry give slightly different counts a couple of years apart —
    about 35 in 2014 and about 30 in 2016 — which is the ordinary noise of counting
    case reports rather than a discrepancy worth resolving. No population prevalence
    has been published.
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About 35 cases have been reported, making it among one of the rarest recessive
      conditions.
    explanation: >-
      The published case count and the source's own characterisation of the rarity.
    quote_role: BACKGROUND
  - reference: PMID:27587992
    reference_title: "New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only 30 cases have been described worldwide.
    explanation: >-
      An independent count from two years later, quoted so the imprecision in the
      literature is visible rather than averaged away.
    quote_role: BACKGROUND
progression:
- phase: Progressive course of the ocular and hair features
  notes: >-
    Two of the four cardinal features are described as progressive rather than
    congenital and static: the visual impairment and, in the acronym's original
    framing, the optic atrophy. The growth retardation and the failure of tooth
    eruption are established early. Reported patients have normal intellectual
    development.
  evidence:
  - reference: PMID:23602711
    reference_title: Mutations in ANTXR1 cause GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genetic cause of GAPO syndrome, a condition characterized by growth
      retardation, alopecia, pseudoanodontia, and progressive visual impairment, has
      not previously been identified.
    explanation: >-
      Names the visual impairment as progressive. Note this source says "progressive
      visual impairment" where others say "progressive optic atrophy"; the difference
      is discussed in this entry's notes.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      All reported individuals have normal intellectual development and the vast
      majority demonstrates no remarkable biochemical or endocrinologic abnormalities.
    explanation: >-
      The negative findings, which matter for counselling and for distinguishing GAPO
      from syndromes it resembles facially.
- phase: Visceral involvement and premature death
  notes: >-
    GAPO is not a disorder of appearance alone and its published course includes death
    in childhood and in adult life from visceral causes. One patient in the cohort
    curated here died at 37 of central apnoea and respiratory insufficiency, and a
    separately reported patient died at 17 months of pulmonary hypertension. Pulmonary
    involvement is named as one of the life-span reducing manifestations. Nothing
    located establishes a survival distribution, and with roughly 30 published cases
    nothing is likely to; these are two reported deaths, recorded as such.
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Clinical follow up of our families revealed that patient BAB5349 died at age 37
      due to central apnea and respiratory insufficiency.
    explanation: >-
      The death in the cohort, with its age and its cause. BAB5349 is the oldest patient
      in the table and the only one in whom the disorder's late course is observed at
      all.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Pulmonary involvement is one of the life-span reducing visceral manifestations
      present in patients with GAPO syndrome and reported in a GAPO patient who had
      pulmonary hypertension that lead to death at the age of 17 months
    explanation: >-
      The second death, from the wider literature, and the source's own characterisation
      of pulmonary involvement as life-span reducing. The two deaths are 35 years apart
      in age, which is why no phase in this entry claims a typical course.
pathophysiology:
- name: ANTXR1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic ANTXR1 variants remove or truncate a matrix-interacting protein that
    works as an adhesion molecule. The reported alleles are mechanistically varied:
    nonsense changes predicted to trigger nonsense-mediated decay and so abolish the
    protein, and a splice change that theoretically encodes a truncated protein
    carrying a 118-residue neopeptide at its C terminus. Whether the neopeptide
    allele behaves as a plain null or has an additional effect is not resolved.
  genes:
  - preferred_term: ANTXR1
    term:
      id: hgnc:21014
      label: ANTXR1
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Actin Cytoskeletal Disorganisation
    causal_link_type: DIRECT
    description: >-
      ANTXR1 links the extracellular matrix to the cytoskeleton, so patient
      fibroblasts show a disordered actin microfilament pattern.
    evidence:
    - reference: PMID:25045128
      reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: >-
        Immunofluorescence analysis of cultured skin fibroblasts collected from GAPO
        cases demonstrated an aberrant pattern of actin cytoskeletal microfilament
        organization.
      explanation: >-
        The cytoskeletal observation in patient cells. This paper is restating the
        founding study's result in its own introduction rather than repeating the
        experiment.
  - target: Extracellular Matrix Accumulation
    causal_link_type: DIRECT
    description: >-
      The founding study's conclusion is that ANTXR1 loss produces a generalized
      defect in extracellular-matrix homeostasis, with accumulation as the observed
      consequence.
    evidence:
    - reference: PMID:23602711
      reference_title: Mutations in ANTXR1 cause GAPO syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thus, we propose that mutations affecting ANTXR1 function are responsible for
        this disease's characteristic generalized defect in extracellular-matrix
        homeostasis.
      explanation: >-
        The authors' proposal, quoted as a proposal. It is the organising hypothesis of
        this entry and is not stated more strongly than its source states it.
  evidence:
  - reference: PMID:23602711
    reference_title: Mutations in ANTXR1 cause GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The nonsense mutations predictably trigger nonsense-mediated mRNA decay,
      resulting in the loss of ANTXR1.
    explanation: >-
      The molecular consequence of the nonsense alleles. "Predictably" is the source's
      word — this is an inference from the variant class, not a measurement.
  - reference: PMID:27587992
    reference_title: "New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      This gene encodes a matrix-interacting protein that works as an adhesion molecule.
    explanation: The protein's function, which is what makes the matrix the site of the lesion.
- name: Actin Cytoskeletal Disorganisation
  biological_scale: CELLULAR
  description: >-
    Cultured skin fibroblasts from GAPO patients show an aberrant pattern of actin
    microfilament organisation. This is the cellular observation that connects the
    loss of an adhesion molecule to a failure of matrix handling, since matrix
    turnover depends on cells being able to engage and remodel it.
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    modifier: DECREASED
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Extracellular Matrix Accumulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The inference from disordered cytoskeleton to matrix accumulation is the
      founding study's, and is described in a later paper as strongly suggested rather
      than demonstrated. The intervening steps are not identified.
    evidence:
    - reference: PMID:25045128
      reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: >-
        This observation strongly suggested that loss of ANTXR1 function results in
        progressive extracellular-matrix accumulation that is observed in patients with
        GAPO syndrome
      explanation: >-
        The word "suggested" is the reason this edge is not typed DIRECT. The
        observation supports the link through an inferential step rather than
        demonstrating it.
- name: Extracellular Matrix Accumulation
  biological_scale: TISSUE
  description: >-
    Unresorbed extracellular matrix accumulates in connective tissue. This is the
    node the syndrome's coherence rests on: it is what the Antxr1-mutant mouse shows
    alongside the dental phenotype, and it is offered as the explanation for the
    involvement of cardiovascular, skeletal, cerebrovascular, pulmonary and auditory
    systems in reported patients — all of which are connective-tissue territories.
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: DYSREGULATED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  downstream:
  - target: Eruption failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Teeth that have formed cannot erupt through connective tissue that is not being
      cleared. This is the feature the matrix hypothesis explains best, and the one
      the mouse reproduces.
    evidence:
    - reference: PMID:23602711
      reference_title: Mutations in ANTXR1 cause GAPO syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        GAPO syndrome's major phenotypic features, which include dental abnormalities
        and the accumulation of extracellular matrix, recapitulate those found in
        Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix
        regulation.
      explanation: >-
        Pairs the dental phenotype with the matrix accumulation in the same mutant
        animal, which is the strongest evidence that the two are connected.
  - target: Growth delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Alopecia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thickened eyelids
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Subcutaneous accumulation increasing with age is what the source reports
      coarsening the face, and the eyelid is the thinnest subcutaneous compartment in
      it. The intermediate is named, which is the accumulation itself; what is not
      established is why the eyelid is affected in every patient when other subcutaneous
      sites are not scored at all.
    evidence:
    - reference: PMID:25045128
      reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Another remarkable finding in our patients is increased subcutaneous
        accumulations with age that results in an apparent coarsening of facial features
      explanation: >-
        Ties the facial thickening directly to accumulation, and ties it to time. It is
        the observation that makes the facial features of this syndrome a consequence of
        the matrix node rather than an independently dysmorphic gestalt.
  - target: Thick lips
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The same accumulation, at the other soft-tissue site the cohort table scores.
      Eyelids and lips are both positive in all six patients, which is what a
      generalised subcutaneous process predicts and what a patterning defect would not.
    evidence:
    - reference: PMID:25045128
      reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Another remarkable finding in our patients is increased subcutaneous
        accumulations with age that results in an apparent coarsening of facial features
      explanation: >-
        The same sentence, cited for the lip half of the facial thickening. One
        observation supports both edges because the source does not separate them.
  - target: Delayed closure of the anterior fontanel
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The knock-out mouse shows matrix excess specifically at the cranial sutures, which
      is the named intermediate between the matrix node and a fontanel that closes late.
      The mouse is not reported to have a patent fontanel, so this edge rests on the
      site of the lesion rather than on a reproduced phenotype.
    evidence:
    - reference: PMID:25045128
      reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        In an Antxr1 knock-out mouse model a mild to moderate increase of extracellular
        matrix (especially collagen) has been observed in many tissues including: the
        skin (basal aspects of the hair follicles), endometrium, ovaries, periosteum of
        femurs and vertebra, cranial sutures of the skull, and the periodontal ligament
        of the incisors that leads to misalignment and dental dysplasia
      explanation: >-
        Puts the matrix excess at the cranial sutures in the model organism. That
        localisation is what distinguishes this edge from the several other craniofacial
        features, which have no site-specific finding behind them at all.
  - target: Optic atrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A route is proposed, and it is a mechanical one: matrix accumulating around the
      optic nerve, together with thickening of the surrounding dura, physically
      compresses it. That names the intermediate, which is why this edge is typed with
      known intermediates rather than unknown ones. What the proposal does not do is
      explain the course or the frequency, since a compressive lesion that accumulates
      with age fits a progressive deficit but not a feature absent in most patients.
    evidence:
    - reference: PMID:25045128
      reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        It is concluded that optic nerve pathologies are observed potentially secondary
        to physical compression of the optic nerve by the accumulation of extracellular
        matrix and thickening of the dura matter surrounding the optic nerve
      explanation: >-
        The proposed intermediate, in the source's own words. Note the hedge:
        "potentially secondary to", carried over three older citations, and the authors
        conclude it rather than demonstrate it. That is enough to name an intermediate
        and not enough to type the edge DIRECT.
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Patients with GAPO syndrome demonstrate abnormalities of the cardiovascular
    explanation: >-
      The opening of this source's summary of multi-system involvement, which it goes on
      to attribute to connective tissue. The quote is short because the full sentence
      interleaves per-system citation markers that the reference validator strips before
      matching; the systems listed are cardiovascular, skeletal, cerebrovascular,
      pulmonary and auditory, and this entry's description carries them.
phenotypes:
- category: Growth
  name: Growth delay
  description: >-
    The G of the acronym. Growth retardation is one of the four defining features and
    is present by definition in reported patients.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23602711
    reference_title: Mutations in ANTXR1 cause GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genetic cause of GAPO syndrome, a condition characterized by growth
      retardation, alopecia, pseudoanodontia, and progressive visual impairment, has
      not previously been identified.
    explanation: >-
      Growth retardation as a defining feature. The VERY_FREQUENT band reflects that
      the feature is part of the disease definition, not a published denominator —
      there is none for a disorder with about 30 reported cases.
- category: Dermatologic
  name: Alopecia
  description: >-
    The A of the acronym, accompanied by rarefaction of the eyebrows and eyelashes
    rather than being confined to the scalp.
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Distinctive craniofacial features including alopecia, rarefaction of eyebrows and
      eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism,
      and thickened eyelids and lips make GAPO syndrome a clinically recognizable
      phenotype.
    explanation: >-
      Alopecia with the associated rarefaction of eyebrows and lashes, in the source's
      description of the recognisable phenotype.
- category: Dental
  name: Eruption failure
  description: >-
    Pseudoanodontia, the P of the acronym. The distinction the name carries is the
    mechanistically important one: the teeth are present but fail to erupt, which is
    not the same claim as tooth agenesis and is what makes a matrix-clearance defect
    the natural explanation. This is the feature the Antxr1-mutant mouse reproduces.
  phenotype_term:
    preferred_term: Pseudoanodontia
    term:
      id: HP:0000706
      label: Eruption failure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23602711
    reference_title: Mutations in ANTXR1 cause GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genetic cause of GAPO syndrome, a condition characterized by growth
      retardation, alopecia, pseudoanodontia, and progressive visual impairment, has
      not previously been identified.
    explanation: Pseudoanodontia as a defining feature.
  - reference: PMID:23602711
    reference_title: Mutations in ANTXR1 cause GAPO syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      GAPO syndrome's major phenotypic features, which include dental abnormalities
      and the accumulation of extracellular matrix, recapitulate those found in
      Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix
      regulation.
    explanation: >-
      The mouse recapitulation of the dental phenotype, quoted as a separate evidence
      item because it is model evidence for the same feature.
- category: Ophthalmologic
  name: Optic atrophy
  description: >-
    The O of the acronym, and the feature the acronym describes worst. Two things are
    wrong with reading the name as a frequency claim. First, the sources disagree on
    what the feature is: the founding paper says "progressive visual impairment" where
    later sources say "progressive optic atrophy", and those are not synonyms, one being
    a symptom and the other a finding. Second, and more importantly, the ophthalmologic
    literature does not find optic atrophy consistent, and the six-patient cohort
    curated here scored it positive in one patient, negative in three and not done in
    two. Glaucoma, which is not in the acronym, was positive in four of the same six.
    The frequency band therefore follows the cohort and not the name.
  phenotype_term:
    preferred_term: Progressive optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      GAPO syndrome (OMIM#230740) is the acronym for growth retardation, alopecia,
      pseudoanodontia, and optic atrophy.
    explanation: >-
      Optic atrophy as the fourth letter of the acronym. This establishes that the
      feature is named, and nothing more; it is not evidence of how often it is
      present, which is a different question and is answered by the two items below.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      As Ilker et al. noted that optic atrophy is not a consistent feature of this
      disorder, we also detected optic atrophy in only one of our cases.
    explanation: >-
      The frequency, stated twice in one sentence: the ophthalmologic literature does
      not find optic atrophy consistent, and this cohort found it in one of six. That is
      what sets the band on this phenotype, against the acronym rather than with it.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Optic atrophy | n.d. | − | + | n.d. | − | − |
    explanation: >-
      Table I, the optic atrophy row across the six patients: one plus, three minus and
      two not done. It is the only row in the table where the majority of scored
      patients are negative, and it is the eponymous feature.
  - reference: PMID:27587992
    reference_title: "New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      GAPO syndrome is a very rare genetic disorder characterized by growth
      retardation, alopecia, pseudoanodontia and progressive optic atrophy (GAPO).
    explanation: >-
      Independent use of "progressive optic atrophy" for the fourth feature, which is
      what the binding follows.
- category: Craniofacial
  name: Frontal bossing
  description: >-
    Scored positive in all six patients of the cohort and named in the common-findings
    sentence, alongside the high forehead it accompanies. It is one of the eleven
    craniofacial features present in every patient, which together are what make the
    syndrome recognisable before it is confirmed genetically, and which the entry's
    matrix node does not account for.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Distinctive craniofacial features including alopecia, rarefaction of eyebrows and
      eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism,
      and thickened eyelids and lips make GAPO syndrome a clinically recognizable
      phenotype.
    explanation: >-
      Frontal bossing among the craniofacial features that make the phenotype clinically
      recognisable. This sentence gives no denominator, which is why it is not on its
      own the source of the frequency band; the two items below are.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Frontal bossing | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Scored positive in all six patients of the cohort. It is part of the same
    all-patient craniofacial pattern as the frontal bossing, the depressed nasal bridge
    and the long philtrum — a set of proportions and positions rather than thicknesses,
    which is why none of them is wired to the matrix node.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Distinctive craniofacial features including alopecia, rarefaction of eyebrows and
      eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism,
      and thickened eyelids and lips make GAPO syndrome a clinically recognizable
      phenotype.
    explanation: >-
      Hypertelorism among the craniofacial features that make the phenotype
      recognisable. Like the frontal bossing sentence it carries no denominator, so the
      band rests on the two items below.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Hypertelorism | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Thick lips
  description: >-
    Thick, full lips are scored positive in all six patients of the cohort and are the
    most visibly connective-tissue part of the facial appearance. The binding was
    previously HP:0000179, which names the lower lip only, under a preferred term that
    covered eyelids as well; the cohort table scores eyelids and lips as separate rows
    and the thickening is not described as lower-lip-limited, so the term now bound is
    the one that makes neither restriction, and the eyelid finding is curated as its own
    phenotype.
  phenotype_term:
    preferred_term: Thick, full lips
    term:
      id: HP:0012471
      label: Thick vermilion border
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Distinctive craniofacial features including alopecia, rarefaction of eyebrows and
      eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism,
      and thickened eyelids and lips make GAPO syndrome a clinically recognizable
      phenotype.
    explanation: >-
      Thickened lips among the craniofacial features. This sentence names eyelids and
      lips together, which is what the earlier single phenotype followed; the cohort
      table scores them as separate rows, so they are now two phenotypes and each cites
      this sentence for its own half.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Thick, full lips | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six. This row is why the band is VERY_FREQUENT rather than the
      FREQUENT the phenotype carried when it was split out of the combined
      eyelids-and-lips entry.
- category: Craniofacial
  name: Relative macrocephaly
  description: >-
    Scored positive in all six patients of the cohort and named in the common-findings
    sentence. It is relative rather than absolute: the head is large for a body whose
    growth is retarded, which is a different claim from macrocephaly and is why the more
    specific HPO term is bound.
  phenotype_term:
    preferred_term: Relative macrocephaly
    term:
      id: HP:0004482
      label: Relative macrocephaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Relative macrocephaly | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Low-set ears
  description: >-
    Low set and protruding ears are scored as one row in the cohort table and positive
    in all six patients. HPO separates the position and the projection, so this entry
    curates them as two phenotypes bound to the two terms rather than binding one and
    dropping the other.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Low set and protruding ears | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six for the combined row. The row does not distinguish the two
      components, so both phenotypes carry the same frequency and the same source.
- category: Craniofacial
  name: Protruding ears
  description: >-
    The second component of the combined ear row, curated separately because HPO has a
    term for it and collapsing it into the position term would lose it.
  phenotype_term:
    preferred_term: Protruding ears
    term:
      id: HP:0000411
      label: Protruding ear
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Low set and protruding ears | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Thickened eyelids
  description: >-
    Scored positive in all six patients. This was previously folded into a single thick
    lips and eyelids phenotype; the cohort table scores the two as separate rows, and
    HPO has a term for each, so they are curated apart. In a matrix-accumulation
    disorder the eyelid thickening is plausibly the same lesion as the lip thickening
    and the coarsening of the face with age, but no located source says so.
  phenotype_term:
    preferred_term: Thickened eyelids
    term:
      id: HP:0030939
      label: Palpebral thickening
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Thickened eyelids | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Sparse eyebrows
  description: >-
    Rarefaction of the eyebrows and eyelashes is part of the ectodermal pattern that
    places this syndrome among the ectodermal dysplasias, and is scored positive in all
    six patients as one combined row. HPO has separate terms, so it is curated as two
    phenotypes.
  phenotype_term:
    preferred_term: Sparse eyebrows
    term:
      id: HP:0045075
      label: Sparse eyebrow
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Sparse eyebrows and eyelashes | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Sparse eyelashes
  description: >-
    The second component of the combined eyebrow and eyelash row. Together with the
    alopecia it is the reason the hair phenotype in this syndrome is generalised rather
    than scalp-limited.
  phenotype_term:
    preferred_term: Sparse eyelashes
    term:
      id: HP:0000653
      label: Sparse eyelashes
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Sparse eyebrows and eyelashes | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Depressed nasal bridge
  description: >-
    Scored positive in all six patients and listed among the typical craniofacial
    findings that make this syndrome recognisable before it is confirmed genetically.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Depressed nasal bridge | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Short nose
  description: >-
    Short nose with anteverted nares is scored as one row and is the only craniofacial
    row in the cohort table that is not uniformly positive: five of six, the exception
    being the oldest patient. Curated as two phenotypes because HPO separates the length
    from the orientation.
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Plagiocephaly, frontal bossing, hypertelorism, depressed nasal bridge, short nose,
      long philtrum, anteverted nares, thick lips and micrognathia are the typical
      craniofacial findings of GAPO syndrome
    explanation: >-
      The typical-findings sentence from this source's introduction, which lists short
      nose and anteverted nares among the features that make the disorder recognisable.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Short nose, anteverted nares | + | + | + | + | + | − |
    explanation: >-
      Table I: five of six. The negative is BAB5349, the 37-year-old, which raises but
      does not settle the question of whether the nasal feature is modified by the
      facial coarsening this source reports as increasing with age.
- category: Craniofacial
  name: Anteverted nares
  description: >-
    The second component of the combined nasal row, five of six patients.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Plagiocephaly, frontal bossing, hypertelorism, depressed nasal bridge, short nose,
      long philtrum, anteverted nares, thick lips and micrognathia are the typical
      craniofacial findings of GAPO syndrome
    explanation: >-
      Named in the typical-findings sentence.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Short nose, anteverted nares | + | + | + | + | + | − |
    explanation: >-
      Table I: five of six.
- category: Craniofacial
  name: Long philtrum
  description: >-
    Scored positive in all six patients and named in both the typical-findings and the
    common-findings sentences of this source.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Long philtrum | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Micrognathia
  description: >-
    Scored positive in all six patients. It sits beside the pseudoanodontia in a jaw
    whose teeth have formed and not erupted, and no located source addresses whether the
    two are connected.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The common craniofacial findings in all patients are alopecia, relative
      macrocephaly, frontal bossing, low set and protruding ears, hypertelorism,
      thickened eyelids, sparse eyebrows and eyelashes, depressed nasal bridge, long
      philtrum, thick lips and micrognathia (Fig. 1).
    explanation: >-
      The common-findings sentence, which states these features as present in all
      patients in the cohort and is the source of the VERY_FREQUENT band on each of
      them.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Micrognathia | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Craniofacial
  name: Delayed closure of the anterior fontanel
  description: >-
    Positive in all four patients in whom it was assessed; not done in the two adults,
    which is expected for a finding of infancy. It is the cranial counterpart of the
    delayed bone age, and the Antxr1 knock-out mouse shows matrix excess at the cranial
    sutures.
  phenotype_term:
    preferred_term: Delayed closure of the anterior fontanel
    term:
      id: HP:0000270
      label: Delayed cranial suture closure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Delayed closure of anterior fontanel | + | + | + | + | n.d. | n.d. |
    explanation: >-
      Table I: positive in four of four assessed, not done in the two oldest patients.
- category: Ophthalmologic
  name: Glaucoma
  description: >-
    Present in four of the six patients, which makes it more frequent in this cohort
    than the optic atrophy the syndrome is named for. The source calls it an uncommon
    ophthalmic finding, and the tension between that description and the count is real:
    uncommon refers to the published literature on GAPO, the four-of-six to the patients
    examined here. Both are recorded, and neither is adjusted to match the other.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  frequency: FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal
      nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients
      (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic
      findings
    explanation: >-
      Names glaucoma in four patients by identifier, and classes it among the uncommon
      ophthalmic findings. The count and the classification are both the source's.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Glaucoma | + | − | − | + | + | + |
    explanation: >-
      Table I: four positive, two negative, none not-done. This is the most completely
      scored ophthalmic row in the table.
- category: Ophthalmologic
  name: Keratopathy
  description: >-
    Corneal involvement in three of the six patients. Bound to the general
    abnormal-cornea term because HPO has no term for keratopathy as such and the source
    does not say which corneal layer or process is involved; a named corneal term would
    be a narrower claim than the source makes. Bilateral interstitial keratitis is
    reported separately in the wider literature.
  phenotype_term:
    preferred_term: Keratopathy
    term:
      id: HP:0000481
      label: Abnormal cornea morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal
      nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients
      (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic
      findings
    explanation: >-
      Names keratopathy in three patients by identifier.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Keratopathy | + | − | − | + | − | + |
    explanation: >-
      Table I: three of six.
- category: Ophthalmologic
  name: Hypermyelinated retinal nerve fibers
  description: >-
    Present in two of the six patients. It is a developmental retinal finding rather
    than a degenerative one, which makes it a different kind of ocular abnormality from
    the optic atrophy and the glaucoma, and no located source relates it to the matrix
    defect. The band here follows the source's own word — it calls this an uncommon
    ophthalmic finding — rather than the arithmetic, which would be 2/6 or 2/4 depending
    on whether the two not-done patients are in the denominator and would land in the
    next band either way. The glaucoma and keratopathy bands are arithmetic because
    those rows are scored in every patient.
  phenotype_term:
    preferred_term: Myelinated retinal nerve fiber layer
    term:
      id: HP:0007922
      label: Hypermyelinated retinal nerve fibers
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal
      nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients
      (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic
      findings
    explanation: >-
      Names myelinated retinal nerve fiber in two patients by identifier.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Myelinated nerve fiber layer | − | + | + | − | n.d. | n.d. |
    explanation: >-
      Table I: two positive, two negative, two not done.
- category: Skeletal
  name: Delayed bone age
  description: >-
    Scored positive in all six patients. With the growth retardation it is the skeletal
    half of the phenotype, and the knock-out mouse shows matrix excess at the periosteum
    of femur and vertebra and at the cranial sutures, which is the nearest thing to a
    mechanism any located source offers for it.
  phenotype_term:
    preferred_term: Delayed bone age
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Delayed bone age | + | + | + | + | + | + |
    explanation: >-
      Table I: six of six.
- category: Integumentary
  name: Breast and nipple hypoplasia
  description: >-
    Positive in all four patients assessed, not done in two. HPO separates breast
    hypoplasia from hypoplastic nipples; the source scores them as one row, so this
    entry binds the breast term and names both in the preferred term rather than
    splitting a claim the source does not split.
  phenotype_term:
    preferred_term: Breast and nipple hypoplasia
    term:
      id: HP:0003187
      label: Breast hypoplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Breast and nipple hypoplasia | + | + | + | + | n.d. | n.d. |
    explanation: >-
      Table I: four of four assessed.
- category: Gastrointestinal
  name: Umbilical hernia
  description: >-
    Positive in three of the four patients assessed. An abdominal wall that gives way is
    a connective-tissue finding and sits with the multi-system involvement this entry
    attributes to the matrix defect, though no located source draws that line explicitly
    for the hernia.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  frequency: FREQUENT
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      | Umblical hernia | + | + | + | − | n.d. | n.d. |
    explanation: >-
      Table I: three positive, one negative, two not done. The row label carries the
      source's own misspelling and is quoted as printed.
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    Reported in the wider GAPO literature as an occasional finding rather than in the
    six-patient cohort curated here, and the cardiovascular system is named first among
    the connective-tissue territories this entry's matrix node is offered as explaining.
    This phenotype is the one place in the entry where no exact quote is available, and
    the reason is worth stating: the review sentence that names dilated cardiomyopathy
    interleaves a bracketed citation after every item in its list, and the reference
    validator strips bracketed spans before matching, so no contiguous span of that
    sentence covers the finding; and the primary case report has no abstract in PubMed,
    so its cached record carries only a title. The case report is cited without a
    snippet rather than the claim being dropped or a title being quoted as if it were a
    finding.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:19206158
    reference_title: "GAPO syndrome associated with dilated cardiomyopathy: an unreported association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The primary case report behind the review's mention. No snippet is given because
      PubMed holds no abstract for this record, so there is no body text to quote;
      quoting the title would be quoting a claim rather than a finding. The reference is
      recorded so the phenotype is traceable to its source, and a curator who obtains
      the full text can add the quote.
- category: Respiratory
  name: Pulmonary hypertension
  description: >-
    Reported in the wider literature and, unlike most of the occasional findings, tied
    to an outcome: a patient who died of it at 17 months. Pulmonary involvement is named
    as one of the life-span reducing visceral manifestations of the disorder.
  phenotype_term:
    preferred_term: Pulmonary hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Pulmonary involvement is one of the life-span reducing visceral manifestations
      present in patients with GAPO syndrome and reported in a GAPO patient who had
      pulmonary hypertension that lead to death at the age of 17 months
    explanation: >-
      Both the finding and its consequence in one sentence, which is why this phenotype
      carries a frequency band from the literature rather than from the cohort table.
- category: Auditory
  name: Bilateral sensorineural deafness
  description: >-
    Reported in the wider literature as an occasional finding, with vestibular
    dysfunction described separately. The auditory system is among the connective-tissue
    territories this source names, so the deafness is consistent with the matrix
    hypothesis without being attributed to it by any located source.
  phenotype_term:
    preferred_term: Bilateral sensorineural deafness
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The other occasional findings of GAPO syndrome published in the literature are
      bilateral sensorineural deafness
    explanation: >-
      The first item in the source's list of occasional findings, quoted up to the
      citation marker that follows it.
genetic:
- name: ANTXR1
  gene_term:
    preferred_term: ANTXR1
    term:
      id: hgnc:21014
      label: ANTXR1
  relationship_type: CAUSATIVE
  notes: >-
    ANTXR cell adhesion molecule 1, at 2p13.3, encoding a matrix-interacting adhesion
    protein. It is better known as anthrax toxin receptor 1 — the name records what it
    was first found doing, not what it does — and biallelic loss of function causes
    GAPO syndrome.

    The allelic spectrum spans nonsense, splice, frameshift and missense variants, all
    reported homozygous. One of them is mechanistically distinctive: the splice change
    c.1435-12A>G theoretically encodes a truncated protein with a 118-residue
    neopeptide at its C terminus, which is a different molecular event from
    nonsense-mediated decay even if the clinical result is the same.
  variants:
  - name: c.262C>T (p.Arg88*) and c.505C>T (p.Arg169*)
    description: >-
      Homozygous nonsense variants in the founding cohort, predicted to trigger
      nonsense-mediated mRNA decay and so to abolish the protein.
  - name: c.1435-12A>G (p.Gly479Phefs*119)
    description: >-
      A splicing variant that theoretically encodes a truncated ANTXR1 carrying a
      neopeptide of 118 unique amino acids at its C terminus.
  - name: c.1220_1221insT (p.Ala408Cysfs*2), c.411A>G (p.Gln137Gln), c.1150G>A (p.Gly384Ser)
    description: >-
      Three novel homozygous variants — frameshift, splice site and non-synonymous —
      found by whole exome sequencing in three Turkish kindreds.
  - name: c.410A>T (p.Q137L)
    description: >-
      A missense variant found homozygous in two siblings.
  evidence:
  - reference: PMID:23602711
    reference_title: Mutations in ANTXR1 cause GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The transcript with the splicing mutation theoretically encodes a truncated
      ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C
      terminus.
    explanation: >-
      The distinctive consequence of the splice allele. "Theoretically" is the source's
      word and the protein was not measured.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Exome sequencing analysis identified three novel homozygous mutations including;
      one frame-shift (c.1220_1221insT; p.Ala408Cysfs*2), one splice site (c.411A>G;
      p.Gln137Gln), and one non-synonymous (c.1150G>A; p.Gly384Ser) mutation in the
      ANTXR1 gene.
    explanation: Three further alleles, expanding the spectrum beyond nonsense variants.
  - reference: PMID:27587992
    reference_title: "New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation produces the substitution of a glutamine in position 137 for a
      leucine (c.410A>T, p.Q137L).
    explanation: A missense allele in two homozygous siblings.
animal_models:
- species: Mouse
  genotype: Antxr1 mutant
  publication: PMID:23602711
  description: >-
    The Antxr1-mutant mouse reproduces the dental abnormalities and the
    extracellular-matrix accumulation. It is the evidence that makes the matrix
    hypothesis more than an interpretation of a fibroblast stain, because it shows the
    two features arising together from the same lesion in an animal.
  modeled_mechanisms:
  - target: Extracellular Matrix Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Shows extracellular-matrix accumulation together with the dental phenotype,
      which is the pairing the human matrix hypothesis rests on.
    limitations: >-
      The tissues assessed are enumerated and the ocular system is not among them. The
      knock-out shows a mild to moderate matrix increase in skin at the basal aspects of
      the hair follicles, endometrium, ovaries, periosteum of femur and vertebra,
      cranial sutures, and the periodontal ligament of the incisors, where it produces
      misalignment and dental dysplasia. Two limits follow. The increase is graded mild
      to moderate, against a human phenotype severe enough to prevent tooth eruption
      entirely and to coarsen the face with age. And nothing reports an optic nerve, a
      retinal or a hair-loss finding in the mouse, so the model speaks to the dental and
      connective-tissue arm and is silent on the two human features this entry types as
      least well explained.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The enumerated tissues cover skin, reproductive tract, bone, cranial sutures and
        periodontal ligament. Neither the optic nerve nor hair loss appears, so the two
        human features with the weakest mechanistic account in this entry are also the
        two the model does not report on.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse matrix increase is graded mild to moderate. The human phenotype it is
        offered as a model of prevents tooth eruption outright, so the same lesion is
        producing quantitatively different tissue consequences in the two species.
    evidence:
    - reference: PMID:25045128
      reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        In an Antxr1 knock-out mouse model a mild to moderate increase of extracellular
        matrix (especially collagen) has been observed in many tissues including: the
        skin (basal aspects of the hair follicles), endometrium, ovaries, periosteum of
        femurs and vertebra, cranial sutures of the skull, and the periodontal ligament
        of the incisors that leads to misalignment and dental dysplasia
      explanation: >-
        The tissue-by-tissue enumeration, which is what the limitations field now
        records. The periodontal ligament clause is the mechanistic core of the dental
        edge: matrix excess in the ligament produces misalignment and dental dysplasia
        in the mouse.
    - reference: PMID:23602711
      reference_title: Mutations in ANTXR1 cause GAPO syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        GAPO syndrome's major phenotypic features, which include dental abnormalities
        and the accumulation of extracellular matrix, recapitulate those found in
        Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix
        regulation.
      explanation: >-
        The recapitulation claim and the inference the authors draw from it, in their
        own words.
discussions:
- discussion_id: gapo_craniofacial_gestalt
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does a generalised matrix defect produce a specific and reproducible
    craniofacial pattern rather than diffuse thickening?
  attaches_to:
  - phenotypes#Relative macrocephaly
  - phenotypes#Depressed nasal bridge
  - phenotypes#Long philtrum
  - phenotypes#Micrognathia
  - phenotypes#Low-set ears
  rationale: >-
    Eleven craniofacial features are positive in all six patients of the cohort curated
    here, which is the reason the disorder is recognisable on sight. Two of them, the
    thickened eyelids and the thick lips, have a stated intermediate: subcutaneous
    accumulation increasing with age. The rest do not. Relative macrocephaly, a
    depressed nasal bridge, a long philtrum, micrognathia and low-set ears are
    proportions and positions, not thicknesses, and nothing located explains how
    unresorbed matrix produces them. They are left with no incoming edge rather than
    attached to the accumulation node, because a generalised accumulation predicts
    diffuse thickening and does not predict a reproducible pattern. Two possibilities
    are open and are not distinguished anywhere: that the matrix defect acts during
    craniofacial morphogenesis, where timing and site would make a pattern out of a
    generalised lesion, or that ANTXR1 has a developmental role separate from matrix
    turnover. The Antxr1 knock-out mouse is reported at the cranial sutures but no
    craniofacial morphometry is reported for it.
- discussion_id: gapo_optic_atrophy_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does optic nerve compression by accumulated matrix account for the ocular feature,
    given that it was present in only one of six patients?
  attaches_to:
  - phenotypes#Optic atrophy
  rationale: >-
    There is a stated account, and it is mechanical: matrix accumulating around the
    optic nerve, with thickening of the surrounding dura, compresses it. The gap is not
    that nobody has proposed a route. It is that the proposed route does not fit the two
    things that are actually observed. A compressive lesion produced by matrix that
    accumulates with age predicts a deficit that is progressive, which matches, but it
    also predicts a deficit that is close to universal in a disorder whose matrix defect
    is generalised, and optic atrophy was scored positive in one of six patients here
    and is described in the ophthalmologic literature as not a consistent feature.
    Glaucoma, which is not in the acronym, was more frequent in the same cohort. Either
    the compression is modified by something not identified, or some of what has been
    called optic atrophy in this syndrome is a different optic neuropathy, or the
    acronym has fixed attention on the wrong ocular feature. Nothing located
    distinguishes those.
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      It is concluded that optic nerve pathologies are observed potentially secondary to
      physical compression of the optic nerve by the accumulation of extracellular
      matrix and thickening of the dura matter surrounding the optic nerve
    explanation: >-
      The proposed route, which the earlier version of this gap incorrectly said did not
      exist. It is quoted here so the gap is visibly about the fit of the proposal
      rather than about its absence.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      keratopathy in three patients (BAB5033, BAB5143, and BAB5349), myelinated retinal
      nerve fiber in two patients (BAB5141 and BAB5142) and glaucoma in four patients
      (BAB5033, BAB5143, BAB5348, and BAB5349) were observed as uncommon ophthalmic
      findings
    explanation: >-
      The observation the proposal has to accommodate: in this cohort glaucoma was
      present in four of six patients and keratopathy in three, while optic atrophy was
      present in one. A generalised matrix defect compressing the optic nerve does not
      obviously predict that ordering.
- discussion_id: gapo_neopeptide_allele
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the c.1435-12A>G splice allele behave as a null, or does its 118-residue
    neopeptide add an effect of its own?
  attaches_to:
  - genetic#ANTXR1
  rationale: >-
    The nonsense alleles are predicted to abolish the protein through nonsense-mediated
    decay, and the splice allele is predicted to produce a truncated protein carrying a
    novel C-terminal peptide, which is a different molecular event. The functional
    answer is partly in hand and narrows the question rather than leaving it open: all
    three of the originally reported alleles, the splice allele included, were confirmed
    to behave as null alleles in patient fibroblasts, and immunohistochemistry on
    patient fibroblast lines showed complete loss of the ANTXR1 isoform. What remains is
    narrower and is an assay question. An antibody raised against the normal isoform
    reporting its loss does not establish that no truncated neopeptide-bearing species
    is made, only that the isoform it detects is gone, and a species that is
    functionally null for adhesion could still do something else. With about 30 reported
    patients that distinction will not emerge from clinical correlation.
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Interestingly, all of them produce null alleles as confirmed by functional studies
      with fibroblasts obtained from GAPO patients.
    explanation: >-
      The functional result that answers the first half of the question: the alleles
      were not only predicted to be null, they were confirmed null in patient cells.
      This is the sentence the earlier version of this rationale contradicted.
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      immunohistochemical studies performed on skin fibroblast cell lines obtained from
      GAPO syndrome patients demonstrated complete loss of the ANTXR1 isoform and
      remarkable alterations in the actin cytoskeletal network in affected fibroblasts
    explanation: >-
      The immunohistochemical half. It reports loss of the ANTXR1 isoform, which is why
      the residual question in this gap is about what the antibody could have detected
      rather than about whether the allele is functionally null.
- discussion_id: gapo_alopecia_route
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the alopecia a consequence of matrix accumulation in the dermis, or a separate
    developmental effect of ANTXR1 loss on the hair follicle?
  attaches_to:
  - phenotypes#Alopecia
  rationale: >-
    Alopecia with rarefaction of eyebrows and eyelashes is an ectodermal pattern, and
    the syndrome is classified among the ectodermal dysplasias for that reason, yet the
    proposed mechanism is mesenchymal. Hair follicle development depends on
    epithelial-mesenchymal signalling, so a dermal matrix defect could produce it, and
    one located source does put the matrix in the right place: in the Antxr1 knock-out
    mouse the extracellular-matrix excess is localised to the skin at the basal aspects
    of the hair follicles specifically, among several other tissues. That is a
    localisation, not a demonstration. No source reports whether that mouse loses hair,
    no source tests whether removing the peri-follicular matrix excess rescues anything,
    and the alternative that ANTXR1 has a follicle-intrinsic role is not excluded. The
    gap is therefore about the step from peri-follicular matrix accumulation to hair
    loss, not about whether anyone has looked at the follicle.
  evidence:
  - reference: PMID:25045128
    reference_title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      In an Antxr1 knock-out mouse model a mild to moderate increase of extracellular
      matrix (especially collagen) has been observed in many tissues including: the skin
      (basal aspects of the hair follicles), endometrium, ovaries, periosteum of femurs
      and vertebra, cranial sutures of the skull, and the periodontal ligament of the
      incisors that leads to misalignment and dental dysplasia
    explanation: >-
      The localisation. Among the tissues listed for the knock-out mouse, the skin entry
      is qualified as the basal aspects of the hair follicles, which is the
      peri-follicular compartment this gap is about. The same sentence carries the
      periodontal ligament finding that underpins the dental edge, so it is one
      observation supporting two very differently typed edges.
notes: >-
  The organising claim of this entry is the founding paper's: that GAPO is a
  generalized defect in extracellular-matrix homeostasis. It is quoted as a proposal
  because that is how its authors state it, and the entry's causal edges are typed to
  show how far it actually reaches.

  It reaches furthest for pseudoanodontia. The name carries the mechanistically
  important distinction — the teeth are formed and fail to erupt, which is not tooth
  agenesis — and that is exactly what a clearance defect predicts, and exactly what
  the Antxr1-mutant mouse reproduces alongside the matrix accumulation itself. That
  edge is INDIRECT_KNOWN_INTERMEDIATES. The multi-system connective-tissue involvement
  reported in case series is consistent with it.

  It reaches least far for the ocular features. A route to the optic atrophy is proposed
  and is mechanical, so that edge is typed INDIRECT_KNOWN_INTERMEDIATES; what the
  proposal does not account for is the frequency, and the knowledge gap on that
  phenotype is now about the fit of the compression account rather than about its
  absence. An earlier version of this entry asserted in four places that no source
  proposed any route, which was simply wrong: the sentence is in the cached full text of
  a reference the entry already cited. The entry had been curated from that paper's
  abstract while its full text and patient table sat in the repository, and the same
  mistake produced a VERY_FREQUENT band on a feature the same paper reports in one of
  six patients.

  Two smaller things a later editor should not silently tidy. First, the sources
  disagree about the fourth feature's name: the founding paper says "progressive visual
  impairment" while later sources say "progressive optic atrophy". They are not
  synonyms — visual impairment is the symptom and optic atrophy is a finding — and the
  binding follows the majority usage while the description records the discrepancy.
  Second, the case counts differ between sources (about 35 in 2014, about 30 in 2016).
  Both are quoted rather than averaged, because that is ordinary noise in counting case
  reports and hiding it would imply a precision the literature does not have.

  The gene's name is a historical accident worth knowing: ANTXR1 is anthrax toxin
  receptor 1, named for what it was first found doing rather than for its role here,
  which is as a matrix-interacting adhesion molecule.

  There is no treatments: and no diagnosis: section. Management of GAPO is supportive
  and no located source describes a disease-directed therapy, but that is not the reason
  for the absence: the deep-research run behind this entry stopped at section 8 of its
  template, before the diagnostics, prognosis and treatment sections, so those topics
  were never searched. The gap is an unsearched one rather than a searched and empty
  one, and a later curator should treat it that way.

  No GeneReviews chapter exists for GAPO syndrome; just check-genereviews reports
  NO_CHAPTER against the committed Bookshelf index.
references:
- reference: PMID:23602711
  title: Mutations in ANTXR1 cause GAPO syndrome.
- reference: PMID:25045128
  title: Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
- reference: PMID:19206158
  title: "GAPO syndrome associated with dilated cardiomyopathy: an unreported association."
- reference: PMID:27587992
  title: "New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report."
📚

References & Deep Research

References

4
PMID:23602711
Mutations in ANTXR1 cause GAPO syndrome.
No top-level findings curated for this source.
PMID:25045128
Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.
No top-level findings curated for this source.
PMID:19206158
GAPO syndrome associated with dilated cardiomyopathy: an unreported association.
No top-level findings curated for this source.
PMID:27587992
New ANTXR1 Gene Mutation for GAPO Syndrome: A Case Report.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Record notes

The organising claim of this entry is the founding paper's: that GAPO is a generalized defect in extracellular-matrix homeostasis. It is quoted as a proposal because that is how its authors state it, and the entry's causal edges are typed to show how far it actually reaches. It reaches furthest for pseudoanodontia. The name carries the mechanistically important distinction — the teeth are formed and fail to erupt, which is not tooth agenesis — and that is exactly what a clearance defect predicts, and exactly what the Antxr1-mutant mouse reproduces alongside the matrix accumulation itself. That edge is INDIRECT_KNOWN_INTERMEDIATES. The multi-system connective-tissue involvement reported in case series is consistent with it. It reaches least far for the ocular features. A route to the optic atrophy is proposed and is mechanical, so that edge is typed INDIRECT_KNOWN_INTERMEDIATES; what the proposal does not account for is the frequency, and the knowledge gap on that phenotype is now about the fit of the compression account rather than about its absence. An earlier version of this entry asserted in four places that no source proposed any route, which was simply wrong: the sentence is in the cached full text of a reference the entry already cited. The entry had been curated from that paper's abstract while its full text and patient table sat in the repository, and the same mistake produced a VERY_FREQUENT band on a feature the same paper reports in one of six patients. Two smaller things a later editor should not silently tidy. First, the sources disagree about the fourth feature's name: the founding paper says "progressive visual impairment" while later sources say "progressive optic atrophy". They are not synonyms — visual impairment is the symptom and optic atrophy is a finding — and the binding follows the majority usage while the description records the discrepancy. Second, the case counts differ between sources (about 35 in 2014, about 30 in 2016). Both are quoted rather than averaged, because that is ordinary noise in counting case reports and hiding it would imply a precision the literature does not have. The gene's name is a historical accident worth knowing: ANTXR1 is anthrax toxin receptor 1, named for what it was first found doing rather than for its role here, which is as a matrix-interacting adhesion molecule. There is no treatments: and no diagnosis: section. Management of GAPO is supportive and no located source describes a disease-directed therapy, but that is not the reason for the absence: the deep-research run behind this entry stopped at section 8 of its template, before the diagnostics, prognosis and treatment sections, so those topics were never searched. The gap is an unsearched one rather than a searched and empty one, and a later curator should treat it that way. No GeneReviews chapter exists for GAPO syndrome; just check-genereviews reports NO_CHAPTER against the committed Bookshelf index.

Review round 1: correct a false negative claim, fix optic atrophy frequency, mine TABLE I · 2026-09-17T16:16:33Z · View source

Addressed the ai4c-reviewer CHANGES_REQUESTED review on PR #12044 in one push: two CRITICAL findings, four IMPORTANT ones, and the suggestions. The reviewer diagnosed one root cause behind all of them and was right: the entry was curated from the abstract of PMID:25045128 while the PR committed that paper's PMC full text and TABLE I. CRITICAL 1 - frequency: VERY_FREQUENT on Optic atrophy was contradicted by the entry's own cited source. Changed to OCCASIONAL. TABLE I scores optic atrophy positive in one of six patients, negative in three and not done in two, and the same paper states it is not a consistent feature of the disorder. Both are now quoted as evidence. The supporting quote that was there before is the acronym expansion, which establishes that the feature is named and nothing about how often it is present; it is kept with an explanation that says so. CRITICAL 2 - the claim that no source proposes a route from matrix accumulation to optic nerve damage was false and was asserted in four places: the disease description, the downstream edge, the notes, and the gapo_optic_atrophy_mechanism rationale. The cached full text states that optic nerve pathologies are potentially secondary to physical compression of the nerve by accumulated extracellular matrix and thickening of the surrounding dura. All four places rewritten. The edge is now INDIRECT_KNOWN_INTERMEDIATES with that sentence as its evidence, and the knowledge gap is narrowed to the real problem: a compressive lesion produced by matrix that accumulates with age predicts a progressive and near-universal deficit, and the feature is present in one of six patients while glaucoma, which is not in the acronym, is present in four. IMPORTANT 3 - gapo_neopeptide_allele said neither protein was measured. Contradicted by the statement that all three originally reported alleles produce null alleles as confirmed by functional studies in patient fibroblasts, and by immunohistochemistry showing complete loss of the ANTXR1 isoform. Rationale rewritten and both sentences attached as evidence. The residual question is narrower and is an assay question: an antibody reporting loss of the normal isoform does not establish that no truncated neopeptide-bearing species is made. IMPORTANT 4 - gapo_alopecia_route said no located source makes the dermal-matrix argument. The knock-out mouse's matrix excess is localised to the skin at the basal aspects of the hair follicles specifically. Rationale rewritten, evidence attached, and the gap restated as the step from peri-follicular accumulation to hair loss rather than as an absence of anyone looking. IMPORTANT 5 - animal model limitations claimed the source reports the recapitulation in a single sentence without naming the features assessed. It enumerates skin, endometrium, ovaries, periosteum, cranial sutures and the periodontal ligament of the incisors. Rewritten around that enumeration, the enumeration attached as evidence, and two typed divergences added: BOUNDARY_OMISSION (neither optic nerve nor hair loss is reported, which are exactly this entry's two weakest edges) and SPECIES_MISMATCH (mild to moderate matrix increase in the mouse against a human phenotype that prevents tooth eruption outright). IMPORTANT 6 - phenotype coverage went from 7 to 28. Added from TABLE I with per-row or common-findings-sentence quotes: relative macrocephaly, low-set ears, protruding ears, thickened eyelids, sparse eyebrows, sparse eyelashes, depressed nasal bridge, short nose, anteverted nares, long philtrum, micrognathia, delayed closure of the anterior fontanel, delayed bone age, breast and nipple hypoplasia, umbilical hernia (all VERY_FREQUENT or as scored), glaucoma 4/6, keratopathy 3/6, hypermyelinated retinal nerve fibers 2/6, and from the wider literature dilated cardiomyopathy, pulmonary hypertension and bilateral sensorineural deafness. Frontal bossing and hypertelorism moved from FREQUENT to VERY_FREQUENT on the six-of-six rows. New progression phase for visceral involvement and premature death, with the two reported deaths. Suggestions: Thick lips rebound from HP:0000179 (lower lip only, under a preferred term that also covered eyelids) to HP:0012471 Thick vermilion border, with the eyelid finding split out as its own phenotype. GO:0030198 modifier changed from DECREASED to DYSREGULATED on an accumulation node; the reviewer suggested ABERRANT, which is not a ModifierEnum value. The tooth ankylosis suggestion was declined: HP:0006481 is Abnormal primary tooth morphology, not tooth ankylosis (that is HP:0033791), and no cached reference or the deep-research report mentions ankylosis at all. A notes paragraph records that the absent treatments: and diagnosis: sections are an unsearched gap rather than a searched and empty one, because the deep-research run stopped at section 8. Three edges wired where a source names an intermediate: thickened eyelids and thick lips from the subcutaneous-accumulation-with-age sentence, and delayed fontanel closure from the mouse's cranial suture finding. The other 21 new phenotypes are left with no incoming edge and a fourth knowledge gap, gapo_craniofacial_gestalt, records why: a generalised accumulation predicts diffuse thickening and does not predict a reproducible pattern of proportions and positions. One phenotype carries a reference with no snippet, which is deliberate and explained in place. Dilated cardiomyopathy is named in the cached review only inside a sentence that interleaves a bracketed citation after every list item, and the reference validator strips bracketed spans before matching, so no contiguous span covers it. The primary case report PMID:19206158 was fetched and has no abstract in PubMed. Citing it without a snippet is better than quoting a title as a finding or dropping a real phenotype. Validation: linkml-validate clean, linkml-term-validator clean, 74/74 snippets verified (was 26/26), validate-disorders clean, check-entity-refs / causal-targets / duplicate-keys / qualifier-terms / enum-values / case-collisions / snippet-grading / title-snippets / snippet-length / folded-hyphens / reference-titles all OK, check-genereviews still NO_CHAPTER. Phenotype causal connectivity 7/28, which is lower as a percentage than the 4/7 before because the denominator is now the real one.

Create: GAPO Syndrome (ANTXR1) · 2026-09-17T15:12:57Z · View source

De-novo curation of GAPO syndrome (MONDO:0009263), biallelic ANTXR1 loss of function, from a Perplexity sonar-deep-research run (research/GAPO_Syndrome-deep-research-perplexity.md, 369s, 17 citations). The report was a lead only; all three references were sourced independently through PubMed esearch and every CURIE was looked up in the step it was written. One term needed a source outside the usual path: ANTXR1 has no row in the repository's cache/hgnc/terms.csv, so hgnc:21014 was read from the HGNC REST API (rest.genenames.org/fetch/symbol/ANTXR1) rather than written from memory or taken from the report. The entry is built around how far the founding paper's proposal actually reaches. That proposal - that GAPO is a generalized defect in extracellular-matrix homeostasis - is quoted as a proposal because that is how its authors state it, and the causal edges are typed to show its reach. It reaches furthest for pseudoanodontia, which is INDIRECT_KNOWN_INTERMEDIATES: the teeth are formed and fail to erupt, which is what a clearance defect predicts and what the Antxr1-mutant mouse reproduces alongside the matrix accumulation itself. It reaches least far for the optic atrophy, one of the four features the syndrome is named for, where no located source proposes any route from accumulated matrix to progressive optic nerve damage; that edge and the alopecia edge are INDIRECT_UNKNOWN_INTERMEDIATES and each carries a KNOWLEDGE_GAP. A third gap records that the c.1435-12A>G splice allele's 118-residue neopeptide is a different molecular event from nonsense-mediated decay and that neither protein was measured - both source words are predictions. Two source discrepancies are preserved rather than resolved. The founding paper calls the fourth feature 'progressive visual impairment' while later sources call it 'progressive optic atrophy'; these are not synonyms (symptom versus finding), so the HPO binding follows majority usage and the description records the difference. The case counts differ between sources (about 35 in 2014, about 30 in 2016) and both are quoted rather than averaged, because averaging would imply a precision the literature does not have. Two snippets had to be shortened because the reference validator strips bracketed spans before matching: the founding genotype sentence carries a bracketed protein change per variant, and the multi-system sentence interleaves per-system citation markers. In both cases the quote was trimmed to a clean substring and the dropped content moved into the explanation and into genetic[].variants, rather than the claim being dropped. Validation: just validate passed; 26/26 snippets verified against cached references; just validate-terms passed; check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms and check-title-snippets all OK; 4 of 7 phenotypes causally connected (57.1%) - the three craniofacial features are deliberately left unconnected because no located source ties them to the matrix node. just check-genereviews reports NO_CHAPTER, recorded in the entry's notes.

Perplexity ▸
1. Disease Information
sonar-deep-research 17 citations 2026-09-17T14:25:31.427657

1. Disease Information

Definition and concise overview

GAPO syndrome is a Mendelian, autosomal recessive disorder characterized primarily by severe growth retardation, alopecia or marked hypotrichosis, failure of tooth eruption termed pseudoanodontia, and progressive optic atrophy or other ocular anomalies.[2][3][9][11] The acronym “GAPO” was introduced by Tipton and Gorlin to capture these four cardinal manifestations—Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy—in the first detailed clinical description that distinguished the syndrome from other causes of short stature and ectodermal dysplasia.[9][7] Subsequent case series and reviews have established GAPO syndrome as a multisystem connective tissue disorder with additional skeletal deformities, craniofacial dysmorphism, hernias, ophthalmic complications such as glaucoma, and occasionally cardiovascular or pulmonary involvement.[4][5][11][12][13] The etiologic basis of the disease has been elucidated in the last decade: it is caused by biallelic pathogenic variants in ANTXR1, encoding a cell surface receptor originally identified as Anthrax Toxin Receptor 1 but now recognized as a broader regulator of extracellular matrix homeostasis in endothelial cells and fibroblasts.[1][2][3][15][16] Because of its extreme rarity and recognizable phenotype, GAPO syndrome is primarily documented through case reports and aggregated reviews rather than large clinical cohorts, and its inclusion in rare disease registries underscores its importance as a paradigmatic matrix‑regulation disorder.[3][4][5][8]

Key identifiers and classification

From an identifier and ontology perspective, GAPO syndrome is catalogued in multiple major disease databases. OMIM assigns phenotype entry #230740 to GAPO syndrome, with phenotype mapping key 3 and links it to the ANTXR1 gene locus (OMIM 606410) on chromosome 2p13.3.[2] Orphanet lists the syndrome under Orpha number 2067, describing it as a “rare, genetic, multiple congenital anomalies syndrome characterized by growth retardation, alopecia, pseudoanodontia and ocular manifestations” and explicitly classifies it as autosomal recessive.[3] The National Institutes of Health Genetic and Rare Diseases (GARD) program likewise registers GAPO syndrome as a rare genetic disorder marked by growth delay, alopecia, pseudoanodontia, and ocular involvement.[8] German‑language resources such as the German Wikipedia entry on GAPO‑Syndrom reiterate its classification as an ultra‑rare congenital disease, with estimated frequency below 1 per 1,000,000 and reporting approximately 60 affected individuals historically.[13] In terms of broader ontologies, the disease corresponds to MONDO:0009263 in the Mondo Disease Ontology, where it is classified as a Mendelian disorder of connective tissue and skeletal development, and it maps to ICD‑10 and ICD‑11 under codes used for “other specified congenital malformation syndromes predominantly affecting facial appearance” and rare genetic growth disorders, though no disease‑specific ICD code exists.[3][13] Within MeSH and SNOMED CT, GAPO syndrome is referenced under rare hereditary connective tissue disorders and craniofacial anomalies, reflecting its multisystem nature.

Synonyms and alternative names

Synonymy for GAPO syndrome is relatively limited but clinically relevant. The most common alternative name is “growth retardation–alopecia–pseudoanodontia–optic atrophy syndrome,” which spells out the acronymic components and is frequently used in older case reports and ophthalmologic literature.[2][9][11] Some authors refer to it as “GAPO (growth retardation, alopecia, pseudoanodontia, optic atrophy) syndrome” or “GAPO complex,” emphasizing the combination of features rather than a single organ system.[7][9][11] Because ANTXR1 is also known as Tumor Endothelial Marker 8 (TEM8), the condition is occasionally described in molecular genetics contexts as “ANTXR1/TEM8‑related GAPO syndrome,” especially in exome sequencing and functional studies that link the phenotype to loss of TEM8 function.[3][15][16] However, unlike some other rare syndromes, GAPO syndrome has not accumulated a large set of historical eponyms or geographically localized names, which simplifies terminological mapping for disease knowledge bases.[2][3][4] In the context of ontologies, GAPO syndrome is best captured as a single disease entity with the acronym and full descriptive name treated as preferred and alternate labels.

Source type: individual patients versus aggregated disease‑level data

Nearly all current information on GAPO syndrome arises from aggregated disease‑level resources synthesized from individual case reports, small family series, and, most recently, a systematic review of all published cases.[4][5][9][11] The first decades of literature consisted primarily of single‑patient or sibling case reports that documented the phenotype in detail and proposed autosomal recessive inheritance based on parental consanguinity and recurrence in sibships.[9][11][10] With the advent of next‑generation sequencing, a small number of families were studied in depth, leading to identification of causative ANTXR1 variants through exome sequencing and targeted gene analysis.[15][16] The 2024 comprehensive review by Troxell and colleagues examined 105 cases reported since 1947, integrating clinical, genetic, radiologic, and histologic data into a cohesive picture of the syndrome’s multisystem manifestations and underlying pathophysiology.[4][5] Orphanet, OMIM, GARD, and curated patient information platforms such as FDNA’s rare disease resource compile these primary data into summary descriptions aimed at clinicians and families, further aggregating the evidence base.[2][3][6][8] Large‑scale electronic health record (EHR)–based cohorts do not exist for GAPO syndrome, given its rarity; consequently, epidemiologic estimates and outcome data are inferred from case‑level reports and expert synthesis rather than population‑based registries.[4][5][13] For a disease knowledge base, this means that most assertions about GAPO syndrome will be supported by case report evidence, small genetic series, and high‑quality narrative reviews rather than randomized trials or large observational studies.

2. Etiology

Genetic causal factors

The primary etiologic factor in GAPO syndrome is biallelic, germline loss‑of‑function variants in ANTXR1, which encodes Anthrax Toxin Receptor 1, also known as Tumor Endothelial Marker 8 (TEM8).[1][2][3][15][16] OMIM and Orphanet both specify that homozygous nonsense or splice‑site mutations in ANTXR1 at 2p13.3 cause GAPO syndrome, aligning molecular genetic evidence with the autosomal recessive inheritance pattern inferred from consanguinity and affected siblings in early reports.[2][3] In the landmark genetic study by Stranecky et al., four ethnically unrelated affected individuals underwent exome sequencing, revealing homozygous nonsense mutations c.262C>T (p.Arg88) and c.505C>T (p.Arg169) or a splicing mutation c.1435‑12A>G, all in ANTXR1; functional analyses demonstrated that the nonsense variants trigger nonsense‑mediated mRNA decay, leading to loss of ANTXR1 protein, while the splicing variant produces a truncated protein with a neopeptide tail.[16] A subsequent genomic study of Turkish families by Bayram et al. identified three novel homozygous ANTXR1 mutations—a frameshift insertion (c.1220_1221insT; p.Ala408Cysfs(^)2), a splice‑site change (c.411A>G; p.Gln137Gln), and a missense variant (c.1150G>A; p.Gly384Ser)—again in the homozygous state in affected individuals from consanguineous families.[15] Across all reported families, the pattern is consistent: individuals with GAPO syndrome carry biallelic loss‑of‑function variants in ANTXR1*, while parents are heterozygous carriers who are clinically unaffected, confirming the autosomal recessive mode of inheritance.[2][3][15][16] At the mechanistic level, these variants result in biallelic loss of functional ANTXR1/TEM8, which impairs actin cytoskeletal organization and extracellular matrix turnover in connective tissues, thereby initiating the downstream pathophysiologic cascade leading to the characteristic phenotype.[1][15][16]

Risk factors: genetic and environmental

In the context of GAPO syndrome, genetic risk factors are essentially synonymous with carrier status for pathogenic ANTXR1 variants. Parents who each carry a single disease‑causing allele have a probability of (25\%) of having an affected child at each pregnancy, consistent with classical autosomal recessive inheritance.[3][6] Orphanet and FDNA emphasize that genetic counseling should be offered to at‑risk couples identified as carriers, to inform them of this recurrence risk and allow consideration of reproductive options.[3][6] Early case reports repeatedly noted that affected individuals often arose from consanguineous unions or had affected siblings, leading Tipton and Gorlin and subsequent authors to propose autosomal recessive inheritance decades before the gene was identified.[2][9][11] With the gene discovery, this consanguinity pattern has been confirmed in multiple families from geographically distinct populations (Czech, Egyptian, Sri Lankan, Turkish), where homozygous variants were detected against a background of parental relatedness.[2][15][16] No susceptibility loci or modifier genes outside ANTXR1 have been reported; GAPO syndrome is a fully penetrant Mendelian disorder, and heterozygous carriers do not appear to have clinically significant phenotypes or increased risk of other conditions based on current evidence.[2][15][16]

Environmental risk factors—such as toxin exposure, lifestyle, infections, or occupational hazards—have not been implicated in GAPO syndrome. Case reports and reviews uniformly present GAPO as a congenital or early childhood onset condition without apparent triggers related to environment or behavior.[4][5][9][11] The presence of affected siblings in multiple families and the consistent identification of causative ANTXR1 variants further support the conclusion that GAPO syndrome arises purely from germline genetic defects rather than environmental causes.[2][3][15][16] Consanguinity can be viewed as a demographic risk factor, as it substantially increases the probability that two carriers of the same rare recessive mutation will have children together; several reported families are from populations where consanguineous marriage is more prevalent, such as parts of the Middle East and North Africa.[2][9][15][16] Beyond this, age, sex, diet, and lifestyle have not been shown to alter the risk of developing GAPO syndrome, which is determined at conception by the zygote’s ANTXR1 genotype.

Protective factors and gene–environment interactions

In contrast to some complex diseases, protective genetic or environmental factors have not been identified for GAPO syndrome. There are no reports of individuals with biallelic ANTXR1 loss‑of‑function variants who remain unaffected, implying that penetrance is high or complete, and no modifier alleles have been described that mitigate severity or delay onset.[2][4][5][15][16] Some phenotypic variability exists—for example, optic atrophy is not observed in all patients, and glaucoma, cardiomyopathy, or pulmonary hypertension occur in only subsets—but this variation has not yet been linked to secondary genetic factors or environmental exposures.[11][12][15] The absence of large cohorts and genetic association studies makes it difficult to systematically search for protective influences, and current knowledge relies on small numbers of patients that are inadequate for robust gene–environment interaction analysis.[4][5]

Similarly, there is no evidence of gene–environment interactions in GAPO syndrome in the sense of environmental exposures modifying disease risk in carriers of ANTXR1 variants. The disease appears to arise directly from the biallelic genetic lesion and to follow a relatively stereotyped developmental course, although environmental and clinical management factors likely influence outcomes such as visual preservation, dental function, and cardiopulmonary health.[4][5][11][12] For example, early detection and treatment of glaucoma may prevent progression to severe optic nerve damage, and timely management of cardiomyopathy or pulmonary hypertension could improve survival, but these influences act on disease severity rather than on penetrance or occurrence.[11][12] From a knowledge base standpoint, GAPO syndrome can therefore be classified as a monogenic disease with primary genetic causation and minimal currently known gene–environment modulation, recognizing that future research may uncover subtle modifiers.

3. Phenotypes

Core acronym features: growth retardation, alopecia, pseudoanodontia, optic atrophy

The defining phenotypes of GAPO syndrome correspond to the acronym GAPO, and each has been extensively documented across case reports and reviews. Growth retardation is a universal feature, typically manifesting as severe short stature with delayed bone age evident from infancy.[9][11][13] In Tipton and Gorlin’s original description and subsequent ophthalmologic case series, all reported patients exhibited marked growth deficiency relative to age‑matched norms, often accompanied by radiographic evidence of delayed ossification and abnormal cranial suture development.[9][11] German resources similarly list “erhebliche Wachstumsverzögerung mit verzögertem Knochenalter” as a core clinical criterion.[13] This phenotype can be mapped to HPO terms such as short stature (HP:0004322) and delayed skeletal maturation (HP:0003433), with onset in infancy and progression as a stable but severe growth deficit throughout childhood and adolescence.[9][11][13] The impact on quality of life is substantial, affecting physical capability, self‑image, and potentially contributing to psychosocial challenges, although formal QoL studies have not been conducted.[4][5]

Alopecia or severe hypotrichosis is another hallmark feature, reflecting underlying ectodermal and connective tissue abnormalities. Patients typically present with sparse or absent scalp hair, eyebrows, and eyelashes, sometimes described as atrichia.[7][9][11][13] Orphanet and FDNA highlight alopecia as a key diagnostic sign, and German descriptions emphasize “alopécie (cheveux rares ou absents)” as characteristic.[3][6][7] In a series of ophthalmic cases, white eyelashes were noted in some individuals, interpreted as a sign of “early senility,” which may reflect altered melanocyte or follicle biology secondary to matrix changes.[11] Alopecia in GAPO syndrome corresponds to HPO terms such as alopecia (HP:0001596) and hypotrichosis (HP:0001006), with congenital or early childhood onset and stable expression over time.[7][11][13] Quality of life effects include aesthetic and psychosocial dimensions, as hair loss is highly visible and may contribute to stigma or distress.

Pseudoanodontia—failure of tooth eruption—is perhaps the most distinctive and pathognomonic feature of GAPO syndrome.[2][9][11][14] Pseudoanodontia refers not to absence of tooth germs but to an eruption failure resulting in apparent toothlessness despite the presence of dental structures within the jaw; in GAPO syndrome, both deciduous and permanent teeth may fail to erupt or do so only partially and very late.[9][11][14] Recent dental studies have shown that in these patients, eruption failure is due to ankylosis of the teeth, with abnormal periodontal ligament and surrounding connective tissue, rather than primary agenesis.[14][15] A 2023 report by Troxell et al. described abnormal dental phenotypes, including emerged sets or partial sets of dentitions and a new gene variant associated with erupted teeth in GAPO syndrome, underscoring the spectrum of dental involvement.[14] These features map to HPO terms such as failure of eruption of teeth (HP:0006334), tooth ankylosis (HP:0006481), and hypodontia (HP:0000674) in some cases.[9][11][14] The impact on quality of life is particularly significant, affecting nutrition, speech, aesthetics, and social functioning; many patients require extensive dental and orthodontic interventions to improve mastication and appearance.[4][5][14]

Optic atrophy, the “O” in GAPO, is an important but not universally present feature. Early descriptions emphasized progressive optic atrophy as a key component of the syndrome, and some individuals presented with visual impairment due to optic nerve degeneration.[2][9][10][11] However, a detailed ophthalmologic analysis of all reported cases and four new patients showed that optic atrophy is not constant; it was present in a minority of patients (one of the four new cases and five previous cases), whereas glaucoma and other ocular manifestations were more frequent.[11] The authors concluded that “optic atrophy is not a constant finding in GAPO syndrome” but that glaucoma, buphthalmia, keratopathy secondary to glaucoma, and characteristic facial and eyelid features were common ocular manifestations.[11] Optic atrophy corresponds to HPO:0000648, glaucoma to HPO:0000501, buphthalmos to HPO:0000520, and corneal opacity/keratopathy to HPO:0001092. These ocular features often emerge in early childhood and may progress, leading to visual impairment or blindness if untreated.[10][11] Quality of life impact is profound when vision is significantly affected, limiting education, employment, and independence, and requiring ophthalmologic surveillance and intervention.

Skeletal and growth phenotypes

Beyond generalized growth retardation, GAPO syndrome presents with a set of skeletal and craniofacial anomalies that reflect connective tissue and bone development disturbances. Tipton and Gorlin and later authors described a characteristic craniofacial appearance: high and bossed forehead, midface hypoplasia, flattened orbital rims, and prominent occiput.[7][9][11] German descriptions list “der Schädel präsentiert ein proeminierendes Occiput, ein abgeflachtes Orbitaldach” as typical, and craniosynostosis has been documented in at least one patient requiring surgical repair, highlighting abnormal cranial suture biology.[7][12][13] Radiologic studies and animal models suggest that thickening of periosteum and cranial sutures due to matrix accumulation contributes to these features.[15] Skeletal anomalies extend beyond the skull: delayed bone age, shortened long bones, and sometimes vertebral or femoral abnormalities have been reported, consistent with global skeletal growth impairment.[11][15] In an Antxr1 knockout mouse model, mild to moderate extracellular matrix accumulation was observed in the periosteum of femurs and vertebrae and cranial sutures, leading to skeletal dysplasia that mirrors aspects of GAPO in humans.[15] These phenotypes can be mapped to HPO terms such as craniosynostosis (HP:0001363), midface hypoplasia (HP:0000322), frontal bossing (HP:0002007), and delayed skeletal maturation (HP:0003433). Functional impact includes increased risk of intracranial pressure issues, facial asymmetry, and orthopedic challenges, though systematic studies of functional outcomes are lacking.[4][5][12][15]

Craniofacial, dermatologic, and hernia phenotypes

Craniofacial dysmorphism in GAPO syndrome is distinctive and contributes to clinical recognition. Patients often show a high, bossed forehead, depressed nasal bridge, midface hypoplasia, and a small chin, combined with sparse hair and sometimes thickened skin or soft tissue around the face.[7][9][11][13] Orbital rims may be flattened, contributing to a “deep‑set eyes” appearance; eyelids can appear thickened, and eyebrows may be sparse or absent.[7][11] These features, together with alopecia and dental anomalies, produce a striking facial gestalt that clinicians can identify even among diverse ethnic backgrounds.[4][5] Dermatologic findings include alopecia as discussed, but also skin changes related to extracellular matrix accumulation. Some authors have suggested an elastin defect with secondary collagen alterations, based on histologic studies showing abnormal connective tissue in the dermis and other organs.[11][15] The Orphanet and GARD descriptions emphasize connective tissue involvement as central to the syndrome, and FDNA notes that GAPO is a “rare congenital syndrome affecting the connective tissue in the body.”[3][6][8] Umbilical hernia is frequently reported, attributed to decreased muscle tone or even absence of abdominal musculature, again reflecting connective tissue and muscle anomalies.[7] Hernias correspond to HPO term umbilical hernia (HP:0001537) and may require surgical repair. The overall impact of craniofacial and dermatologic phenotypes on quality of life is considerable, affecting appearance, identity, and sometimes function (e.g., nasal breathing, eyelid closure), though quantitative QoL metrics have not been reported.[4][5]

Ophthalmologic and neurologic phenotypes

Ophthalmologic manifestations are both part of the acronym and extend beyond optic atrophy. In a detailed survey of all reported cases combined with four new patients, all individuals had severe growth retardation, delayed bone age, characteristic facial appearance, alopecia or hypotrichosis, and pseudoanodontia, but ocular findings varied.[11] Glaucoma was present in five cases, including two of the four new patients; buphthalmia and keratopathy secondary to glaucoma were also observed.[11] White eyelashes, reported only in the new cases, were interpreted as potential signs of premature aging or altered follicular melanocyte function.[11] Congenital glaucoma was described in an ophthalmology case report, where GAPO syndrome co‑occurred with congenital glaucoma, reinforcing the association between abnormal connective tissue in ocular structures and intraocular pressure dysregulation.[10] Optic atrophy, while not universal, occurred in several patients and could be secondary to physical compression of the optic nerve by thickened dura mater and excessive extracellular matrix around the optic nerve sheath, as proposed by Gagliardi, Wajntal, Ilker, and others.[15]

Neurologically, most patients do not exhibit major cognitive impairment, but some may have developmental delays, particularly in motor domains, due to short stature, skeletal deformities, and visual deficits.[4][5] Intracranial vascular malformations have been reported in at least one case, and thickening of meninges with matrix accumulation could theoretically predispose to intracranial pressure abnormalities.[12][15] However, systematic neuroimaging data are limited, and neurologic phenotypes remain incompletely characterized. HPO mappings include glaucoma (HP:0000501), optic atrophy (HP:0000648), buphthalmos (HP:0000520), and keratopathy (HP:0001092); congenital glaucoma is a specific term (HP:0007688). These ocular and potential neurologic manifestations can significantly affect quality of life, particularly where vision is compromised, and require early and ongoing ophthalmologic care.[10][11]

Cardiovascular, pulmonary, and other systemic phenotypes

Although initially defined by growth, hair, dental, and ocular features, GAPO syndrome has increasingly been recognized as a multisystem disorder with important cardiovascular and pulmonary manifestations. Case reports and anesthetic management discussions have noted associations with dilated cardiomyopathy, pulmonary hypertension, and intracranial vascular malformations.[12] For example, Kocabay and Mert described GAPO syndrome associated with dilated cardiomyopathy, an “unreported association” suggesting that matrix accumulation in myocardial and vascular connective tissues can lead to structural and functional heart disease.[12] Pulmonary hypertension has also been reported, potentially arising from vascular remodeling and altered matrix in pulmonary arteries.[12] These systemic findings reinforce the notion that ANTXR1/TEM8 plays a role in extracellular matrix regulation across multiple organs, and that its loss can precipitate cardiovascular and pulmonary pathology akin to fibrotic or connective tissue disorders.[4][5][15][16]

Other systemic features include hernias (umbilical, inguinal), as noted above, and possibly reproductive organ involvement, given that Antxr1 knockout mice show matrix accumulation in endometrium and ovaries.[15] However, human data on fertility or gynecologic phenotypes in GAPO syndrome are scarce. Gastrointestinal manifestations are not prominently reported, suggesting that the disease may spare visceral organs to some extent or that such involvement has not been systematically sought.[4][5] HPO terms relevant to systemic manifestations include dilated cardiomyopathy (HP:0001644), pulmonary hypertension (HP:0002093), and intracranial vascular malformation (HP:0005307). These features can have major implications for survival and morbidity, and their presence mandates careful cardiopulmonary evaluation in GAPO patients, especially before anesthesia or major surgery.[12]

Phenotype impact on quality of life and HPO term suggestions

Taken as a whole, the phenotype spectrum of GAPO syndrome severely affects quality of life across multiple domains—physical functioning, sensory perception, nutrition, appearance, and psychosocial well‑being. Short stature and skeletal abnormalities limit physical capacity and may demand orthopedic interventions; alopecia and craniofacial dysmorphism impact body image and social interactions; pseudoanodontia impairs chewing, speech, and appearance; ocular disease endangers vision; and cardiovascular or pulmonary complications can be life‑threatening.[4][5][11][12] Formal quality‑of‑life instruments such as EQ‑5D or SF‑36 have not been reported in this ultra‑rare disease, but extrapolation from similar multisystem disorders suggests substantial decrements in physical and social functioning domains.[4][5]

For knowledge base mapping, core HPO terms should include at minimum: short stature (HP:0004322), delayed skeletal maturation (HP:0003433), alopecia (HP:0001596), hypotrichosis (HP:0001006), failure of eruption of teeth (HP:0006334), tooth ankylosis (HP:0006481), optic atrophy (HP:0000648), glaucoma (HP:0000501), buphthalmos (HP:0000520), umbilical hernia (HP:0001537), frontal bossing (HP:0002007), midface hypoplasia (HP:0000322), craniosynostosis (HP:0001363), dilated cardiomyopathy (HP:0001644), and pulmonary hypertension (HP:0002093). These encode the principal clinical signs and symptoms described across case series and basic research, and they provide a structured vocabulary for integration into phenotype‑based diagnostic and research tools.[2][3][4][5][9][11][12][13][14][15][16]

4. Genetic and Molecular Information

Causal gene: ANTXR1 (TEM8)

The causal gene for GAPO syndrome is ANTXR1 (Anthrax Toxin Receptor 1), also known as Tumor Endothelial Marker 8 (TEM8), located on chromosome 2p13.3 and comprising 22 exons in humans.[1][2][3][15][16] OMIM lists ANTXR1 under MIM number 606410 and associates homozygous mutations in this gene with the GAPO phenotype, while Orphanet similarly states that “homozygous nonsense or splicing mutations in the ANTXR1 gene (2p13.3), encoding anthrax toxin receptor 1, also known as tumor endothelial marker 8 (TEM8) causes GAPO Syndrome.”[2][3] Wikipedia and German sources reiterate that GAPO syndrome arises from mutations in ANTXR1 at 2p13.3, encoding Anthrax Toxin Receptor 1, confirming the gene locus and functional identity.[1][13]

At the protein level, ANTXR1/TEM8 is a type I transmembrane glycoprotein expressed mainly in endothelial cells and fibroblasts, with extracellular domains that bind to ligands including protective antigen, a component of anthrax toxin, and to extracellular matrix components such as collagen.[15][16] The gene has multiple isoforms, which may differ in expression patterns and functional roles, but GAPO syndrome is primarily associated with loss of the full‑length isoform that participates in matrix regulation and actin cytoskeletal organization.[15][16] In knockout mice, Antxr1 deficiency leads to increased extracellular matrix deposition in multiple tissues, supporting its role as a regulator of matrix homeostasis rather than merely an anthrax toxin receptor.[15]

In ontology terms, ANTXR1 corresponds to HGNC symbol ANTXR1, UniProt entry Q9H6X2, and NCBI Gene ID 84168, and it is annotated with GO biological processes such as extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), and regulation of cytoskeleton organization (GO:0051493), reflecting its known roles from genetic and functional studies.[15][16]

Spectrum of pathogenic variants

The pathogenic variant spectrum in ANTXR1 associated with GAPO syndrome consists predominantly of nonsense, frameshift, and splice‑site mutations that cause loss of protein function, with at least one missense variant documented as pathogenic in the homozygous state.[2][3][15][16] Stranecky et al. identified two homozygous nonsense mutations—c.262C>T (p.Arg88) and c.505C>T (p.Arg169)—and a splicing mutation c.1435‑12A>G in four unrelated affected individuals; the nonsense variants were predicted to trigger nonsense‑mediated decay, eliminating ANTXR1 mRNA, while the splicing variant generated a truncated protein with a unique 118‑amino‑acid neopeptide tail.[16] The OMIM entry notes that the R169X (606410.0002) and R88X (606410.0003) nonsense mutations were identified in Czech and Egyptian patients, respectively, and a splice‑site mutation (606410.0004) in a Sri Lankan patient, demonstrating recurrent and private variants across populations.[2]

Bayram et al. performed exome sequencing in five affected individuals from three Turkish families and identified three novel homozygous mutations: a frame‑shift insertion c.1220_1221insT leading to p.Ala408Cysfs(^*)2, a splice‑site change c.411A>G, and a non‑synonymous missense mutation c.1150G>A resulting in p.Gly384Ser.[15] This work expanded the allelic spectrum and provided functional insights, as immunofluorescence analysis of skin fibroblasts from GAPO cases demonstrated aberrant actin cytoskeletal organization and loss of ANTXR1 isoform, consistent with a loss‑of‑function mechanism.[15]

Orphanet and OMIM summarize these findings by stating that GAPO syndrome is caused by “homozygous nonsense or splicing mutations” in ANTXR1, emphasizing loss‑of‑function alleles, but the presence of at least one pathogenic missense variant suggests that missense changes disrupting critical domains or folding can also cause disease when biallelic.[2][3][15][16] All reported variants are germline, inherited from heterozygous parents, with no somatic or mosaic forms documented.[2][15][16] From an ACMG/AMP standpoint, these variants would be classified as pathogenic based on null allele type (nonsense, frameshift, canonical splice‑site), segregation in affected families, functional data showing protein loss or dysfunction, and absence from large population databases.[2][15][16]

Variant types, classification, and population frequencies

Pathogenic ANTXR1 variants in GAPO syndrome fall into several classical variant types: nonsense mutations that create premature stop codons; frameshift insertions or deletions that disrupt the reading frame and lead to truncation; splice‑site mutations that alter RNA splicing, producing aberrant transcripts; and rare missense variants that likely disrupt structural integrity or ligand binding domains.[2][3][15][16] All are located within the coding region or splice junctions of ANTXR1 and operate via a loss‑of‑function mechanism.[16]

Population allele frequencies for these variants are extremely low or absent in large databases such as gnomAD, reflecting the ultra‑rare nature of GAPO syndrome and the deleteriousness of complete ANTXR1 loss.[15][16] The OMIM entry notes that the causative mutations identified in Czech, Egyptian, Sri Lankan, and Turkish families were not present in control databases and occurred in homozygous form only in affected individuals, supporting their pathogenicity.[2][15] Given the rarity of the disease, carrier frequency in the general population is expected to be very low, likely below 1 in several thousand, although precise estimates are unavailable.[3][13]

ClinVar and similar variant repositories, while not explicitly cited in the available search results, would likely classify these alleles as pathogenic or likely pathogenic based on established criteria, but no variants of uncertain significance (VUS) have been reported in association with a GAPO phenotype.[2][15][16] No structural chromosomal abnormalities (e.g., deletions encompassing ANTXR1) have been documented as a mechanism; the pathogenic lesions are point mutations and small indels within the gene locus.[2][15][16]

Somatic versus germline origin and functional consequences

All known GAPO‑associated ANTXR1 variants are germline, present in all tissues of affected individuals, and inherited in an autosomal recessive manner.[2][15][16] There is no evidence that somatic mutations in ANTXR1 cause GAPO syndrome or a phenocopy thereof; somatic ANTXR1 alterations have instead been studied in cancer biology, where TEM8 overexpression may relate to tumor angiogenesis, but this is distinct from the germline loss‑of‑function seen in GAPO.[15][16]

Functionally, the variants lead to various forms of loss of ANTXR1 function. Nonsense and frameshift mutations create premature termination codons that either provoke nonsense‑mediated decay, reducing mRNA levels, or produce truncated proteins that lack essential extracellular or cytoplasmic domains.[16] Splice‑site mutations cause aberrant splicing, resulting in truncated proteins or isoform loss, as demonstrated in functional studies of patient fibroblasts, which show complete loss of the ANTXR1 isoform and marked alteration in actin cytoskeletal microfilament organization.[15] Missense mutations such as p.Gly384Ser may disrupt folding, ligand binding, or membrane trafficking, thereby impairing function even without truncation.[15]

The net consequence is failure of ANTXR1/TEM8 to perform its normal roles in extracellular matrix regulation, collagen interaction, and actin cytoskeleton organization, which in turn leads to progressive extracellular matrix accumulation and connective tissue abnormalities that drive the GAPO phenotype.[1][4][5][15][16]

Modifier genes, epigenetic information, and chromosomal abnormalities

At present, modifier genes influencing GAPO syndrome severity or expression have not been identified. The phenotypic variability observed, such as the presence or absence of optic atrophy, glaucoma, cardiomyopathy, or pulmonary hypertension, has not been systematically correlated with specific genetic backgrounds or additional variants on other genes.[4][5][11][12][15] The small number of world‑wide cases makes detection of modifiers challenging, and no genome‑wide or exome‑wide modifier analyses have been reported.[4][5]

Epigenetic mechanisms—such as DNA methylation or histone modifications affecting ANTXR1 or related matrix‑regulating genes—have not been studied in the context of GAPO syndrome, and no epigenetic signatures specific to this disorder have been described.[4][5][15][16] Similarly, large‑scale chromosomal abnormalities (aneuploidy, translocations, inversions) are not implicated; GAPO patients have otherwise normal karyotypes, and pathogenic lesions are confined to ANTXR1 sequence variants.[2][15][16]

For ontology mapping, GO biological process terms such as extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), and actin cytoskeleton organization (GO:0030036) capture the functional disruption caused by ANTXR1 loss, while GO cellular component terms such as extracellular matrix (GO:0031012), plasma membrane (GO:0005886), and actin cytoskeleton (GO:0015629) reflect the loci of dysfunction.[15][16] No specific epigenetic GO terms have yet been linked, due to absence of research in that area.

5. Environmental Information

Environmental factors and lifestyle influences

GAPO syndrome is a paradigmatic monogenic, germline, autosomal recessive disorder, and environmental factors have not been implicated in its causation. Case reports and reviews consistently describe the syndrome as congenital or early childhood onset, arising in families with consanguinity or unexplained recurrence, without reference to toxic exposures, infections, nutritional deficiencies, or occupational hazards as etiologic or triggering factors.[2][3][4][5][9][11][12] The identification of ANTXR1 mutations as the necessary and sufficient cause of GAPO phenotype in multiple unrelated families further supports the view that environment plays no primary role in disease initiation.[2][15][16]

Lifestyle factors such as smoking, diet, exercise, or alcohol consumption are similarly not documented as influencing risk or severity. Given that onset typically occurs in infancy or early childhood, lifestyle differences later in life cannot be causative; they may, at most, influence cardiovascular or pulmonary outcomes, but such effects are speculative and not studied in the GAPO population.[4][5][12] Infectious agents—bacteria, viruses, fungi, parasites—are not implicated in GAPO syndrome, and there is no evidence of infectious triggers or mimicry.[2][3][4][5][9][11] Therefore, from a disease knowledge base perspective, GAPO syndrome should be categorized as a non‑environmental, non‑infectious Mendelian disease, with risk determined solely by genotype.

6. Mechanism / Pathophysiology

Ordered causal chain from mutation to phenotype

The pathophysiology of GAPO syndrome can be conceptualized as an ordered causal chain running from the initiating genetic lesion to the multisystem clinical manifestations. First, biallelic germline loss‑of‑function variants in ANTXR1 lead to absence or truncation of functional ANTXR1/TEM8 protein on the surface of endothelial cells, fibroblasts, and other connective tissue–associated cells.[2][15][16] Second, loss of ANTXR1 function results in disruption of actin cytoskeletal organization and impaired interaction with extracellular matrix components such as collagen, leading to reduced matrix turnover and altered cell–matrix adhesion; some details are inferred from in vitro fibroblast studies and mouse models rather than directly demonstrated in all human tissues.[1][15][16] Third, this cellular dysfunction leads to progressive accumulation of extracellular matrix—particularly collagen and elastin—in multiple tissues including skin, periosteum, cranial sutures, periodontal ligament, dura mater, and vascular walls, producing thickened connective tissue and fibrosis.[4][5][11][15] Fourth, tissue‑level matrix accumulation causes structural changes such as delayed bone growth, cranial deformities, ankylosed teeth, compressed optic nerves, stiffened myocardium, and remodeled pulmonary arteries, which represent downstream organ‑level pathology.[4][5][11][12][15] Fifth, these organ‑level changes manifest clinically as growth retardation, alopecia, pseudoanodontia, glaucoma, optic atrophy, hernias, cardiomyopathy, pulmonary hypertension, and other features that constitute the GAPO syndrome phenotype.[2][3][4][5][9][11][12][13][14][15][16]

Molecular pathways: ANTXR1/TEM8 and extracellular matrix regulation

At the molecular level, ANTXR1/TEM8 is involved in pathways governing extracellular matrix organization and cell–matrix interactions. Originally characterized as a receptor for protective antigen, a component of anthrax toxin, ANTXR1 also binds collagen and participates in endothelial cell function.[15][16] Knockout and functional studies have led to the hypothesis that ANTXR1 regulates extracellular matrix homeostasis by modulating collagen deposition, matrix turnover, and actin cytoskeleton, although the precise pathways remain incompletely defined.[15][16]

Immunohistochemical and fibroblast culture studies from GAPO patients show complete loss of ANTXR1 isoform and remarkable alterations in the actin cytoskeletal network, resulting in aberrant microfilament organization.[15] The authors of the genetic study concluded that “loss of ANTXR1 function results in progressive extracellular-matrix accumulation that is observed in patients with GAPO syndrome,” and that this finding aligns with observations in Antxr1 mutant mice.[15][16] Histological analyses across reported cases underscore the critical role of excessive extracellular matrix deposition in pathogenesis, providing direct tissue‑level evidence.[4][5]

While specific canonical pathways such as Wnt, MAPK, or PI3K-AKT have not been explicitly mapped in GAPO, GO term annotations and functional inferences suggest involvement of processes like extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), regulation of cell adhesion (GO:0007155), and actin cytoskeleton organization (GO:0030036).[15][16] It is plausible that ANTXR1/TEM8 interacts with integrins or other receptors to modulate focal adhesion formation and matrix internalization, but these mechanisms are inferred from broader literature on TEM8 and not yet demonstrated specifically in GAPO tissues.[15][16]

Cellular processes: actin cytoskeleton, adhesion, and matrix turnover

Cellularly, GAPO syndrome reflects disruptions in actin cytoskeletal dynamics, cell adhesion, and extracellular matrix turnover. Cultured skin fibroblasts from GAPO patients exhibit an aberrant pattern of actin microfilaments, with disorganized cytoskeletal networks that presumably impair normal cell shape, traction forces, and matrix remodeling.[15] This is consistent with ANTXR1’s role as a transmembrane receptor whose cytoplasmic domains interact with cytoskeletal components and whose extracellular domains bind matrix ligands, thereby coordinating cell–matrix mechanics.[15][16]

In mice lacking Antxr1, a mild to moderate increase of extracellular matrix—especially collagen—has been observed in many tissues, including the basal aspects of hair follicles, endometrium, ovaries, periosteum of femurs and vertebrae, cranial sutures of the skull, and periodontal ligament of incisors.[15] These changes indicate reduced matrix degradation and/or increased deposition, possibly due to impaired cell‑mediated matrix turnover and altered expression or activity of matrix metalloproteinases, although specific enzyme changes have not yet been characterized in GAPO.[15][16]

Cell adhesion may also be compromised, as Wikipedia notes that disruption of ANTXR1 function inhibits proper actin network function, leading to degraded cell adhesions and extracellular matrix buildup.[1] Over time, these cellular disturbances translate into tissue‑level fibrosis and abnormal structure. GO process terms relevant to these mechanisms include regulation of cell adhesion (GO:0030155), extracellular matrix organization (GO:0030198), and actin cytoskeleton organization (GO:0030036), while cellular component terms include focal adhesion (GO:0005925) and extracellular matrix (GO:0031012).[1][15][16]

Tissue damage mechanisms: extracellular matrix accumulation and fibrosis

The predominant tissue damage mechanism in GAPO syndrome is progressive extracellular matrix accumulation, which leads to structural and functional derangements akin to fibrosis in multiple tissues.[4][5][11][15][16] Histological findings across reported cases emphasize excessive deposition of collagen and other matrix components in skin, periosteum, cranial sutures, periodontal ligament, and dura mater.[4][5][15] In Antxr1 knockout mice, collagen accumulation in the basal aspects of hair follicles correlates with alopecia, while thickening of cranial sutures and periosteum corresponds to craniosynostosis and skeletal abnormalities.[15] Excess matrix in the periodontal ligament leads to misalignment and dental dysplasia, providing an animal model explanation for pseudoanodontia and tooth ankylosis in human GAPO patients.[15][14]

For the optic nerve, pathologies are thought to be secondary to physical compression by accumulated matrix and thickening of the dura mater surrounding the nerve, as described by Gagliardi, Wajntal, and Ilker.[15] The genetic and histological evidence prompted investigators to propose that “mutations affecting ANTXR1 function are responsible for this disease's characteristic generalized defect in extracellular-matrix homeostasis.”[16] This defect primarily manifests as fibrotic thickening rather than inflammatory destruction, with little evidence of immune‑mediated tissue injury.[4][5][11][15][16]

From a GO perspective, relevant terms include extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), and fibrosis (GO:0061045), while CHEBI terms such as glycosaminoglycans (CHEBI:18085) and collagen peptides could be used to annotate the chemical entities involved in matrix deposition. The net effect of these tissue‑level changes is structural rigidity, compression of adjacent structures (e.g., optic nerve, cranial sutures, myocardial chambers), and impaired function of organs dependent on compliant connective tissue.

Organ‑level pathophysiology for major phenotypes

The tissue‑level processes described above translate into distinctive organ‑level pathophysiology:

In the skeletal system, matrix accumulation in periosteum and cranial sutures leads to delayed ossification, craniosynostosis, and abnormal skull shape, producing frontal bossing, midface hypoplasia, and prominent occiput.[11][12][13][15] Short stature arises from generalized impairment of bone growth due to altered matrix in growth plates and surrounding tissues, though detailed histology of long bones in humans is limited.[4][5][11][15]

In hair follicles and skin, excess matrix around the basal aspects of hair follicles, as seen in Antxr1 knockout mice, likely impairs follicle cycling and hair shaft emergence, resulting in alopecia or hypotrichosis.[15] Thickened dermis and altered elastin and collagen may contribute to the “early senility” impression in some ocular cases, with white eyelashes and aged facial appearance in childhood.[11]

In teeth and periodontal structures, matrix accumulation and ankylosis of periodontal ligament cause failure of tooth eruption, pseudoanodontia, and dental dysplasia. The 2023 dental study noted that deciduous and permanent teeth fail to erupt due to ankylosis, and abnormal dental phenotypes such as partial eruption and misalignment reflect this underlying matrix pathology.[14][15]

In the ocular system, excess connective tissue in sclera, cornea, trabecular meshwork, and optic nerve sheath may disrupt aqueous humor dynamics, leading to glaucoma and buphthalmia, and compress optic nerve fibers, causing optic atrophy.[10][11][15] Histologic studies in some patients have shown thickening of dura mater around optic nerves and matrix accumulation in orbital tissues, consistent with mechanical compression as a pathophysiologic mechanism.[15]

In the cardiovascular system, collagen accumulation in myocardium and vascular walls can stiffen chambers, impair contractility, and raise vascular resistance, contributing to dilated cardiomyopathy and pulmonary hypertension reported in some GAPO patients.[12][15] Intracranial vascular malformations may similarly reflect disordered matrix in vessel walls, although data are sparse.[12][15]

In abdominal and pelvic walls, weakened or abnormal connective tissue gives rise to umbilical hernias and possibly other hernias, as described by early authors.[7][13]

Taken together, these organ‑level manifestations reflect a unified pathophysiologic theme: generalized connective tissue and extracellular matrix dysregulation due to loss of ANTXR1 function, with clinical consequences varying according to tissue type and mechanical demands.

Immune system, metabolic, and epigenetic aspects

The available literature on GAPO syndrome does not highlight a major role for the immune system. There is no evidence of autoimmunity, chronic inflammation, or immunodeficiency as primary mechanisms; histologic studies focus on matrix composition rather than inflammatory infiltrates, and clinical reports do not mention recurrent infections or immune dysregulation as features.[4][5][11][15][16] Thus, GO terms such as immune response (GO:0006955) or inflammatory response (GO:0006954) are not central to the disease mechanism in current understanding.

Metabolic changes are also not prominently reported. There are no documented alterations in energy metabolism, lipid metabolism, or amino acid metabolism specific to GAPO syndrome; laboratory tests, where described, are generally unremarkable aside from structural and functional measures of affected organs.[4][5][12][15] Similarly, epigenetic changes have not been investigated, and there is no evidence of DNA methylation or histone modification patterns specific to GAPO or to ANTXR1 regulation in this context.[4][5][15][16] The pathophysiology appears to reside primarily at the level of matrix biology, cytoskeletal organization, and mechanical cell–tissue interactions rather than metabolic or epigenetic regulation.

Molecular profiling and advanced technologies

Because GAPO syndrome is extremely rare, comprehensive molecular profiling (transcriptomics, proteomics, metabolomics) has not been widely applied to cohorts of patients. The primary molecular data come from exome sequencing used to identify ANTXR1 mutations and from immunohistochemical and fibroblast culture studies in a small number of individuals.[15][16] Stranecky et al. used exome sequencing (whole exome sequencing, WES) to identify causative variants, indicating the utility of this technology for Mendelian gene discovery, but they did not report broader gene expression changes beyond ANTXR1.[16] Bayram et al. combined WES with immunofluorescence analysis of cultured skin fibroblasts, demonstrating aberrant actin cytoskeletal organization and loss of ANTXR1 isoform, but again did not provide transcriptomic or proteomic profiles at scale.[15]

No single‑cell RNA sequencing, spatial transcriptomics, or multi‑omics integration studies have been reported for GAPO syndrome, reflecting both its rarity and the limited number of available patient samples.[4][5][15][16] Functional genomics screens (e.g., CRISPR or RNAi) have not been applied specifically to ANTXR1 in the context of GAPO, although TEM8 has been studied in cancer biology.[15][16] For knowledge base annotation, GAPO syndrome can thus be characterized as having focused molecular evidence (gene sequencing, fibroblast immunohistochemistry, mouse knockouts) rather than comprehensive systems‑level profiling. This suffices to outline a robust mechanistic chain from ANTXR1 loss‑of‑function to extracellular matrix dysregulation and the multisystem phenotype, but leaves room for future research to explore downstream transcriptomic and proteomic changes in more detail.

Cell types and GO/CL ontology mapping

Cell types central to GAPO pathophysiology include fibroblasts, endothelial cells, osteoblasts, periodontal ligament cells, hair follicle keratinocytes and dermal papilla cells, and optic nerve glial cells, among others. Fibroblasts (CL:0000057) are key producers and remodelers of extracellular matrix in skin, periosteum, periodontal ligament, and dura mater, and fibroblast cultures from GAPO patients show ANTXR1 loss and cytoskeletal abnormalities.[15] Endothelial cells (CL:0000115) express TEM8 and contribute to vascular matrix regulation, relevant to cardiovascular and pulmonary manifestations.[15][16] Osteoblasts (CL:0000062) and osteocytes are involved in bone formation and cranial suture biology, and their interaction with matrix is likely altered in GAPO, though direct data are limited.[11][15] Periodontal ligament cells (a fibroblast‑like population) are central to tooth eruption and ankylosis; matrix accumulation in these cells’ environment causes dental dysplasia in mice and pseudoanodontia in humans.[14][15] Hair follicle–associated cells are affected by matrix deposition in the basal region of follicles, leading to alopecia.[15] Optic nerve glial cells and axons are indirectly affected by thickened dura mater and perineural matrix, resulting in compression and eventual optic atrophy in some patients.[10][11][15]

GO biological process terms relevant to these cell type functions include extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), actin cytoskeleton organization (GO:0030036), regulation of cell adhesion (GO:0007155), and tooth eruption (GO:0042472), while CL terms identify the cellular players driving these processes. This ontology mapping allows computational integration of GAPO syndrome into mechanistic disease networks.

7. Anatomical Structures Affected

Organ‑ and system‑level involvement

GAPO syndrome affects multiple organ systems, with primary involvement of the skeletal, integumentary, dental, ocular, cardiovascular, and pulmonary systems. The skeleton, particularly the skull, shows craniofacial abnormalities including frontal bossing, midface hypoplasia, and prominent occiput, as well as delayed bone age and short stature.[9][11][13][15] Anatomically, these correspond to UBERON entities skull (UBERON:0002384), cranial sutures (UBERON:0002379), facial skeleton (UBERON:0002415), and long bones of the limbs (e.g., femur, UBERON:0000981).

The integumentary system is involved via scalp and body hair, with alopecia affecting hair follicles (UBERON:0001627) and skin (UBERON:0002097).[7][11][13][15] Dental structures, including teeth (UBERON:0003457), periodontal ligament (UBERON:0001754), alveolar bone (UBERON:0002500), and jaws (UBERON:0001680), are affected by pseudoanodontia and ankylosis.[9][11][14][15]

Ocular involvement encompasses the eyeball (UBERON:0000970), optic nerve (UBERON:0001043), cornea (UBERON:0001784), sclera (UBERON:0001773), trabecular meshwork, and orbital tissues, with glaucoma, buphthalmia, keratopathy, and optic atrophy as clinical manifestations.[10][11][15]

Cardiovascular involvement affects the heart (UBERON:0000948), specifically myocardium and cardiac chambers, and the vascular system (UBERON:0004111), including pulmonary arteries (UBERON:0002045), leading to dilated cardiomyopathy and pulmonary hypertension.[12][15] Pulmonary involvement includes lungs (UBERON:0002048) and pulmonary vasculature.[12][15]

Abdominal and pelvic walls, including the umbilical region (UBERON:0002541), show hernias due to weakened connective tissue.[7][13] Overall, GAPO syndrome substantially involves the connective tissue framework across multiple organs rather than parenchymal cells per se, aligning with its classification as a connective tissue disorder.[3][4][5][11][15][16]

Tissue and cell types

From a tissue standpoint, GAPO syndrome predominantly affects connective tissue, including dermis, periosteum, cranial sutures, periodontal ligament, dura mater, and vascular adventitia.[4][5][11][15][16] Epithelial, muscular, and nervous tissues are secondarily affected through their dependence on normal connective tissue scaffolds. For example, skeletal muscle of the abdominal wall may be reduced or absent in some patients with hernias, but the primary defect lies in connective tissue composition and strength.[7]

Specific cell populations include fibroblasts (CL:0000057) in dermis, periosteum, and periodontal ligament; endothelial cells (CL:0000115) in vascular endothelium; osteoblasts (CL:0000062) in bone; chondrocytes (CL:0000138) in growth plates; hair follicle keratinocytes and dermal papilla cells (various CL terms); and optic nerve glial cells (astrocytes, oligodendrocytes) surrounded by matrix‑rich meninges.[11][14][15] These cells are responsible for producing, remodeling, and responding to extracellular matrix, and their function is perturbed when ANTXR1 is lost.[15][16]

In terms of tissue classification, HPO and UBERON annotations emphasize connective tissue as the dominant affected type, with secondary involvement of bone, dental tissue, ocular structures, and myocardium. This pattern should guide the knowledge base to categorize GAPO syndrome under connective tissue and skeletal dysplasia disorders.

Subcellular compartments

At the subcellular level, ANTXR1/TEM8 is a plasma membrane (GO:0005886) protein whose dysfunction affects the actin cytoskeleton (GO:0015629), focal adhesions (GO:0005925), and perhaps endocytic pathways involved in matrix uptake and turnover.[15][16] Fibroblast studies show altered actin microfilament organization, implicating cytoskeletal compartments as key loci of disruption.[15] The extracellular matrix (GO:0031012) itself is an anatomical and functional compartment whose composition and organization are altered in GAPO syndrome, with increased collagen and elastin deposition.[4][5][11][15][16]

Other subcellular compartments, such as the nucleus, mitochondria, endoplasmic reticulum, and lysosomes, have not been specifically studied in GAPO syndrome and are not known to be primary loci of dysfunction, though they may be indirectly affected by altered mechanical and signaling environments.[4][5][15][16]

Localization and lateralization

Anatomically, GAPO syndrome manifestations are generally bilateral and symmetric, reflecting a germline genetic defect rather than localized lesions. Alopecia affects the entire scalp and body hair, craniofacial features are symmetric, short stature is generalized, and pseudoanodontia involves both dental arches.[7][9][11][13][14][15] Ocular manifestations such as glaucoma and optic atrophy may sometimes be asymmetric or unilateral at presentation but often involve both eyes over time, given the systemic nature of matrix dysregulation.[10][11] Cardiomyopathy and pulmonary hypertension are global organ processes and not lateralized.[12][15]

Localization is defined by tissue type: cranial sutures, periosteum, periodontal ligament, dermis, dura mater, vascular walls, and hair follicles are key sites of pathological matrix accumulation.[4][5][11][14][15][16] In addition, the umbilical region of the abdominal wall is a common site of hernia due to connective tissue weakness.[7][13] Recognition of these anatomical localizations helps guide diagnostic imaging and biopsies where needed.

8. Temporal Development

Onset patterns

GAPO syndrome is overwhelmingly a congenital or early childhood onset disorder. Growth retardation is typically apparent in infancy, with affected children showing small size and delayed bone age relative to peers.[9][11][13] Alopecia or hypotrichosis is usually present from birth or early infancy, with sparse hair that does not thicken with age.[7][11][13][15] Craniofacial dysmorphism becomes evident in infancy and early childhood, as skull growth and facial development diverge from typical trajectories.[9][11][13]

Dental anomalies, particularly failure of eruption of deciduous teeth, become apparent in late infancy and early childhood when teeth are expected to erupt; pseudoanodontia may be initially suspected when deciduous teeth fail to appear, and is confirmed when permanent teeth likewise fail to erupt or do so very late.[9][11][14] Ocular manifestations such as congenital glaucoma may present in infancy, whereas optic atrophy and other progressive visual impairments tend to arise in later childhood.[10][11][15] Cardiomyopathy and pulmonary hypertension, where present, typically emerge in adolescence or adulthood, though data are sparse.[12][15]

Overall, the onset pattern can be described as chronic and insidious, with certain features (short stature, alopecia, craniofacial dysmorphism) present from birth or infancy, and others (pseudoanodontia, glaucoma, optic atrophy, cardiomyopathy) developing as the child grows.[4][5][9][10][11][12][13][14][15][16]

Progression, stages, and disease course

The progression of GAPO syndrome varies by organ system but is generally slowly progressive rather than rapidly deteriorating. Growth retardation stabilizes at a low percentile; affected individuals remain short throughout life, but linear growth may proceed slowly, reflecting ongoing but impaired skeletal development.[9][11][13] Craniofacial features and alopecia are relatively stable once established, with no dramatic changes after childhood, though “early senility” appearance may become more pronounced.[11]

Dental anomalies progress as teeth fail to erupt, and pseudoanodontia becomes more obvious with age; dental interventions such as surgical exposure or prosthetics can alter appearance and function but do not reverse underlying ankylosis.[14][15] Ocular disease has a more clearly progressive course: congenital glaucoma can lead to buphthalmia, keratopathy, and optic nerve damage over time if untreated, while optic atrophy, when present, tends to progress and may ultimately lead to severe visual impairment or blindness.[10][11]

Cardiomyopathy and pulmonary hypertension may progress to heart failure or right ventricular dysfunction, although detailed longitudinal data are lacking due to rarity.[12][15] Systemic matrix accumulation likely continues throughout life, but its clinical impact is moderated by the slow tempo of connective tissue deposition. Disease duration is lifelong and chronic; there is no remission or cure, and features remain present or evolve slowly over time.[4][5][9][11][12][13][15][16]

Stages can be conceptualized informally as early childhood (dominant features: growth retardation, alopecia, craniofacial dysmorphism, emerging pseudoanodontia), middle childhood and adolescence (consolidation of dental and ocular anomalies, possible development of glaucoma), and adulthood (potential cardiomyopathy, pulmonary hypertension, and long‑term sequelae). However, no formal staging system exists for GAPO syndrome.[4][5]

Critical periods and windows for intervention

Within this chronic course, certain critical periods can be identified that offer windows of opportunity for intervention. Early childhood is critical for diagnosing GAPO syndrome based on growth, hair, craniofacial, and dental features, allowing timely genetic counseling and surveillance for ocular and cardiovascular complications.[3][4][5][6][8][9][11][14][15][16] The period of early ocular development is a window for detecting congenital glaucoma and initiating treatment to preserve vision, as irreversible optic nerve damage can be averted or mitigated by timely intervention.[10][11] Similarly, adolescence and young adulthood may be critical for cardiologic evaluation to identify and manage dilated cardiomyopathy and pulmonary hypertension before they progress to severe heart failure.[12][15]

From a disease management standpoint, these critical periods highlight the importance of longitudinal multidisciplinary follow‑up rather than one‑time diagnosis. However, because GAPO syndrome is rare, no standardized natural history studies or clinical guidelines define these windows formally; they are inferred from case reports and general principles of managing connective tissue and ophthalmic disorders.[4][5][10][11][12][15]

9. Inheritance and Population Characteristics

Inheritance pattern, penetrance, and expressivity

GAPO syndrome follows a classic autosomal recessive inheritance pattern. OMIM and Orphanet both state that GAPO syndrome is autosomal recessive, with homozygous mutations in ANTXR1 causing disease.[2][3] Parental consanguinity and the occurrence of affected siblings in several families, as documented by Tipton and Gorlin in 1984, provided early evidence for this inheritance pattern before the gene was identified.[2][9] Later, exome sequencing and molecular studies confirmed that affected individuals are homozygous for pathogenic ANTXR1 variants, while parents are heterozygous carriers.[2][15][16] FDNA and GARD explain autosomal recessive inheritance to patients and families, noting that two carrier parents have a (25\%) chance of having an affected child with each pregnancy.[6][8]

Penetrance appears to be high or complete, in the sense that every individual known to carry biallelic loss‑of‑function ANTXR1 variants has exhibited GAPO‑like features.[2][4][5][15][16] There are no reports of asymptomatic individuals with homozygous null ANTXR1 alleles. Expressivity, however, is variable, especially regarding ocular and cardiovascular features. For example, the ophthalmologic review concluded that optic atrophy is not a constant finding, and glaucoma is present only in a subset of cases.[11] Cardiomyopathy and pulmonary hypertension are likewise occasional rather than universal.[12][15] Core features—growth retardation, alopecia, pseudoanodontia, craniofacial dysmorphism—have more consistent expressivity.[4][5][9][11][13][14][15][16]

There is no evidence of genetic anticipation (increasing severity in successive generations), as GAPO syndrome is caused by loss‑of‑function point mutations rather than repeat expansions.[2][15][16] Germline mosaicism has not been reported, although it is theoretically possible in any autosomal recessive condition; available families show typical Mendelian segregation with carrier parents and affected offspring.[2][9][15][16]

Epidemiology: prevalence, incidence, and case numbers

GAPO syndrome is ultra‑rare. Early reports in the 1980s and 1990s noted only a handful of patients. Tipton and Gorlin were aware of five published patients when they coined the term GAPO syndrome.[9] Wikipedia, based on literature, states that fewer than 30 cases had been observed before 2011.[1] FDNA mentions that “there have been just 38 identified cases to date,” reflecting an update at the time of their resource creation.[6] German sources report that “über etwa 60 Betroffene” have been described, with frequency estimated at under 1 per 1,000,000.[13]

A recent comprehensive review by Troxell and colleagues examined 105 cases reported in the literature since the first description of GAPO syndrome in 1947, providing the most expansive account of the syndrome’s clinical phenotype and genetic basis.[4][5] This discrepancy between earlier counts and the 105‑case review likely reflects inclusion of historical and less well‑known cases identified through systematic literature search and cross‑referencing. Regardless, the global prevalence remains extremely low, and incidence (new cases per year) is likely in the single digits worldwide.[3][4][5][13] There are no population‑based registries for GAPO syndrome, so these numbers derive from published case reports and reviews rather than epidemiologic surveillance.

From a disease knowledge base perspective, GAPO syndrome should be classified as a very rare disease, with prevalence <1 per 1,000,000 and an evidence base dominated by case reports and small series.[3][4][5][13]

Founder effects, consanguinity, and population distribution

Consanguinity plays a notable role in the occurrence of GAPO syndrome. OMIM highlights that parental consanguinity and affected siblings suggest autosomal recessive inheritance in several cases.[2] Many of the families studied genetically were from populations with higher rates of consanguineous marriage: a Czech family, Egyptian patients, a Sri Lankan patient, and Turkish families.[2][15][16] In each, homozygous ANTXR1 mutations were identified in affected individuals, indicating that consanguinity increases the probability of inheriting two copies of the same rare recessive mutation.[2][15][16]

However, no specific founder mutation has been described. Variants identified across different populations are distinct (e.g., R88X in Egyptian patients, R169X in Czech families, various frame‑shift and splice‑site changes in Turkish families), suggesting multiple independent mutational events rather than a single ancestral allele disseminated widely.[2][15][16] Carrier frequency is unknown but assumed to be extremely low given the rarity of the disease; heterozygous carriers are clinically unaffected and not typically identified outside family studies.[2][3][13][15][16]

Geographically, reported cases originate from diverse regions, including Europe (Czech Republic, Turkey), Middle East and North Africa (Egypt), South Asia (Sri Lanka), and possibly other locales

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 6
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 62
Resolved 54
Unresolved (possible confabulation) 1
Obsolete 3
Unverifiable 4
Terms whose name was checked 2
Terms named correctly 2
Terms named as a different term 0

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0003433 (3 mentions) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0001006 (obsolete Hypotrichosis) (2 mentions) - replaced by HP:0008070
  • HP:0006334 (obsolete Hypoplasia of the primary teeth) (2 mentions) - replaced by HP:0006347
  • UBERON:0001784 (obsolete macula lutea) (1 mention)

Prefixes with no resolver

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