Ablepharon-Macrostomia Syndrome

Mendelian MONDO:0008693 Pathograph 44 Show in embeddings browser ectodermal dysplasia syndrome TWIST2-related disorder

Ablepharon-macrostomia syndrome is a congenital ectodermal dysplasia with multiple malformations, recognisable at birth by severely shortened or apparently absent eyelids (ablepharon), a wide "fish-like" mouth from unfused lateral commissures, first-degree microtia, an underdeveloped or notched nose, thin, wrinkled and redundant skin, sparse or absent scalp hair, eyebrows, eyelashes and lanugo, hypoplastic or absent nipples, and genital anomalies. Cutaneous syndactyly and camptodactyly of the fingers, ventral hernia or other abdominal wall and umbilical anomalies, and absent zygomatic arches occur in a minority. Most affected individuals have normal or near-normal cognition; motor or language delay is reported in some, with variable severity. The eyelid lesion is a deficiency of the anterior lamella rather than true absence of the lids, and it exposes the cornea from the first hours of life, so ocular surface protection and early eyelid reconstruction with skin grafts determine the visual outcome. It is autosomal dominant and caused by a heterozygous substitution of lysine for the conserved glutamic acid at residue 75 (p.Glu75Lys, c.223G>A) in the basic DNA-binding domain of the bHLH transcription factor TWIST2; all seven families in the gene-discovery series carried this one allele. Most cases are de novo; mildly affected parents have transmitted the disorder to more severely affected children, and somatic mosaicism gives a milder phenotype. Glutamine or alanine at the same residue causes the allelic Barber-Say syndrome, and biallelic loss-of-function TWIST2 alleles cause Setleis syndrome. In HeLa cells the Glu75 substitutions alter the genome-wide DNA-binding pattern of TWIST2. Whether the disorder results mainly from interference with the wild-type protein (dominant-negative) or from new target binding (neomorphic) is unresolved, and both models are recorded under mechanistic_hypotheses.

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1
Inheritance
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Pathophys.
47
Phenotypes
2
Hypotheses
4
Gaps
44
Pathograph
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Genes
7
Medical Actions
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Differentials
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Models
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References
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Deep Research
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Classifications

Harrison's Part
DERMATOLOGY GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous TWIST2 p.Glu75Lys causes the disorder. Most probands carry a de novo variant. Before the gene was known, autosomal recessive inheritance had been proposed; familial cases with an affected parent and child, in which the parent was more mildly affected, argued for dominant transmission with variable expression. Somatic mosaicism for a TWIST2 variant gives a milder phenotype, so a mildly affected parent may be mosaic. As for any autosomal dominant disorder, a child of a non-mosaic affected person has a 50 percent chance of inheriting the variant.
Autosomal dominant inheritance
Show evidence (5 references)
PMID:21595001 SUPPORT Human Clinical
"We present the second familial case of ablepharon-macrostomia syndrome in a newborn female and her 22-year-old father making autosomal dominant inheritance more likely than the previously proposed autosomal recessive transmission for this disorder."
Father-to-daughter transmission supporting dominant inheritance.
PMID:11038439 SUPPORT Human Clinical
"The father has facial anomalies that suggest autosomal dominant inheritance."
First familial report; affected siblings whose father has facial anomalies, interpreted as dominant transmission from a mildly affected parent.
PMID:21595001 SUPPORT Human Clinical
"Additionally, the child shows more prominent features of the disorder when compared to her father documenting variable expression and possible anticipation."
A more mildly affected transmitting father. The authors' suggestion of anticipation predates the recognition of parental mosaicism, which explains the same observation.
+ 2 more references
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Mechanistic Hypotheses

2
Glu75Lys interferes with the wild-type TWIST2 pool
twist2_glu75_dominant_negative EMERGING
Evidence balance 4 support
Mutant TWIST2 is proposed to sequester wild-type TWIST2 or other bHLH partners in transcriptionally ineffective complexes. Residual DNA binding is possible, so this model does not require complete loss of promoter occupancy. In C. elegans, the AMS-equivalent Glu29Lys heterozygote perturbs egg laying and target-gene expression while the heterozygous frameshift-null control resembles wild-type. This favors dominant interference over simple dose reduction in that model. It remains unresolved in human craniofacial and dermal tissues, and is not mutually exclusive with a neomorphic effect.
Pathograph links
Altered TWIST2 Genomic DNA-Binding Pattern -> Dysregulated TWIST2-Dependent Mesenchymal Transcription INDIRECT UNKNOWN INTERMEDIATES Mutant-containing TWIST2 complexes are proposed to lose occupancy at normal targets or occupy new sites, altering downstream transcription. The effects in patient mesenchyme and the physiological balance of mutant and wild-type dimers remain unresolved.
Dysregulated TWIST2-Dependent Mesenchymal Transcription -> Hair Follicle Development Deficit INDIRECT UNKNOWN INTERMEDIATES Under the dominant-negative model, reduced effective TWIST2 activity in dermal mesenchyme would impair hair follicle formation, as Twist2 loss does in mice. This edge is a hypothesis: no study has examined hair follicles in AMS, and the allelic Barber-Say substitutions cause the opposite hair phenotype (hypertrichosis).
Show evidence (4 references)
PMID:28369379 SUPPORT Model Organism
"The genetic analysis favors a predominantly dominant-negative mechanism for the action of amino acid substitutions at this highly conserved glutamic acid residue"
Conclusion of the C. elegans allelic series, which included p.Glu75Lys engineered at the equivalent hlh-8 residue.
PMID:27196381 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"The resemblance between the three syndromes is considerable, and likely differences seem larger than they actually are due to insufficiently complete evaluation for all characteristics of the three entities in the past."
Clinical overlap between AMS, Barber-Say and the loss-of-function disorder Setleis syndrome. INDIRECT: resemblance to a loss-of-function phenotype is consistent with, not proof of, a dominant-negative effect.
PMID:30450715 SUPPORT BACKGROUND Human Clinical
"Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively."
A later TWIST1 case report restates the Glu75 alleles as antimorphic, summarising the earlier functional work rather than adding new data.
+ 1 more reference
Glu75Lys gives TWIST2 new genomic targets
twist2_glu75_neomorphic_binding EMERGING
Evidence balance 4 support
Mutant TWIST2 may alter transcription by binding sites that wild-type protein does not occupy. Mutant-only ChIP-seq peaks directly support altered genomic occupancy in HeLa cells. Whether those new targets drive the tissue-specific phenotype, rather than loss of normal binding or both effects, remains unresolved. The worm Glu29Lys allele also produces a sex-myoblast proliferation defect more severe than the null, which the authors interpret as possible interference with another bHLH pathway; this does not establish a specific new human target.
Pathograph links
Altered TWIST2 Genomic DNA-Binding Pattern -> Dysregulated TWIST2-Dependent Mesenchymal Transcription INDIRECT UNKNOWN INTERMEDIATES Mutant-containing TWIST2 complexes are proposed to lose occupancy at normal targets or occupy new sites, altering downstream transcription. The effects in patient mesenchyme and the physiological balance of mutant and wild-type dimers remain unresolved.
Show evidence (4 references)
PMID:33272268 SUPPORT BACKGROUND In Vitro
"Previous studies have shown that the E75K mutation in twsit2 altered the DNA binding activity of itself, leading to both gain of function and dominant-negative effects."
Restates the earlier binding studies of p.Glu75Lys as showing a gain of function alongside the dominant-negative effect. Graded IN_VITRO for the cell-based binding work it summarises.
PMID:26119818 SUPPORT INDIRECT Human Clinical
"Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS."
Different substitutions at one residue give different syndromes, which a residue-specific change in target binding would explain. INDIRECT because the correlation does not itself show new binding.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT In Vitro
"A significant number of binding peaks detected for the mutant TWIST2 proteins were not detected for the wild-type protein"
Marchegiani et al. (2015), PMID:26119818: direct binding evidence underlying the neomorphic hypothesis; disease mediation remains proposed.
+ 1 more reference
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Discussions and Knowledge Gaps

4
Why does lysine at TWIST2 residue 75 give ablepharon with sparse hair, when glutamine or alanine at the same residue gives ectropion with generalized hypertrichosis?
KNOWLEDGE GAP OPEN ams_residue_specific_phenotype_gap
Attached to
phenotypes#Sparse Scalp Hair pathophysiology#Hair Follicle Development Deficit mechanistic_hypotheses#twist2_glu75_neomorphic_binding
The two allelic syndromes differ most in hair and in eyelid severity, yet no study among the references cited here has examined hair follicles, eyelid mesenchyme or target genes in either. The binding comparison of the alleles was done in HeLa cells. The hair follicle node in this entry is therefore hypothetical, and a residue-specific difference in target binding is the leading but untested explanation.
Show evidence (1 reference)
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur in both entities, and general hypertrichosis occurs in BSS."
The opposite hair phenotypes of the two allelic syndromes.
How often does molecularly confirmed AMS cause developmental delay, and is any delay intrinsic to TWIST2 p.Glu75Lys or secondary to visual and hearing impairment and prolonged hospitalisation?
KNOWLEDGE GAP OPEN ams_developmental_outcome_gap
Attached to
phenotypes#Developmental Delay
Older clinically diagnosed series reported delay in about two-thirds of patients. The molecular series documents variable motor and language delays alongside normal development, with two individuals unassessed and one delayed individual having cerebral hemorrhage. Later patient-perspective reports largely describe normal cognition. These are different outcomes and ascertainment frames; sensory impairment and prolonged hospitalization may also affect development. A systematic prospective assessment of genotyped patients is lacking.
Show evidence (3 references)
PMID:11807864 SUPPORT Human Clinical
"Developmental impairment was present in two-thirds of patients but was usually mild."
The higher estimate from a clinically diagnosed series.
PMID:28690482 SUPPORT Human Clinical
"Both are characterized by abnormalities in ectoderm-derived structures and cause a very unusual morphology of mainly the face in individuals with otherwise normal cognition and normal physical functioning."
The later view, from contact with affected individuals, that cognition is normal.
PMID:31462237 SUPPORT Human Clinical
"Her intellectual and motor development was normal."
Normal development in an adult with molecularly confirmed AMS.
Would a heterozygous Twist2 Glu75Lys knock-in mouse reproduce the eyelid, skin and hair phenotype, and which mesenchymal targets would it show to be lost or newly bound?
HUMAN MODEL MISMATCH OPEN ams_model_fidelity_gap
Attached to
animal_models#Zebrafish twist2 p.Glu78Lys base-edited knock-in pathophysiology#Altered TWIST2 Genomic DNA-Binding Pattern pathophysiology#Craniofacial Soft-Tissue Patterning Defect
The functional results for p.Glu75Lys come from overexpressed human protein (zebrafish mRNA injection, tagged protein in HeLa cells), from engineered alleles in the single C. elegans Twist homolog, and from one heterozygous zebrafish twist2 knock-in whose phenotype (jaw and mouth, emaciation) was described qualitatively in a methods paper. None of these organisms has eyelids, hair or mammalian dermis. Twist2 knockout mice model loss of function, which corresponds to Setleis syndrome rather than to this dominant allele. Whether the mechanism is dominant-negative, neomorphic or both cannot be settled until the allele is studied in mammalian mesenchyme. No mammalian knock-in model was found among the references cited here.
Show evidence (1 reference)
PMID:20691403 SUPPORT Human Clinical
"Notably, Setleis syndrome patients and Twist2 knockout mice have similar facial features, indicating the gene's conserved role in mammalian development."
The knockout mouse matches the recessive loss-of-function disorder, not AMS.
Which older reports should be excluded from the AMS phenotype spectrum?
INTERPRETATION RESOLVED ams_historical_case_reclassification
The 2016 critical review excluded the Pellegrino chromosome-18q case (PMID:8834257), the Amor/Savarirayan CNS case (PMID:11746001), the Kallish limb-anomaly case (PMID:22002929), and the Larumbe dental/skin case (PMID:23198177). The authors considered the Kallish phenotype an acrofacial dysostosis, possibly Nager syndrome, and the Larumbe phenotype severe congenital ichthyosis. The Amor/Savarirayan and Kallish cases tested negative for TWIST2 mutations. These exclusions limit the use of older clinically assembled series for phenotype frequencies and prevent transferring case-specific findings or interventions to molecularly defined AMS.
Show evidence (4 references)
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"The patient reported by Kallish et al. ... showed the phenotype of an acrofacial dysostosis, possibly Nager syndrome, and the differences to AMS were too significant to allow inclusion."
De Maria et al. (2016), PMID:27196381: differential reassessment of the Kallish report.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Lastly, the patient reported by Larumbe et al. ... clearly had severe congenital ichthyosis."
De Maria et al. (2016), PMID:27196381: the dental/skin case is excluded from AMS.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"This chromosome imbalance, the less marked eye signs, the pres- ence of supernumerary nipples, cutis laxa, widely spread joint contractures, edema, and marked developmental delay and seiz- ures make it unlikely that this patient should be diagnosed as having AMS."
De Maria et al. (2016), PMID:27196381: reasons for excluding the Pellegrino 18q-rearrangement case.
+ 1 more reference
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Pathophysiology

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TWIST2 p.Glu75Lys Basic-Domain Substitution
Mechanism confidence: Established
A heterozygous substitution of lysine for the conserved glutamic acid at codon 75 of TWIST2 (NM_057179.2 c.223G>A), in the basic region of the bHLH domain that contacts DNA. It was the allele found in all seven AMS families of the gene-discovery series. Glutamine or alanine at the same residue gives Barber-Say syndrome instead, so the substituting amino acid, not only the position, sets the phenotype.
TWIST2 hgnc:20670 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TWIST2 (hgnc:20670). hgnc:20670 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context TWIST2 hgnc:20670 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns TWIST2 (hgnc:20670). hgnc:20670 is a gene from the HUGO Gene Nomenclature Committee. allele_type: SNV zygosity: HETEROZYGOUS
Heterozygous missense p.Glu75Lys (c.223G>A), mostly de novo and occasionally inherited from a mosaic parent. functional_impact_category is left unset deliberately: the primary functional study reports both lost wild-type binding and gained off-target binding and names a dominant-negative and a neomorphic mechanism as alternatives, while the C. elegans allelic series favours a predominantly dominant-negative mechanism. Picking one enum value would assert more than either source does; see mechanistic_hypotheses.
Downstream
Altered TWIST2 Genomic DNA-Binding Pattern The substituted basic domain changes where TWIST2 binds the genome.
Show evidence (3 references)
PMID:26119818 SUPPORT Human Clinical
"We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families."
The same allele recurs across unrelated AMS families.
PMID:31462237 SUPPORT Human Clinical
"She was known for AMS with the specific genetic mutation in the gene TWIST2 (c.223G > A), no pathogenic sequence changes were found in both her parents"
Names the nucleotide change (c.223G>A) in an independently reported case.
PMID:26119818 SUPPORT Human Clinical
"a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS"
The residue-level genotype-phenotype correlation that separates this disorder from Barber-Say syndrome.
Altered TWIST2 Genomic DNA-Binding Pattern
Mechanism confidence: Provisional
In HeLa cells overexpressing tagged TWIST2, the disease alleles changed the genomic binding pattern relative to wild-type. Wild-type TWIST2 had 630 binding peaks with a canonical E-box consensus. Mutants, including p.Glu75Lys, retained only a fraction of wild-type peaks and bound additional sites. This supports both loss of normal binding and acquisition of abnormal binding; the relative contribution of each to human disease remains unresolved. The relevance to endogenous TWIST2 in craniofacial or dermal mesenchyme is provisional because the assay used overexpression in a cancer cell line.
Glu75Lys gives TWIST2 new genomic targets Glu75Lys interferes with the wild-type TWIST2 pool
E-box binding GO:0070888 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased E-box binding (GO:0070888). GO:0070888 is a molecular function from the Gene Ontology. ↓ DECREASED DNA-binding transcription factor activity GO:0003700 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology. ↕ DYSREGULATED
Experimental models
HeLa ChIP-seq of wild-type and mutant FLAG-TWIST2 CELL LINE Direct measurement of genome-wide binding of the AMS mutant protein against wild-type.
Downstream
Dysregulated TWIST2-Dependent Mesenchymal Transcription Mutant-containing TWIST2 complexes are proposed to lose occupancy at normal targets or occupy new sites, altering downstream transcription. The effects in patient mesenchyme and the physiological balance of mutant and wild-type dimers remain unresolved. Glu75Lys interferes with the wild-type TWIST2 pool Glu75Lys gives TWIST2 new genomic targets
Show evidence (4 references)
PMID:26119818 SUPPORT In Vitro
"All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells."
Direct measurement of altered DNA binding by the mutant proteins.
PMID:26119818 SUPPORT Human Clinical
"Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding."
The authors' overall conclusion that altered DNA binding is the disease-relevant lesion; graded HUMAN_CLINICAL because it rests on the patient genetics as well as the cell assay.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT In Vitro
"ChIP-seq showed that the numbers of binding sites for p.Glu75Lys, p.Glu75Gln, p.Glu75Ala, and p.Gln77_Arg78dup TWIST2 were reduced compared to WT TWIST2 and that the mutants bound to many sites not shared with WT TWIST2."
Marchegiani et al. (2015), PMID:26119818, Figure 3B: reduced normal binding and mutant-only binding in HeLa cells.
+ 1 more reference
Dysregulated TWIST2-Dependent Mesenchymal Transcription
Mechanism confidence: Provisional
Expression of the AMS p.Glu75Lys or Barber-Say p.Glu75Gln protein in zebrafish embryos changed the transcriptome relative to wild-type TWIST2 overexpression. The strongest decreases involved extracellular matrix, membrane and cytoskeletal gene sets. These are whole-embryo results, not a patient-mesenchyme transcriptome. Wild-type overexpression itself caused mild developmental defects, so dose and experimental context matter. Homozygous zebrafish carrying the equivalent knock-in allele also showed increased twist2 and pro-inflammatory cytokine expression.
Glu75Lys interferes with the wild-type TWIST2 pool
mesenchymal cell CL:0008019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mesenchymal cell (CL:0008019). CL:0008019 is a cell type from the Cell Ontology. fibroblast of dermis CL:0002551 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast of dermis (CL:0002551). CL:0002551 is a cell type from the Cell Ontology.
skin development GO:0043588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal skin development (GO:0043588). GO:0043588 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Zebrafish embryos injected with mutant human TWIST2 mRNA Zebrafish partially recapitulates Shows that p.Glu75Lys changes developmental transcription relative to wild-type TWIST2.
hlh-8 Glu29 allelic series (C. elegans) Caenorhabditis elegans partially recapitulates Models the molecular character of the residue substitution in a single-Twist background, separating interference with the wild-type product from loss of dose.
Downstream
Dermal Extracellular Matrix Disorganization Reduced expression of extracellular matrix gene sets in mutant-expressing zebrafish and abnormal dermal matrix in affected people suggest a transcriptional route to the tissue lesion. Mediation by particular matrix genes has not been demonstrated in patient tissue.
Eyelid Anterior Lamella Underdevelopment Disturbed TWIST2-directed mesenchymal development is inferred to underlie the eyelid malformation. No cited source demonstrates this step, and the stages of eyelid morphogenesis affected are not known.
Craniofacial Soft-Tissue Patterning Defect The same disturbance is proposed to produce the facial patterning defects of the mouth, nose, ears and malar region.
Hair Follicle Development Deficit Under the dominant-negative model, reduced effective TWIST2 activity in dermal mesenchyme would impair hair follicle formation, as Twist2 loss does in mice. This edge is a hypothesis: no study has examined hair follicles in AMS, and the allelic Barber-Say substitutions cause the opposite hair phenotype (hypertrichosis). Glu75Lys interferes with the wild-type TWIST2 pool
Show evidence (4 references)
PMID:26119818 SUPPORT BACKGROUND Other
"TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues."
The developmental role of TWIST2 on which this node rests, stated as background in the abstract and naming no species, so graded OTHER.
PMID:26119818 SUPPORT Model Organism
"Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes."
Transcriptional effect of the mutant proteins, including p.Glu75Lys, in zebrafish embryos.
PMID:33272268 SUPPORT Model Organism
"Quantitative RT-PCR showed that twsit2 itself expression was indeed increased in homozygous embryos, and the proinflammatory cytokines, Il-1β and tnfa, were found highly expressed."
Expression changes in homozygous zebrafish carrying the AMS-equivalent knock-in (the source spells twist2 as "twsit2").
+ 1 more reference
Dermal Extracellular Matrix Disorganization
Mechanism confidence: Provisional
Skin electron microscopy in affected individuals showed thin, elongated or disrupted elastic fibers, disordered collagen orientation and microfibrillar or amorphous deposits. Reticulodermal collagen staining was abnormal in AMS-7.1 and AMS-7.2, although elastic-fiber staining appeared normal. The tissue abnormality is directly observed; its precise causal relation to TWIST2 target-gene changes and the clinical skin phenotype remains provisional.
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Redundant Skin Presumed tissue basis of lax, redundant skin; no study has tested the link directly.
Thin Skin Presumed tissue basis of the thin skin.
Wrinkled Skin Presumed tissue basis of the excessive wrinkling.
Show evidence (2 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"Electron microscopy of skin biopsies of AMS-7.1 and AMS-7.2 showed thin, disrup- ted elastic fibers with areas of amorphous deposits along abnormally oriented collagen fibers and adjacent areas of microfibrillar proliferation"
Marchegiani et al. (2015), PMID:26119818: direct ultrastructural findings in two affected family members. The PDF line-break hyphenation is retained.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"Masson-Trichrome staining showed abnormal reticulodermal collagen pat- terns in AMS-7.1 and AMS-7.2 ... staining appeared within normal limits"
Collagen organization was abnormal, whereas the elastic-fiber stain appeared normal; ultrastructure and routine staining are distinct readouts.
Eyelid Anterior Lamella Underdevelopment
Mechanism confidence: Provisional
The defining lesion. The eyelids are present but their anterior lamella (skin and orbicularis) is severely short, with shortening of the septum and levator aponeurosis also described, so the lids cannot cover the globe. Clinically this reads as ablepharon, and in milder or mosaic cases as short, hypoplastic lids. Oculoplastic reports stress that the lids are not truly absent, which is why grafting to lengthen the anterior lamella, rather than building a new lid, is effective. PROVISIONAL because no study has traced p.Glu75Lys through eyelid morphogenesis; the link from TWIST2 to the eyelid is inferred from the phenotype and from where TWIST2 is expressed.
eyelid development in camera-type eye GO:0061029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased eyelid development in camera-type eye (GO:0061029). GO:0061029 is a biological process from the Gene Ontology. ↓ DECREASED
eyelid UBERON:0001711 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eyelid (UBERON:0001711). UBERON:0001711 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ablepharon Severe anterior lamellar deficiency presents as apparently absent lids.
Eyelid Hypoplasia Milder deficiency, particularly in mosaic individuals, presents as hypoplastic lids.
Ectropion Anterior-lamellar shortening causes outward turning of the lid margin.
Show evidence (5 references)
PMID:8746822 SUPPORT Human Clinical
"We report one more case showing that the condition is better described as a severe microblepharon because only the anterior lamella of the eyelids is shortened."
Oculoplastic characterisation of the lesion as anterior lamellar shortening.
PMID:11038439 SUPPORT Human Clinical
"Ablepharon-macrostomia syndrome (AMS) is a rare condition comprising severe deficiency of the anterior lamella of both eyelids, abnormal ears, macrostomia, anomalous genitalia, redundant skin, and absence of lanugo."
Defines the eyelid lesion as anterior lamellar deficiency.
PMID:31373987 SUPPORT Human Clinical
"The lids in AMS are not absent and should not be managed with complex reconstructive techniques."
Long-term surgical series concluding the lids are present but deficient.
+ 2 more references
Hair Follicle Development Deficit
Mechanism confidence: Hypothetical
Sparse or absent scalp hair, eyebrows, eyelashes and lanugo are consistent features of AMS and separate it from Barber-Say syndrome, in which the same residue substituted by glutamine or alanine gives generalized hypertrichosis. Twist2 is expressed in dermal mesenchyme and is required for normal hair follicle formation in mice, so impaired follicle induction is the most direct candidate mechanism. HYPOTHETICAL: no hair or scalp histology from an AMS patient has been reported, and the opposite hair phenotypes of the two allelic syndromes show that the lesion is not simple loss of TWIST2 function.
hair follicle development GO:0001942 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased hair follicle development (GO:0001942). GO:0001942 is a biological process from the Gene Ontology. ↓ DECREASED
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sparse Scalp Hair
Absent Lanugo
Absent Eyebrows
Absent Eyelashes
Show evidence (3 references)
PMID:38740788 SUPPORT Model Organism
"Twist2 knockdown on E13 left visible marks at the wound site, inhibited regeneration, and resulted in defective follicle formation."
Experimental loss of Twist2 in fetal mouse skin impairs hair follicle formation; the setting is wound regeneration, not development of the normal pelt.
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur in both entities, and general hypertrichosis occurs in BSS."
The hair phenotype that this node is meant to explain, and its contrast with BSS.
PMID:33994357 SUPPORT INDIRECT Model Organism
"Our knockout analysis reveals that twist2/dermo1 gene functions in the maintenance of the scale shape and organization during development as well as regeneration."
twist2 loss disturbs dermal skin appendages (scales) in zebrafish. INDIRECT because scales are not hair follicles and a knockout is not the human missense allele.
Craniofacial Soft-Tissue Patterning Defect
Mechanism confidence: Hypothetical
The facial gestalt - wide mouth with unfused commissures, first-degree microtia with low-set ears, depressed nasal bridge with underdeveloped alae, widely spaced eyes, flat or absent zygomatic arches and cheek pads at the mouth corners - is attributed to abnormal patterning of the TWIST2-expressing craniofacial mesenchyme. HYPOTHETICAL: this is the primary paper's stated rationale, supported in zebrafish only by non-specific head hypoplasia; the tissue-level mechanism of each feature is unstudied in AMS. The strongest model support is the heterozygous zebrafish twist2 p.Glu78Lys knock-in (the equivalent of human p.Glu75Lys), whose adults develop a protruding jaw and a mouth that does not close.
mouth UBERON:0000165 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in mouth (UBERON:0000165). UBERON:0000165 is an anatomical location from the Uberon multi-species anatomy ontology. nose UBERON:0000004 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in nose (UBERON:0000004). UBERON:0000004 is an anatomical location from the Uberon multi-species anatomy ontology. external ear UBERON:0001691 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in external ear (UBERON:0001691). UBERON:0001691 is an anatomical location from the Uberon multi-species anatomy ontology. zygomatic arch UBERON:0002500 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in zygomatic arch (UBERON:0002500). UBERON:0002500 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Zebrafish twist2 p.Glu78Lys base-edited knock-in Zebrafish partially recapitulates Heterozygous animals show an adult jaw and mouth phenotype, the closest model analogue of the human facial malformation.
Downstream
Incomplete Fusion of the Lateral Oral Commissures
First-Degree Microtia
Low-Set Ears
Depressed Nasal Bridge
Underdeveloped Nasal Alae
Hypertelorism
Aplastic Zygomatic Arch
Malar Flattening
Cheek Pads at the Oral Commissures
Thin Upper Lip Vermilion
Show evidence (1 reference)
PMID:33272268 SUPPORT INDIRECT Model Organism
"Interestingly, heterozygous mutants can survive to adults and be fertile, but most heterozygous adults showed the phenotypes of protruding jaw, unclosed mouth, and emaciated body at about 6 months"
A heterozygous knock-in of the AMS-equivalent residue disturbs jaw and mouth morphology. INDIRECT because the fish jaw is not the human facial soft tissue and no eyelid or ear phenotype can be assessed.
Incomplete Fusion of the Lateral Oral Commissures
Mechanism confidence: Provisional
The wide mouth of AMS is described as a failure of lip fusion at the lateral commissures. PROVISIONAL: based on clinical description, without imaging or histology of the perioral tissues.
lip UBERON:0001833 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lip (UBERON:0001833). UBERON:0001833 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Macrostomia Unfused lateral commissures widen the oral aperture.
Show evidence (1 reference)
PMID:4003491 SUPPORT Human Clinical
"failure of lip fusion that results in an enlarged, fish-like mouth"
States the causal relation between failed lip fusion and the wide mouth.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ablepharon-Macrostomia 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

47
Breast 2
Hypoplastic Nipples HP:0002557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic nipples (HP:0002557). HP:0002557 is a phenotype from the Human Phenotype Ontology.
Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
Show evidence (3 references)
PMID:15103726 SUPPORT Human Clinical
"Additional features include alopecia or sparse hair, hypoplastic malar region, redundant skin, rudimentary nipples, abnormal genitalia."
Rudimentary nipples among the additional features.
PMID:31462237 SUPPORT Human Clinical
"including multiple surgeries for eyelids and ears lobes reconstruction, mastoplasty for mammary glands absence and lips correction"
Absent mammary glands requiring surgery in an adult woman with confirmed AMS.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Nipples small or absent 81 44 ? g Skin thin 44 38 10–50 d"
De Maria et al. (2016), PMID:27196381. Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
Absent Nipples HP:0002561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent nipple (HP:0002561). HP:0002561 is a phenotype from the Human Phenotype Ontology.
Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
Show evidence (3 references)
PMID:29538102 SUPPORT Human Clinical
"A prematurely born male baby presented with severe ablepharon, hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge, coarse and redundant body skin, absent scalp and body hair, lax abdominal wall, absent nipples, camptodactyly, and ambiguous genitalia."
Absent nipples in a severely affected neonate.
PMID:26600791 SUPPORT Human Clinical
"She also had absent nipples, abnormal skin tension throughout her entire body with absence of hair or lanugo, and abnormal genitalia."
Absent nipples in a severely affected infant.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Nipples small or absent 81 44 ? g Skin thin 44 38 10–50 d"
De Maria et al. (2016), PMID:27196381. Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
Digestive 3
Ventral Hernia HP:0002933 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventral hernia (HP:0002933). HP:0002933 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:4003491 SUPPORT Human Clinical
"abnormally shaped ears and nose, absence of lanugo, ventral hernia, and ambiguous genitalia"
Ventral hernia in an early case.
Anteriorly Placed Anus HP:0001545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anteriorly placed anus (HP:0001545). HP:0001545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"AMS-2.39 ... small nails omphalocele, anteriorly placed anus"
Marchegiani et al. (2015), PMID:26119818, Table 1: the subject identifier and terminal cells identify AMS-2.3 (the attached 9 is a citation marker). An anteriorly placed anus also appears in AMS-4.1 and AMS-7.2; these are selected-case observations, not a population frequency.
Omphalocele HP:0001539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Omphalocele (HP:0001539). HP:0001539 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"AMS-7.1 ... low anterior hairline, omphalocele normal"
Marchegiani et al. (2015), PMID:26119818, Table 1: AMS-7.1 other-findings cell followed by normal development. Omphalocele also appears in AMS-2.3 and AMS-7.2.
Ear 3
First-Degree Microtia Microtia, first degree HP:0011266 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microtia, first degree (HP:0011266). HP:0011266 is a phenotype from the Human Phenotype Ontology.
The ten-person molecular series includes related individuals and mosaics; its observed count is not a population prevalence estimate.
Show evidence (3 references)
PMID:26600791 SUPPORT Human Clinical
"This patient had many dysmorphic features consistent with a severe phenotype of ablepharon-macrostomia syndrome (AMS) including a fish-like appearance of the mouth, rudimentary ears, absence of body hair, thin skin, absent nipples, abdominal distension, and genital abnormalities."
Rudimentary ears in a severely affected infant.
PMID:3293678 SUPPORT Human Clinical
"In addition to ablepharon and macrostomia, other anomalies common to all patients include auricular deformity, nasal alar deformity, absence of lanugo hair, dry, ichthyotic skin and ambiguous genitalia."
Auricular deformity common to the early reported patients.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"normal microtia first degree, increased posterior angulation normal sparse normal normal normal"
Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-2.1: first-degree microtia despite otherwise mild findings. Every other AMS row also records first-degree microtia.
Low-Set Ears 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:39792429 SUPPORT Human Clinical
"This condition is characterized by redundant skin, low-set ears, macrostomia, ambiguous genitalia, and underdevelopment of the both upper and lower eyelids."
Low-set ears among the characteristic features.
PMID:29538102 SUPPORT Human Clinical
"A prematurely born male baby presented with severe ablepharon, hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge, coarse and redundant body skin, absent scalp and body hair, lax abdominal wall, absent nipples, camptodactyly, and ambiguous genitalia."
Low-set dysplastic ears in a neonate.
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Bound to the general term because the type of loss is not reported.
Show evidence (2 references)
PMID:11807864 SUPPORT Human Clinical
"Hearing loss, poor hair growth, finger contractures, and growth retardation were also chronic problems."
Hearing loss as a chronic problem in the natural-history series.
PMID:21595001 SUPPORT Human Clinical
"Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities."
Hearing loss among the additional anomalies.
Eye 11
Exposure Keratitis HP:0000491 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exposure keratitis, annotated with Keratitis (HP:0000491), qualified as neonatal onset. HP:0000491 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Bound to the general Keratitis term, as in the Barber-Say_Syndrome entry: runoak -i ols:hp search "Exposure keratopathy" and search "Corneal exposure" returned no hits when re-run on 2026-09-25. The exposure mechanism is carried in preferred_term and the sequelae edges.
Sequelae: Corneal Ulceration
Show evidence (2 references)
PMID:29538102 SUPPORT Human Clinical
"Despite intensive ocular lubrication, severe exposure keratopathy developed within the first days after birth."
Neonatal exposure keratopathy despite lubrication.
PMID:26600791 SUPPORT Human Clinical
"Upon presentation, there was severe exposure keratopathy causing large bilateral sterile ulcers culminating in corneal melting of both eyes."
Severe exposure keratopathy progressing to ulceration in an infant.
Corneal Ulceration HP:0012804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal ulceration (HP:0012804). HP:0012804 is a phenotype from the Human Phenotype Ontology.
Sequelae: Corneal Opacity
Show evidence (1 reference)
PMID:38967579 SUPPORT BACKGROUND Human Clinical
"Timely intervention is critical to prevent exposure keratopathy, corneal ulceration, and permanent vision loss."
Names corneal ulceration as a complication of untreated exposure.
Corneal Opacity FREQUENT HP:0007957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal opacity (HP:0007957). HP:0007957 is a phenotype from the Human Phenotype Ontology.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Sequelae: Visual Impairment
Show evidence (2 references)
PMID:4003491 SUPPORT Human Clinical
"Corneal opacities present initially improved in one eye, allowing a view of the pupil and a normal anterior chamber."
Corneal opacities in an infant with AMS, improving after lid reconstruction.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"continuous exposure may cause corneal clouding occurring in half of the patients with AMS."
De Maria et al. (2016), PMID:27196381. The review explicitly reports corneal clouding in half of accepted AMS cases.
Visual Impairment FREQUENT HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (3 references)
PMID:11807864 SUPPORT Human Clinical
"Many have persistent visual problems, often related to early corneal exposure."
Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
PMID:2036354 SUPPORT Human Clinical
"One such case is reported which illustrates the importance of immediate postnatal ocular management to minimise severe visual loss."
Severe visual loss as the outcome early management aims to prevent.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Visual impairments have been reported in almost one-third of patients. Photophobia may occur"
De Maria et al. (2016), PMID:27196381. The ocular discussion reports visual impairment in almost one-third; this is a literature cohort, not a population estimate.
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.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (3 references)
PMID:33055564 SUPPORT BACKGROUND Human Clinical
"Features of AMS include ablepharon, hypertelorism, macrostomia, dysplastic ears, sparse body hair, and ambiguous genitalia."
Hypertelorism listed among the features of AMS.
PMID:29538102 SUPPORT Human Clinical
"A prematurely born male baby presented with severe ablepharon, hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge, coarse and redundant body skin, absent scalp and body hair, lax abdominal wall, absent nipples, camptodactyly, and ambiguous genitalia."
Hypertelorism in a severely affected neonate.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Hypertelorism 88 81 ? Small/absent eyelids 69/6 19/75 10–50"
De Maria et al. (2016), PMID:27196381. Table IV reports hypertelorism in 81% of accepted AMS cases.
Alacrima HP:0000522 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alacrima (HP:0000522). HP:0000522 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Alacrimia was present in two AMS patients"
De Maria et al. (2016), PMID:27196381: the lacrimal-system section identifies the Cesarino and Rohena reports.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Strabismus was also present in three BSS patients ... and three AMS patients"
De Maria et al. (2016), PMID:27196381: the AMS count is distinguished from the separate Barber-Say count.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:4003491 SUPPORT Human Clinical
"Nystagmus was severe. The retina was attached in one eye and detached in the other."
The 1985 report describes these ocular complications in one clinically diagnosed child.
Retinal Detachment HP:0000541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal detachment (HP:0000541). HP:0000541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:4003491 SUPPORT Human Clinical
"The retina was attached in one eye and detached in the other."
Unilateral retinal detachment in the Hornblass/Reifler case accepted by the 2016 review.
Microcornea HP:0000482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcornea (HP:0000482). HP:0000482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26600791 SUPPORT Human Clinical
"Corneal diameters were 7 mm OD and 8 mm OS."
Direct ocular measurements in the clinically diagnosed 2015 case; not a prevalence estimate.
Photophobia HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Visual impairments have been reported in almost one-third of patients. Photophobia may occur"
De Maria et al. (2016), PMID:27196381. The review names photophobia among ocular manifestations without assigning it the preceding visual-impairment frequency.
Genitourinary 2
Ambiguous Genitalia HP:0000062 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ambiguous genitalia (HP:0000062). HP:0000062 is a phenotype from the Human Phenotype Ontology.
No frequency band. The 2002 series (PMID:11807864) reports abnormal genitalia in every patient without saying how many were ambiguous.
Show evidence (2 references)
PMID:29538102 SUPPORT Human Clinical
"A prematurely born male baby presented with severe ablepharon, hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge, coarse and redundant body skin, absent scalp and body hair, lax abdominal wall, absent nipples, camptodactyly, and ambiguous genitalia."
Ambiguous genitalia in a severely affected boy.
PMID:39792429 SUPPORT Human Clinical
"This condition is characterized by redundant skin, low-set ears, macrostomia, ambiguous genitalia, and underdevelopment of the both upper and lower eyelids."
Ambiguous genitalia among the characteristic features.
Hypoplastic Labia Majora HP:0000059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic labia majora (HP:0000059). HP:0000059 is a phenotype from the Human Phenotype Ontology.
Table IV combines small labia majora and small scrotum (56%); this is not a female-specific labial frequency.
Show evidence (2 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"hypoplastic labia majora small nails omphalocele"
Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-2.3, spanning genitalia, hands and other columns. The genital finding also appears in AMS-2.2 and AMS-4.1; the ambiguous sex/genital description in AMS-7.2 is not used for this assignment.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Small labia majora or scrotum 13 56 10–50 h Small or ambiguous genitalia 6 38 —"
De Maria et al. (2016), PMID:27196381. Table IV combines small labia majora and small scrotum (56%); this is not a female-specific labial frequency.
Head and Neck 14
Ablepharon FREQUENT HP:0011224 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ablepharon (HP:0011224), qualified as congenital onset. HP:0011224 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (4 references)
PMID:31373987 SUPPORT Human Clinical
"In 60% of the cases, the lids were described as absent."
Literature review of 15 published patients; the basis for the FREQUENT band.
PMID:4003491 SUPPORT Human Clinical
"The ablepharon macrostomia syndrome is a severe congenital condition that includes total absence of the upper and lower eyelids"
Early case description of apparently absent upper and lower lids.
PMID:33055564 SUPPORT BACKGROUND Human Clinical
"Features of AMS include ablepharon, hypertelorism, macrostomia, dysplastic ears, sparse body hair, and ambiguous genitalia."
Ablepharon listed first among the features of AMS.
+ 1 more reference
Eyelid Hypoplasia Hypoplasia of eyelid HP:0430009 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microblepharon, annotated with Hypoplasia of eyelid (HP:0430009). HP:0430009 is a phenotype from the Human Phenotype Ontology.
Table 1 describes severe bilateral eyelid hypoplasia in AMS-1.1, AMS-6.1 and AMS-7.1, and a right-upper-eyelid defect in mosaic AMS-2.1. The other six individuals have bilateral ablepharon. These descriptions reflect a selected molecular series and the clinical continuum of anterior-lamellar deficiency.
Show evidence (3 references)
PMID:21595001 SUPPORT Human Clinical
"Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients."
Short rather than absent eyelids in part of the reported patients.
PMID:34092176 SUPPORT Human Clinical
"Mosaic expression of TWIST2 variants is correlated with a less severe phenotype than that reported for the typical expression of TWIST2 variants associated with BSS or AMS."
Mosaic individuals present at the milder end of the eyelid spectrum.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"AMS-1.120 p.Glu75Lys M severe hypoplastic eyelids bilateral"
Marchegiani et al. (2015), PMID:26119818. Table 1: severe bilateral eyelid hypoplasia in AMS-1.1. The attached 20 is the original-report citation marker.
Ectropion VERY_FREQUENT HP:0000656 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ectropion (HP:0000656). HP:0000656 is a phenotype from the Human Phenotype Ontology.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Sequelae: Lagophthalmos
Show evidence (2 references)
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Corneal clouding 6 50 ? Ectropion 81 94 ? Entropion — 6 10–50"
De Maria et al. (2016), PMID:27196381. Table IV columns are BSS, AMS and Setleis syndrome; the AMS ectropion value is 94%.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"anterior lamella causes ectropion, causing in turn lagophtalmus, which may need surgical correction"
De Maria et al. (2016), PMID:27196381. The ocular discussion explicitly describes anterior-lamellar deficiency causing ectropion and then incomplete lid closure.
Lagophthalmos HP:0030001 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lagophthalmos (HP:0030001). HP:0030001 is a phenotype from the Human Phenotype Ontology.
Sequelae: Exposure Keratitis
Show evidence (1 reference)
PMID:31373987 SUPPORT Human Clinical
"At long-term follow-up, all 3 cases who underwent upper eyelid lengthening with full thickness skin grafts placed over Müller muscle had clear corneas with a small amount of lagophthalmos."
Residual lagophthalmos after lid lengthening in three patients.
Absent Eyelashes HP:0000561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent eyelashes (HP:0000561). HP:0000561 is a phenotype from the Human Phenotype Ontology.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence. Sparse or absent eyebrows and eyelashes were each recorded in 100%; that combined value is not assigned to this narrower absence phenotype.
Show evidence (3 references)
PMID:11807864 SUPPORT Human Clinical
"These four patients, as well as those previously reported, all had absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia."
The historical mixed series described absent brows and lashes; its denominator includes cases subsequently excluded from AMS.
PMID:34850759 SUPPORT Human Clinical
"He was dysmorphic with absent eyelids, eyelashes and eyebrows, large fish-shaped mouth, hyperpigmented thick anterior abdominal wall, absent prepuce amongst other features."
Absent eyelashes in a neonate.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Eyelashes sparse or absent 69 b 100c 50–100 f Hypertrichosis general 94 — —"
De Maria et al. (2016), PMID:27196381. Table IV records the combined sparse-or-absent category in 100% of accepted AMS cases; footnote c says mainly absent. It does not provide a separate numerical frequency for complete absence.
Absent Eyebrows HP:0002223 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent eyebrow (HP:0002223). HP:0002223 is a phenotype from the Human Phenotype Ontology.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence. Sparse or absent eyebrows and eyelashes were each recorded in 100%; that combined value is not assigned to this narrower absence phenotype.
Show evidence (3 references)
PMID:11807864 SUPPORT Human Clinical
"These four patients, as well as those previously reported, all had absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia."
The historical mixed series described absent brows and lashes; its denominator includes cases subsequently excluded from AMS.
PMID:34850759 SUPPORT Human Clinical
"He was dysmorphic with absent eyelids, eyelashes and eyebrows, large fish-shaped mouth, hyperpigmented thick anterior abdominal wall, absent prepuce amongst other features."
Absent eyebrows in a neonate.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Eyebrows sparse or absent 63 b 100c 50–100 e Eyelashes sparse or absent 69 b 100c 50–100 f"
De Maria et al. (2016), PMID:27196381. Table IV records the combined sparse-or-absent category in 100% of accepted AMS cases; footnote c says mainly absent. It does not provide a separate numerical frequency for complete absence.
Sparse Scalp Hair FREQUENT HP:0002209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse scalp hair (HP:0002209), qualified as congenital onset. HP:0002209 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (4 references)
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur in both entities, and general hypertrichosis occurs in BSS."
Sparse scalp hair as the AMS-specific hair feature.
PMID:11807864 SUPPORT Human Clinical
"These four patients, as well as those previously reported, all had absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia."
Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
PMID:11807864 SUPPORT Human Clinical
"Hearing loss, poor hair growth, finger contractures, and growth retardation were also chronic problems."
Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
+ 1 more reference
Macrostomia VERY_FREQUENT Wide mouth HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrostomia, annotated with Wide mouth (HP:0000154), qualified as congenital onset. HP:0000154 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (3 references)
PMID:11807864 SUPPORT Human Clinical
"These four patients, as well as those previously reported, all had absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia."
Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
PMID:34850759 SUPPORT Human Clinical
"He was dysmorphic with absent eyelids, eyelashes and eyebrows, large fish-shaped mouth, hyperpigmented thick anterior abdominal wall, absent prepuce amongst other features."
A large fish-shaped mouth in a neonate.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Wide mouth 100 81 1–10 Cheek pads 38 69 1–10"
De Maria et al. (2016), PMID:27196381. Table IV records wide mouth in 81% of accepted AMS cases.
Thin Upper Lip Vermilion FREQUENT HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (2 references)
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"Major facial characteristics present in both entities, albeit often in differing frequencies, are excessive facial creases, hypertelorism, underdevelopment of the anterior part of the eyelids (anterior lamella), ectropion, broad nasal ridge and tip, thick and flaring alae nasi, protruding..."
Thin upper vermilion among the major facial characteristics of both syndromes.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Cheek pads 38 69 1–10 Thin upper vermillion 88 50 —"
De Maria et al. (2016), PMID:27196381. Table IV reports thin upper lip vermilion in 50% of accepted AMS cases.
Depressed Nasal Bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flattened nasal bridge, annotated with Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26600791 SUPPORT Human Clinical
"Other facial abnormalities were a sloped forehead, hypertelorism, flattened nasal bridge, macrostomia, micrognathia, deformed ear lobes, thin upper lip with a long philtrum, and reduced hair of the scalp and eyebrows"
Flattened nasal bridge in a severely affected infant.
Underdeveloped Nasal Alae HP:0000430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Underdeveloped nasal alae (HP:0000430). HP:0000430 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:3293678 SUPPORT Human Clinical
"In addition to ablepharon and macrostomia, other anomalies common to all patients include auricular deformity, nasal alar deformity, absence of lanugo hair, dry, ichthyotic skin and ambiguous genitalia."
Nasal alar deformity common to the early reported patients.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"macrostomia under- developed ala nasi microtia first degree, high- frequency hearing loss"
Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-6.1, spanning mouth, nose and ear columns.
Aplastic Zygomatic Arch HP:0034260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplastic zygomatic arch (HP:0034260). HP:0034260 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:3293678 SUPPORT Human Clinical
"A new feature of the syndrome is described--absence of the zygomatic arches."
Original description of absent zygomatic arches in AMS.
PMID:21595001 SUPPORT Human Clinical
"Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities."
Absent zygomatic arches among the additional anomalies.
Malar Flattening HP:0000272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malar hypoplasia, annotated with Malar flattening (HP:0000272). HP:0000272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15103726 SUPPORT Human Clinical
"Additional features include alopecia or sparse hair, hypoplastic malar region, redundant skin, rudimentary nipples, abnormal genitalia."
Hypoplastic malar region among the additional features.
Cleft Nasal Alae Cleft ala nasi HP:0003191 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft ala nasi (HP:0003191). HP:0003191 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"depressed nasal bridge, cleft ala nasi"
Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-3.1 and AMS-4.1 nose columns; the table also records cleft alae in AMS-5.1. Row assignments were checked on the PDF page.
Integument 6
Absent Lanugo HP:0034262 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent lanugo (HP:0034262). HP:0034262 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11038439 SUPPORT Human Clinical
"Ablepharon-macrostomia syndrome (AMS) is a rare condition comprising severe deficiency of the anterior lamella of both eyelids, abnormal ears, macrostomia, anomalous genitalia, redundant skin, and absence of lanugo."
Absent lanugo among the defining features.
PMID:21595001 SUPPORT Human Clinical
"Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients."
Absent lanugo among the characteristic features.
Redundant Skin HP:0001582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Redundant skin (HP:0001582). HP:0001582 is a phenotype from the Human Phenotype Ontology.
Skin descriptions vary: the molecular series includes redundant, thin or wrinkled skin, while the mildly affected mosaic individual AMS-2.1 has normal skin recorded in Table 1. A universal frequency is therefore not assigned.
Show evidence (2 references)
PMID:11807864 SUPPORT Human Clinical
"These four patients, as well as those previously reported, all had absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia."
Redundant skin in all patients reported up to 2002.
PMID:39792429 SUPPORT Human Clinical
"This condition is characterized by redundant skin, low-set ears, macrostomia, ambiguous genitalia, and underdevelopment of the both upper and lower eyelids."
Redundant skin listed first among the characteristic features.
Thin Skin HP:0000963 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin skin (HP:0000963). HP:0000963 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26600791 SUPPORT Human Clinical
"This patient had many dysmorphic features consistent with a severe phenotype of ablepharon-macrostomia syndrome (AMS) including a fish-like appearance of the mouth, rudimentary ears, absence of body hair, thin skin, absent nipples, abdominal distension, and genital abnormalities."
Thin skin in a severely affected infant.
Wrinkled Skin Excessive wrinkled skin HP:0007392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Excessive wrinkled skin (HP:0007392). HP:0007392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"Major facial characteristics present in both entities, albeit often in differing frequencies, are excessive facial creases, hypertelorism, underdevelopment of the anterior part of the eyelids (anterior lamella), ectropion, broad nasal ridge and tip, thick and flaring alae nasi, protruding..."
Excessive facial creases among the major facial characteristics.
Dry Skin HP:0000958 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dry skin (HP:0000958). HP:0000958 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:3293678 SUPPORT Human Clinical
"In addition to ablepharon and macrostomia, other anomalies common to all patients include auricular deformity, nasal alar deformity, absence of lanugo hair, dry, ichthyotic skin and ambiguous genitalia."
Dry, ichthyotic skin common to the early reported patients.
PMID:21595001 SUPPORT Human Clinical
"Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities."
Dry skin among the additional anomalies.
Blaschko-line Hyperpigmentation Linear Hyperpigmentation along Blaschko's lines HP:6000010 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Linear hyperpigmentation along Blaschko lines, annotated with Linear Hyperpigmentation along Blaschko's lines (HP:6000010). HP:6000010 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"Shoulder photographs of AMS-6.1 and AMS-7.1 highlight Blaschko-like hyperpig- mented banding indicative of mosaicism."
Marchegiani et al. (2015), PMID:26119818, Figure 1A: clinical pigment pattern in two mosaic individuals.
Limbs 2
Cutaneous Finger Syndactyly HP:0010554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Webbed fingers, annotated with Cutaneous finger syndactyly (HP:0010554). HP:0010554 is a phenotype from the Human Phenotype Ontology.
Table IV records finger syndactyly in 44%; the table does not restrict this aggregate to cutaneous rather than bony syndactyly.
Show evidence (2 references)
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"Hands show mild cutaneous syndactyly and clinodactyly."
Marchegiani et al. (2015), PMID:26119818, Figure 1A: hand photographs of the molecularly characterized AMS family members.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Syndactyly fingers 6 44 — Camptodactyly fingers — 38 —"
De Maria et al. (2016), PMID:27196381. Table IV records finger syndactyly in 44%; the table does not restrict this aggregate to cutaneous rather than bony syndactyly.
Camptodactyly of Finger FREQUENT HP:0100490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly of finger (HP:0100490). HP:0100490 is a phenotype from the Human Phenotype Ontology.
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (3 references)
PMID:11807864 SUPPORT Human Clinical
"Hearing loss, poor hair growth, finger contractures, and growth retardation were also chronic problems."
Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
PMID:21595001 SUPPORT Human Clinical
"Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities."
Camptodactyly among the additional anomalies.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Syndactyly fingers 6 44 — Camptodactyly fingers — 38 —"
De Maria et al. (2016), PMID:27196381. Table IV reports finger camptodactyly in 38% of accepted AMS cases.
Nervous System 1
Developmental Delay Neurodevelopmental delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
The older two-thirds estimate comes from clinically diagnosed patients and is not assigned as an overall frequency for molecularly confirmed AMS. Normal cognition in later reports does not exclude motor or language delay, and sensory impairment and other complications may affect developmental assessment.
Show evidence (3 references)
PMID:11807864 SUPPORT Human Clinical
"Developmental impairment was present in two-thirds of patients but was usually mild."
Frequency and severity of delay in the clinically diagnosed series.
PMID:21595001 SUPPORT Human Clinical
"Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients."
The same two-thirds estimate, restated for the reported patients up to 2011.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf SUPPORT Human Clinical
"mild gross motor delay, mild receptive language delay, significant early expressive language delay"
Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-7.2: domains and severity differ, so a uniform mild global-delay qualifier is not used.
Respiratory 1
Laryngotracheal Stenosis HP:0004894 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngotracheal stenosis (HP:0004894). HP:0004894 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31462237 SUPPORT Human Clinical
"To our knowledge, this is the first patient affected by AMS presenting with laryngo-tracheal stenosis."
Single case report; attribution to AMS is uncertain.
PMID:31462237 SUPPORT Human Clinical
"A definite etiology of the laryngo-tracheal stenosis could not therefore be established."
The authors note that repeated intubation may have contributed, so the stenosis may not be a primary feature.
Growth 1
Growth Delay 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 (4 references)
PMID:11807864 SUPPORT Human Clinical
"Hearing loss, poor hair growth, finger contractures, and growth retardation were also chronic problems."
Growth retardation as a chronic problem.
PMID:26600791 SUPPORT Human Clinical
"Systemically, the patient could not thrive properly with weight loss requiring the placement of a gastric tube."
Failure to thrive in a severely affected infant.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Physical growth was reported to be normal in all patients except two who showed a decreased growth in height"
De Maria et al. (2016), PMID:27196381. This sentence refers to the combined BSS/AMS review, not two independently counted molecular AMS patients.
+ 1 more reference
Other 1
Cheek Pads at the Oral Commissures FREQUENT
Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
Show evidence (2 references)
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"in both the medial parts of the cheeks bulge towards the corners of the mouth (cheek pads)"
Describes the cheek pads in both TWIST2 Glu75 syndromes.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Wide mouth 100 81 1–10 Cheek pads 38 69 1–10"
De Maria et al. (2016), PMID:27196381. Table IV reports cheek pads in 69% of accepted AMS cases.
🧬

Genetic Associations

1
TWIST2 (CAUSATIVE)
Gene: TWIST2 hgnc:20670 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TWIST2 (hgnc:20670). hgnc:20670 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (5 references)
PMID:26119818 SUPPORT Human Clinical
"We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families."
The recurrent de novo AMS allele across unrelated families.
PMID:31462237 SUPPORT Human Clinical
"She was known for AMS with the specific genetic mutation in the gene TWIST2 (c.223G > A), no pathogenic sequence changes were found in both her parents"
An independently reported de novo c.223G>A case.
PMID:34092176 SUPPORT Human Clinical
"Mosaic expression of TWIST2 variants is correlated with a less severe phenotype than that reported for the typical expression of TWIST2 variants associated with BSS or AMS."
Somatic mosaicism gives a milder phenotype.
+ 2 more references
💊

Medical Actions

7
Ocular Surface Protection
Action: ocular lubrication and corneal protectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is ocular lubrication and corneal protection, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Urgent protection of the exposed cornea with intensive lubrication and a protective eye shield while arranging definitive lid reconstruction. A bedside amniotic membrane graft has been used as a temporary measure, although migration and corneal melting occurred in one severely affected infant. Lubrication alone may fail within days in severe cases.
Target Phenotypes: Exposure keratitis HP:0000491 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Exposure keratitis, annotated with Keratitis (HP:0000491). HP:0000491 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26600791 SUPPORT Human Clinical
"Early amniotic membrane grafting may be done at the bedside and may help preserve the ocular in patients with severe eyelid deformities until more definitive treatment is performed."
Amniotic membrane grafting as a temporising measure.
PMID:29538102 REFUTE Human Clinical
"Despite intensive ocular lubrication, severe exposure keratopathy developed within the first days after birth."
Lubrication alone failed to prevent keratopathy in a severe case, arguing against relying on it without early surgical cover.
PMID:26600791 SUPPORT BACKGROUND Other
"A hard eye shield should also be placed over each eye to prevent contact of the corneal surface."
Protective shielding recommended in the accepted clinically diagnosed Feinstein report; molecular confirmation was not reported.
Eyelid Reconstruction
Action: eyelid reconstructionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is eyelid reconstruction (NCIT:C157852). NCIT:C157852 is a clinical intervention from the NCI Thesaurus. Ontology label: Eyelid Reconstruction NCIT:C157852
Platform: Surgery
Early surgery to cover the cornea, followed by lengthening of the deficient anterior lamella. Reported approaches include lateral tarsorrhaphy, full-thickness skin grafts from the retroauricular area or prepuce placed over the conjunctiva-Müller muscle complex or the smooth tarsal muscles, masquerade flaps to close the eyes temporarily, a modified reverse hatchet flap, and autologous rib cartilage with fat grafting for the lower lid. Grafts over Müller muscle gave clear corneas at 10-15-year follow-up with only minor lagophthalmos. Sun protection prevented graft hyperpigmentation in one patient with dark skin.
Target Phenotypes: Ablepharon HP:0011224 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ablepharon (HP:0011224). HP:0011224 is a phenotype from the Human Phenotype Ontology. Lagophthalmos HP:0030001 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Lagophthalmos (HP:0030001). HP:0030001 is a phenotype from the Human Phenotype Ontology.
Show evidence (7 references)
PMID:31373987 SUPPORT Human Clinical
"Full thickness skin grafts placed over the inner aspect of the palpebral conjunctiva allow permanent eye protection."
Long-term outcome of anterior lamellar lengthening with skin grafts.
PMID:39792429 SUPPORT Human Clinical
"We report a new AMS case with a quantitative analysis of palpebral fissure changes following skin grafts over the upper and lower smooth tarsal muscles and lateral tarsorrhaphy."
Grafting over the tarsal muscles with lateral tarsorrhaphy.
PMID:29538102 SUPPORT Human Clinical
"In a secondary procedure at the adjusted age of 3 weeks, the flaps were partially divided, and visual input and development were successfully achieved, while maintaining corneal protection."
Masquerade flaps for temporary closure, then division for visual input.
+ 4 more references
Penetrating Keratoplasty
Action: penetrating keratoplastyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is penetrating keratoplasty (NCIT:C222070). NCIT:C222070 is a clinical intervention from the NCI Thesaurus. Ontology label: Penetrating Keratoplasty NCIT:C222070
Platform: Surgery
Bilateral penetrating keratoplasty, combined with full-thickness lid reconstruction and temporary tarsorrhaphy, in an infant whose corneas melted from exposure; she tracked light binocularly at five and a half months. A salvage procedure reported once.
Target Phenotypes: Corneal ulceration HP:0012804 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Corneal ulceration (HP:0012804). HP:0012804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26600791 SUPPORT Human Clinical
"Extensive surgical reconstruction of both eyelids and bilateral penetrating keratoplasty was ultimately performed successfully to protect the ocular surfaces while trying to maximize the visual potential."
Keratoplasty with lid reconstruction after corneal melting.
Reconstruction of the Mouth and Face
Action: reconstructive surgery of mouth and faceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is reconstructive surgery of mouth and face, annotated with Reconstructive Surgery (NCIT:C25351). NCIT:C25351 is a clinical intervention from the NCI Thesaurus. Ontology label: Reconstructive Surgery NCIT:C25351
Platform: Surgery
Repair of macrostomia and individualized reconstructive procedures are reported. One adult with molecularly confirmed AMS had undergone 17 operations, including eyelid and ear-lobe reconstruction, lip correction and breast surgery. The 2016 review recommends an experienced multidisciplinary team and generally deferring major elective facial procedures until craniofacial growth is complete; urgent corneal protection is a separate priority.
Target Phenotypes: Macrostomia HP:0000154 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Macrostomia, annotated with Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:4003491 SUPPORT Human Clinical
"The child later underwent successful mouth reconstruction."
Surgical repair of the macrostomia.
PMID:31462237 SUPPORT Human Clinical
"The patient underwent 17 previously maxillofacial operations requiring intubation, including multiple surgeries for eyelids and ears lobes reconstruction, mastoplasty for mammary glands absence and lips correction."
The cumulative surgical burden in one adult with confirmed AMS.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Other
"In our opinion, such major proce- dures are best deferred until craniofacial growth is completed."
De Maria et al. (2016), PMID:27196381: timing advice for major elective reconstructive procedures in AMS and Barber-Say syndrome, not for urgent ocular protection.
Multidisciplinary Care and Psychosocial Support
Action: multidisciplinary supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is multidisciplinary supportive care, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Coordinate ophthalmic, surgical, audiologic, developmental, dental and genetic care with psychological support. The patient-perspective study emphasizes family and peer acceptance, early age-appropriate discussion of visible differences, and attention to self-esteem as well as physical treatment. Its questionnaire sample included ten people with Barber-Say syndrome and two with AMS; pooled social and surgical outcomes should not be presented as AMS-specific rates. Specialist centers and exchange of surgical experience are recommended by the authors.
Show evidence (5 references)
PMID:28690482 SUPPORT Human Clinical
"The importance of paying particular attention to the management of both the physical appearance and the consequences of these entities on the quality of life is stressed by the affected individuals themselves."
Patient-reported priorities for psychosocial care.
url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf SUPPORT Human Clinical
"Early and honest communication, adapted to the level of the child, has been performed, sometimes by treating physicians, sometimes by parents."
De Maria et al. (2017), PMID:28690482, Table 1: communication practices reported across the mixed AMS/Barber-Say sample.
url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf SUPPORT REVIEW SYNTHESIS Other
"surgical procedures should be performed in centers specialized in treating these specific conditions."
De Maria et al. (2017), PMID:28690482: author recommendation based on experience with these very rare disorders.
+ 2 more references
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counselling after TWIST2 testing of the proband and both parents. Most cases are de novo, but a parent can be mildly affected or mosaic, so an apparently unaffected parent does not exclude recurrence. As for any autosomal dominant disorder, the risk to a child of a non-mosaic affected adult is 50 percent.
Show evidence (3 references)
PMID:21595001 SUPPORT Human Clinical
"Additionally, the child shows more prominent features of the disorder when compared to her father documenting variable expression and possible anticipation."
A mildly affected transmitting parent, the case parental testing is meant to detect.
PMID:34092176 SUPPORT Human Clinical
"Mosaic expression of TWIST2 variants is correlated with a less severe phenotype than that reported for the typical expression of TWIST2 variants associated with BSS or AMS."
A mosaic parent may be only mildly affected.
url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf SUPPORT REVIEW SYNTHESIS Other
"The recurrence risk for a child of a non-mosaic affected person will likely be 50%"
De Maria et al. (2017), PMID:28690482, Table 1: autosomal dominant transmission counseling. The paper notes uncertainty about live-born recurrence and provides no quantified risk for mosaic individuals.
Management of Symptomatic Laryngotracheal Stenosis
Action: Temporary tracheostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Temporary tracheostomy, annotated with Tracheotomy (NCIT:C15341). NCIT:C15341 is a clinical intervention from the NCI Thesaurus. Ontology label: Tracheotomy NCIT:C15341
Platform: Surgery
Temporary tracheostomy, ventilation and corticosteroids restored spontaneous breathing in the reported adult with severe airway stenosis and mucosal inflammation. Residual narrowing remained on follow-up. This is a single complication-specific intervention, and the relationship of the stenosis to AMS itself was uncertain.
Mechanism Target:
Laryngotracheal Stenosis
Show evidence (1 reference)
PMID:31462237 SUPPORT Human Clinical
"Treatment of the stenosis by means of temporary tracheostomy and corticosteroids therapy resulted in airway patency restoration and patient's return to her normal activities."
Single adult case with confirmed TWIST2 c.223G>A; not evidence for corticosteroid treatment of the inherited malformations.
🔬

Diagnosis

2
TWIST2 Sequencing With Parental Testing
The diagnosis is clinical at birth and is confirmed by sequencing TWIST2. Because the substituting amino acid at Glu75 distinguishes AMS from Barber-Say syndrome, the report should name the variant. Testing both parents establishes de novo or inherited origin; a mildly affected parent may be mosaic.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:26119818 SUPPORT Human Clinical
"Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS."
Why the reported variant must name the substituting amino acid.
PMID:34092176 SUPPORT Human Clinical
"Here, we describe the phenotype of a patient with mosaic expression of a TWIST2 mutation that is typically associated with AMS."
Mosaic carriers of the AMS allele exist and present more mildly.
PMID:31462237 SUPPORT Human Clinical
"She was known for AMS with the specific genetic mutation in the gene TWIST2 (c.223G > A), no pathogenic sequence changes were found in both her parents"
Proband and parental testing establishing a de novo variant.
Prenatal Ultrasound
AMS has been suspected on prenatal ultrasound in the child of an affected father; the abstract does not state which features were seen.
Fetal ultrasound imaging NCIT:C222238 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21595001 SUPPORT Human Clinical
"These cases likely represent the 16th and 17th reported cases of AMS and the first case suspected on prenatal ultrasound."
First prenatal suspicion of AMS by ultrasound.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
A 2016 critical review accepted 16 individuals as reliably diagnosed with AMS after excluding earlier reports it judged misdiagnosed or insufficiently documented. A 2025 case report counted 21 documented cases since the first description in 1977 without stating its inclusion criteria.
Show evidence (2 references)
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"There remain 16 reliably diagnosed individuals with BSS and 16 with AMS."
Literature case count from a critical review of published patients.
PMID:39792429 SUPPORT BACKGROUND Human Clinical
"Since McCarthy and West's first report in 1977, 21 AMS cases have been documented."
A later literature count, stated as background in a case report.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Ablepharon-Macrostomia Syndrome:

Barber-Say syndrome MONDO:0008853
Overlapping Features Allelic TWIST2 disorder caused by p.Glu75Gln or p.Glu75Ala at the same residue. Shares macrostomia, eyelid underdevelopment, cheek pads, ear, nipple and genital anomalies; distinguished by generalized hypertrichosis and mostly ectropion rather than ablepharon, whereas AMS has sparse scalp hair. The variant settles the call.
Show evidence (4 references)
PMID:26119818 SUPPORT Human Clinical
"a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS"
The molecular discriminator between the two syndromes.
PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical
"Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur in both entities, and general hypertrichosis occurs in BSS."
The hair phenotype that separates the two clinically.
PMID:11807864 SUPPORT Human Clinical
"It also adds further evidence that AMS is distinct from Barber-Say syndrome, which has similar features."
Clinical argument for separating the two before the gene was known.
+ 1 more reference
Fraser syndrome MONDO:0009046
Overlapping Features Autosomal recessive FRAS-FREM complex disorder (FRAS1, FREM2, GRIP1) with cryptophthalmos, cutaneous syndactyly, genital and renal anomalies and laryngeal malformations. Its craniofacial and genital pattern overlaps closely with AMS, and one family with an AMS-like phenotype carried biallelic FRAS1 variants. In AMS the eyelids are short rather than fused over the globe, inheritance is dominant, and the Fraser genes were excluded in a clinically diagnosed AMS cohort.
Show evidence (3 references)
PMID:24115501 SUPPORT Human Clinical
"These findings demonstrate that AMS is genetically distinct from FS."
Exclusion of the Fraser syndrome genes in an AMS cohort.
PMID:17163535 SUPPORT Human Clinical
"We conclude that a phenotype resembling AMS is a rare clinical expression of FS with no obvious genotype-phenotype correlation."
An AMS-like phenotype caused by biallelic FRAS1 variants.
PMID:31462237 SUPPORT Human Clinical
"Laryngo-tracheal anomalies do not belong to the AMS phenotype"
The authors contrast AMS with Fraser syndrome, in which laryngotracheal anomalies are common.
Setleis syndrome (focal facial dermal dysplasia type III) Not Yet Curated MONDO:0009203
Overlapping Features Autosomal recessive TWIST2 disorder caused by biallelic truncating variants, with bitemporal scar-like lesions and eyelash and eyebrow abnormalities. It overlaps facially with AMS, but its inheritance, its loss-of-function mechanism and the focal temporal lesions distinguish it.
Show evidence (3 references)
PMID:20691403 SUPPORT Human Clinical
"Homozygous TWIST2 nonsense mutations, c.324C>T and c.486C>T, were identified in the affected members of the Arab and PR families, respectively."
Biallelic TWIST2 truncation as the cause of Setleis syndrome.
PMID:36942595 SUPPORT BACKGROUND Human Clinical
"Setleis syndrome (SS), or focal facial dermal dysplasia type III (FFDD3, MIM #227260), is an autosomal recessive condition caused by biallelic loss-of-function variants in TWIST2."
Restates the recessive loss-of-function basis of Setleis syndrome.
PMID:28663233 SUPPORT REVIEW SYNTHESIS Human Clinical
"the overlapping facial abnormalities in FFDD3 and two other genetic disorders, Ablepharon macrostomia syndrome and Barber-Say syndrome, are noted"
Review noting facial overlap between Setleis syndrome and AMS.
Sweeney-Cox syndrome MONDO:0060592
Overlapping Features Autosomal dominant TWIST1 disorder caused by substitutions at Glu117, the paralogous residue to TWIST2 Glu75. It shares ablepharon or eyelid underdevelopment, hypertelorism and cheek pads with AMS, and adds frontonasal dysplasia and, in some patients, craniosynostosis. Sequencing TWIST1 and TWIST2 separates them.
Show evidence (2 references)
PMID:30450715 SUPPORT Human Clinical
"Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth."
The shared facial features of the TWIST1 and TWIST2 basic-domain disorders.
PMID:28369379 SUPPORT Human Clinical
"Here, we describe a new clinical entity, Sweeney-Cox syndrome, associated with distinct de novo amino acid substitutions (p.Glu117Val and p.Glu117Gly) at a highly conserved glutamic acid residue located in the basic DNA binding domain of TWIST1, in two subjects with frontonasal dysplasia and..."
Defines the paralogous TWIST1 disorder.
🧫

Experimental Models

1
HeLa ChIP-seq of wild-type and mutant FLAG-TWIST2 CELL_LINE
Tetracycline-inducible T-REx HeLa lines overexpressing FLAG-HA-tagged wild-type TWIST2 or each disease allele, including p.Glu75Lys, profiled by anti-FLAG ChIP-seq.
Publication
PMID:26119818
Pathograph links
Altered TWIST2 Genomic DNA-Binding Pattern measures fidelity: low observes: molecular Direct measurement of genome-wide binding of the AMS mutant protein against wild-type.
Limitations: Overexpression in a cervical cancer cell line without a wild-type allele co-expressed at physiological ratio, and not in craniofacial or dermal mesenchyme, so which peaks are relevant in patient tissue is unknown.
Show evidence (1 reference)
PMID:26119818 SUPPORT In Vitro
"All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells."
The measurement this model provides.
🐁

Animal Models

3
Zebrafish embryos injected with mutant human TWIST2 mRNA
Mutant TWIST2 overexpression caused more severe head, trunk and cardiac-edema phenotypes than wild-type overexpression. Wild-type human TWIST2 itself caused mild developmental defects in approximately 65% of injected embryos, limiting interpretation of the assay as a specific disease model. RNA-seq at shield stage identified altered developmental transcription, with reductions in extracellular matrix, membrane and cytoskeleton gene sets. Stable inducible transgenic experiments supported the reported effects.
Species
Zebrafish
Genotype
Wild-type embryos injected at the one-cell stage with human TWIST2 mRNA (wild-type, p.Glu75Lys or p.Glu75Gln); stable Cre-inducible transgenic lines confirmed the phenotypes
Publication
PMID:26119818
Pathograph links
Dysregulated TWIST2-Dependent Mesenchymal Transcription partially recapitulates fidelity: low observes: organism Shows that p.Glu75Lys changes developmental transcription relative to wild-type TWIST2.
Limitations: Global overexpression of human mRNA from the one-cell stage, not a heterozygous allele expressed in mesenchyme, so any effect of TWIST2 dose itself is mixed with the effect of the substitution. Fish have no eyelids or hair, so the defining features cannot be assessed.
Show evidence (2 references)
PMID:26119818 SUPPORT Model Organism
"Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes."
Supports the model as informative for the transcriptional node.
+ 1 more reference
Zebrafish twist2 p.Glu78Lys base-edited knock-in
Knock-in of the AMS-equivalent substitution at the endogenous zebrafish twist2 locus by cytidine base editing. Homozygotes had a short trunk and curved tail and died at about 15 days post-fertilisation; heterozygotes were viable and fertile, and most developed a protruding jaw, an unclosed mouth and an emaciated body by 6 months. Homozygous embryos showed raised twist2, il1b and tnfa expression and reduced expression of bone development genes by qRT-PCR.
Species
Zebrafish
Genotype
twist2 c.C>T base edit giving p.Glu78Lys, the residue equivalent to human TWIST2 p.Glu75Lys; heterozygous and homozygous animals
Publication
PMID:33272268
Pathograph links
Craniofacial Soft-Tissue Patterning Defect partially recapitulates fidelity: low observes: organism Heterozygous animals show an adult jaw and mouth phenotype, the closest model analogue of the human facial malformation.
Limitations: Fish have no eyelids, external ears, hair or nipples, so the defining features cannot be assessed; the jaw phenotype appears in adults rather than at hatching, and the report is a methods paper that describes the phenotype qualitatively without penetrance figures or histology.
Show evidence (2 references)
PMID:33272268 SUPPORT Model Organism
"zAncBE4max successfully generated the Twist2 p.E78K mutation in zebrafish, recapitulating pathological features of human ablepharon macrostomia syndrome (AMS)."
The authors' claim that the knock-in models AMS.
+ 1 more reference
hlh-8 Glu29 allelic series (C. elegans)
CRISPR-engineered endogenous hlh-8 Glu29 substitutions model the conserved TWIST1/TWIST2 residue. The AMS-equivalent Glu29Lys heterozygotes retained embryos and had markedly reduced egl-15 reporter expression, whereas the heterozygous frameshift-null control resembled wild-type. Homozygous Glu29Lys additionally impaired sex-myoblast proliferation more severely than the null allele. These readouts support dominant interference and a possible additional neomorphic effect, without modeling human eyelids or skin.
Species
Caenorhabditis elegans
Genotype
hlh-8 Glu29 substitutions equivalent to the five human TWIST1/TWIST2 disease alleles
Publication
PMID:28369379
Pathograph links
Dysregulated TWIST2-Dependent Mesenchymal Transcription partially recapitulates fidelity: moderate observes: cellular Models the molecular character of the residue substitution in a single-Twist background, separating interference with the wild-type product from loss of dose.
Limitations: C. elegans has one Twist homolog and none of the affected human tissues; the M-lineage cellular readout speaks to allele behaviour and relative severity, not to skin, hair or eyelid development. Binding sites were not mapped in this model.
Show evidence (2 references)
PMID:28369379 SUPPORT Model Organism
"This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype, which we incorporate into a model explaining the various human disease phenotypes."
Grades the Glu75-equivalent alleles in vivo.
+ 1 more reference
{ }

Source YAML

click to show 
name: Ablepharon-Macrostomia Syndrome
creation_date: "2026-09-25T13:56:18Z"
category: Mendelian
synonyms:
- ablepharon macrostomia syndrome
- congenital ablepharon, absent eyelashes/eyebrows, macrostomia, auricular, nasal, genital and other systemic anomalies
description: >-
  Ablepharon-macrostomia syndrome is a congenital ectodermal dysplasia with multiple malformations, recognisable
  at birth by severely shortened or apparently absent eyelids (ablepharon), a wide "fish-like" mouth from unfused
  lateral commissures, first-degree microtia, an underdeveloped or notched nose, thin, wrinkled and redundant skin,
  sparse or absent scalp hair, eyebrows, eyelashes and lanugo, hypoplastic or absent nipples, and genital anomalies.
  Cutaneous syndactyly and camptodactyly of the fingers, ventral hernia or other abdominal wall and umbilical anomalies,
  and absent zygomatic arches occur in a minority. Most affected individuals have normal or near-normal cognition;
  motor or language delay is reported in some, with variable severity. The eyelid lesion is a deficiency of the
  anterior lamella rather than true absence of the lids, and it exposes the cornea from the first hours of life,
  so ocular surface protection and early eyelid reconstruction with skin grafts determine the visual outcome.

  It is autosomal dominant and caused by a heterozygous substitution of lysine for the conserved glutamic acid at
  residue 75 (p.Glu75Lys, c.223G>A) in the basic DNA-binding domain of the bHLH transcription factor TWIST2; all
  seven families in the gene-discovery series carried this one allele. Most cases are de novo; mildly affected parents
  have transmitted the disorder to more severely affected children, and somatic mosaicism gives a milder phenotype.
  Glutamine or alanine at the same residue causes the allelic Barber-Say syndrome, and biallelic loss-of-function
  TWIST2 alleles cause Setleis syndrome.

  In HeLa cells the Glu75 substitutions alter the genome-wide DNA-binding pattern of TWIST2. Whether the disorder
  results mainly from interference with the wild-type protein (dominant-negative) or from new target binding (neomorphic)
  is unresolved, and both models are recorded under mechanistic_hypotheses.
disease_term:
  preferred_term: ablepharon macrostomia syndrome
  term:
    id: MONDO:0008693
    label: ablepharon macrostomia syndrome
parents:
- ectodermal dysplasia syndrome
- TWIST2-related disorder
notes: >-
  Lump/split. Curated as its own Disease entry, with Barber-Say syndrome (MONDO:0008853, entry Barber-Say_Syndrome) as the allelic differential rather than a subtype, matching the decision recorded in that entry. MONDO, OMIM (200110 versus 209885) and Orphanet (ORPHA:920 versus ORPHA:1231) keep the two separate, and in the gene-discovery series lysine at TWIST2 residue 75 gave AMS while glutamine or alanine gave Barber-Say syndrome (PMID:26119818). The opposing view, that Barber-Say syndrome, AMS and Setleis syndrome form one continuum, is documented in the 2016 critical review (PMID:27196381) and in a 2009 case report (PMID:19760652). If the two are ever lumped as a single TWIST2 Glu75 disorder, the residue-level genotype-phenotype correlation is what should be carried as subtypes. The paralogous TWIST1 Glu117 disorder, Sweeney-Cox syndrome, also presents with ablepharon and has its own entry.

  The abbreviation "AMS" is omitted from the synonym list because it is widely used for unrelated conditions (for example acute mountain sickness); it is used as shorthand in the prose of this entry only.

  Case reports published before 2015 were diagnosed clinically, and several AMS-like patients were later shown to have other disorders: a family with an AMS-like phenotype carried biallelic FRAS1 variants (Fraser syndrome, PMID:17163535), and the 2016 review excluded several earlier reports as misdiagnosed. Frequency estimates from the older literature, notably developmental delay in about two-thirds, therefore describe a clinically defined and probably heterogeneous group; see the discussion on developmental outcome.

  No disease-specific GeneReviews chapter or ClinGen gene-validity assertion was identified in the consulted resources.

  Additional clinical reports include the familial report with eyelid-structure observations (PMID:10721975) and a multidisciplinary-care case (PMID:33689605). They are leads for a curator with full-text access. The institutional full-text PDF references correspond to: PMID:26119818 — Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes; PMID:27196381 — Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview; PMID:28690482 — Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View; PMID:28369379 — Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous TWIST2 p.Glu75Lys causes the disorder. Most probands carry a de
    novo variant. Before the gene was known, autosomal recessive inheritance had
    been proposed; familial cases with an affected parent and child, in which
    the parent was more mildly affected, argued for dominant transmission with
    variable expression. Somatic mosaicism for a TWIST2 variant gives a milder
    phenotype, so a mildly affected parent may be mosaic. As for any
    autosomal dominant disorder, a child of a non-mosaic affected person has a
    50 percent chance of inheriting the variant.
  evidence:
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present the second familial case of ablepharon-macrostomia syndrome in
      a newborn female and her 22-year-old father making autosomal dominant
      inheritance more likely than the previously proposed autosomal recessive
      transmission for this disorder.
    explanation: Father-to-daughter transmission supporting dominant inheritance.
  - reference: PMID:11038439
    reference_title: "Ablepharon-macrostomia syndrome: first report of familial occurrence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The father has facial anomalies that suggest autosomal dominant
      inheritance.
    explanation: >-
      First familial report; affected siblings whose father has facial
      anomalies, interpreted as dominant transmission from a mildly affected
      parent.
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, the child shows more prominent features of the disorder
      when compared to her father documenting variable expression and possible
      anticipation.
    explanation: >-
      A more mildly affected transmitting father. The authors' suggestion of
      anticipation predates the recognition of parental mosaicism, which
      explains the same observation.
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a recurrent de novo mutation in TWIST2 in seven independent
      AMS-affected families
    explanation: De novo origin of the AMS allele in unrelated families.
  - reference: PMID:34092176
    reference_title: Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mosaic expression of TWIST2 variants is correlated with a less severe
      phenotype than that reported for the typical expression of TWIST2
      variants associated with BSS or AMS.
    explanation: Somatic mosaicism gives a milder phenotype, relevant to parental testing.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2016 critical review accepted 16 individuals as reliably diagnosed with
    AMS after excluding earlier reports it judged misdiagnosed or insufficiently
    documented. A 2025 case report counted 21 documented cases since the first
    description in 1977 without stating its inclusion criteria.
  evidence:
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      There remain 16 reliably diagnosed individuals with BSS and 16 with AMS.
    explanation: Literature case count from a critical review of published patients.
  - reference: PMID:39792429
    reference_title: Upper and lower eyelid contour and positional changes after deep skin grafts in ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Since McCarthy and West's first report in 1977, 21 AMS cases have been
      documented.
    explanation: A later literature count, stated as background in a case report.
classifications:
  harrisons_chapter:
  - classification_value: DERMATOLOGY
    evidence:
    - reference: PMID:26119818
      reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are
        rare congenital ectodermal dysplasias characterized by similar clinical
        features.
      explanation: Classifies the disorder as an ectodermal dysplasia, a skin disorder.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:31462237
      reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ablepharon macrostomia syndrome (AMS) is a rare congenital malformation
        disorder caused by the autosomal-dominant mutations in gene TWIST2.
      explanation: A single-gene autosomal dominant malformation syndrome.
pathophysiology:
- name: TWIST2 p.Glu75Lys Basic-Domain Substitution
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    A heterozygous substitution of lysine for the conserved glutamic acid at
    codon 75 of TWIST2 (NM_057179.2 c.223G>A), in the basic region of the bHLH
    domain that contacts DNA. It was the allele found in all seven AMS families
    of the gene-discovery series. Glutamine or alanine at the same residue
    gives Barber-Say syndrome instead, so the substituting amino acid, not only
    the position, sets the phenotype.
  gene:
    preferred_term: TWIST2
    term:
      id: hgnc:20670
      label: TWIST2
  genetic_context:
    gene:
      preferred_term: TWIST2
      term:
        id: hgnc:20670
        label: TWIST2
    allele_type: SNV
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous missense p.Glu75Lys (c.223G>A), mostly de novo and
      occasionally inherited from a mosaic parent. functional_impact_category
      is left unset deliberately: the primary functional study reports both
      lost wild-type binding and gained off-target binding and names a
      dominant-negative and a neomorphic mechanism as alternatives, while the
      C. elegans allelic series favours a predominantly dominant-negative
      mechanism. Picking one enum value would assert more than either source
      does; see mechanistic_hypotheses.
  evidence:
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a recurrent de novo mutation in TWIST2 in seven independent
      AMS-affected families, as well as another recurrent de novo mutation
      affecting the same amino acid in ten independent BSS-affected families.
    explanation: The same allele recurs across unrelated AMS families.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was known for AMS with the specific genetic mutation in the gene
      TWIST2 (c.223G > A), no pathogenic sequence changes were found in both
      her parents
    explanation: Names the nucleotide change (c.223G>A) in an independently reported case.
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or
      alanine yielded BSS
    explanation: >-
      The residue-level genotype-phenotype correlation that separates this
      disorder from Barber-Say syndrome.
  downstream:
  - target: Altered TWIST2 Genomic DNA-Binding Pattern
    causal_link_type: DIRECT
    description: >-
      The substituted basic domain changes where TWIST2 binds the genome.
    evidence:
    - reference: PMID:26119818
      reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        All identified mutations fell in the basic domain of TWIST2 and altered
        the DNA-binding pattern of Flag-TWIST2 in HeLa cells.
      explanation: >-
        Links the basic-domain substitutions, including p.Glu75Lys, to altered
        DNA binding in a cell system.
- name: Altered TWIST2 Genomic DNA-Binding Pattern
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In HeLa cells overexpressing tagged TWIST2, the disease alleles changed the genomic binding pattern relative
    to wild-type. Wild-type TWIST2 had 630 binding peaks with a canonical E-box consensus. Mutants, including p.Glu75Lys,
    retained only a fraction of wild-type peaks and bound additional sites. This supports both loss of normal binding
    and acquisition of abnormal binding; the relative contribution of each to human disease remains unresolved.
    The relevance to endogenous TWIST2 in craniofacial or dermal mesenchyme is provisional because the assay used
    overexpression in a cancer cell line.
  molecular_functions:
  - preferred_term: E-box binding
    term:
      id: GO:0070888
      label: E-box binding
    modifier: DECREASED
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All identified mutations fell in the basic domain of TWIST2 and altered
      the DNA-binding pattern of Flag-TWIST2 in HeLa cells.
    explanation: Direct measurement of altered DNA binding by the mutant proteins.
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or
      BSS by inducing protean effects on the transcription factor's DNA
      binding.
    explanation: >-
      The authors' overall conclusion that altered DNA binding is the
      disease-relevant lesion; graded HUMAN_CLINICAL because it rests on the
      patient genetics as well as the cell assay.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ChIP-seq showed that the numbers of binding sites for p.Glu75Lys, p.Glu75Gln, p.Glu75Ala, and p.Gln77_Arg78dup
      TWIST2 were reduced compared to WT TWIST2 and that the mutants bound to many sites not shared with WT TWIST2.
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818, Figure 3B: reduced normal binding and mutant-only binding in HeLa
      cells.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: "https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Chromatin from HeLa cells overexpressing wild-type TWIST2 was subjected to ChIP-seq, identifying 630 DNA binding sites with a consensus sequence typical of an E-box motif.
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818, Figure 3A: the wild-type ChIP-seq comparison.
  downstream:
  - target: Dysregulated TWIST2-Dependent Mesenchymal Transcription
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - twist2_glu75_dominant_negative
    - twist2_glu75_neomorphic_binding
    description: >-
      Mutant-containing TWIST2 complexes are proposed to lose occupancy at normal targets or occupy new sites, altering
      downstream transcription. The effects in patient mesenchyme and the physiological balance of mutant and wild-type
      dimers remain unresolved.
    evidence:
    - reference: PMID:26119818
      reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Comparison of wild-type and mutant TWIST2 expressed in zebrafish
        identified abnormal developmental phenotypes and widespread
        transcriptome changes.
      explanation: >-
        Mutant TWIST2 changes developmental transcription in vivo. INDIRECT
        because it is overexpression in zebrafish embryos, not the
        heterozygous allele in human mesenchyme.
- name: Dysregulated TWIST2-Dependent Mesenchymal Transcription
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Expression of the AMS p.Glu75Lys or Barber-Say p.Glu75Gln protein in zebrafish embryos changed the transcriptome
    relative to wild-type TWIST2 overexpression. The strongest decreases involved extracellular matrix, membrane
    and cytoskeletal gene sets. These are whole-embryo results, not a patient-mesenchyme transcriptome. Wild-type
    overexpression itself caused mild developmental defects, so dose and experimental context matter. Homozygous
    zebrafish carrying the equivalent knock-in allele also showed increased twist2 and pro-inflammatory cytokine
    expression.
  cell_types:
  - preferred_term: mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  - preferred_term: fibroblast of dermis
    term:
      id: CL:0002551
      label: fibroblast of dermis
  biological_processes:
  - preferred_term: skin development
    term:
      id: GO:0043588
      label: skin development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      TWIST2 encodes a basic helix-loop-helix transcription factor that
      regulates the development of mesenchymal tissues.
    explanation: >-
      The developmental role of TWIST2 on which this node rests, stated as
      background in the abstract and naming no species, so graded OTHER.
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Comparison of wild-type and mutant TWIST2 expressed in zebrafish
      identified abnormal developmental phenotypes and widespread
      transcriptome changes.
    explanation: Transcriptional effect of the mutant proteins, including p.Glu75Lys, in zebrafish embryos.
  - reference: PMID:33272268
    reference_title: An optimized base editor with efficient C-to-T base editing in zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Quantitative RT-PCR showed that twsit2 itself expression was indeed
      increased in homozygous embryos, and the proinflammatory cytokines,
      Il-1β and tnfa, were found highly expressed.
    explanation: >-
      Expression changes in homozygous zebrafish carrying the AMS-equivalent
      knock-in (the source spells twist2 as "twsit2").
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gene ontology (GO) analyses revealed the greatest reduction in the expression of genes related to extracellular
      matrix (ECM), membrane components, and cytoskeleton
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818: RNA-seq of injected zebrafish embryos compared mutant with wild-type
      TWIST2 expression.
  downstream:
  - target: Dermal Extracellular Matrix Disorganization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced expression of extracellular matrix gene sets in mutant-expressing zebrafish and abnormal dermal matrix
      in affected people suggest a transcriptional route to the tissue lesion. Mediation by particular matrix genes
      has not been demonstrated in patient tissue.
    evidence:
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Gene ontology (GO) analyses revealed the greatest reduction in the expression of genes related to extracellular
        matrix (ECM), membrane components, and cytoskeleton
      explanation: >-
        Marchegiani et al. (2015), PMID:26119818: RNA-seq of injected zebrafish embryos compared mutant with wild-type
        TWIST2 expression.
  - target: Eyelid Anterior Lamella Underdevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disturbed TWIST2-directed mesenchymal development is inferred to underlie
      the eyelid malformation. No cited source demonstrates this step, and the
      stages of eyelid morphogenesis affected are not known.
  - target: Craniofacial Soft-Tissue Patterning Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same disturbance is proposed to produce the facial patterning
      defects of the mouth, nose, ears and malar region.
    evidence:
    - reference: PMID:33272268
      reference_title: An optimized base editor with efficient C-to-T base editing in zebrafish.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Interestingly, heterozygous mutants can survive to adults and be fertile,
        but most heterozygous adults showed the phenotypes of protruding jaw,
        unclosed mouth, and emaciated body at about 6 months
      explanation: >-
        The heterozygous AMS-equivalent knock-in disturbs jaw and mouth
        morphology in zebrafish. INDIRECT because the fish jaw is not the
        human facial soft tissue.
  - target: Hair Follicle Development Deficit
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - twist2_glu75_dominant_negative
    description: >-
      Under the dominant-negative model, reduced effective TWIST2 activity in
      dermal mesenchyme would impair hair follicle formation, as Twist2 loss
      does in mice. This edge is a hypothesis: no study has examined hair
      follicles in AMS, and the allelic Barber-Say substitutions cause the
      opposite hair phenotype (hypertrichosis).
    evidence:
    - reference: PMID:38740788
      reference_title: Twist2 contributes to skin regeneration and hair follicle formation in mouse fetuses.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        In mice, Twist2 knockout reportedly caused progressive growth
        retardation, possibly as a result of upregulated cytokine signaling,
        leading to thin skin and sparse distorted hair follicles before death
      explanation: >-
        Loss of Twist2 in mice gives sparse, distorted hair follicles. INDIRECT
        and BACKGROUND: it restates earlier knockout work in a paper about
        fetal wound healing, and a null allele is not the human heterozygous
        missense allele.
- name: Dermal Extracellular Matrix Disorganization
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Skin electron microscopy in affected individuals showed thin, elongated or disrupted elastic fibers, disordered
    collagen orientation and microfibrillar or amorphous deposits. Reticulodermal collagen staining was abnormal
    in AMS-7.1 and AMS-7.2, although elastic-fiber staining appeared normal. The tissue abnormality is directly
    observed; its precise causal relation to TWIST2 target-gene changes and the clinical skin phenotype remains
    provisional.
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy of skin biopsies of AMS-7.1 and AMS-7.2 showed thin, disrup- ted elastic fibers with areas
      of amorphous deposits along abnormally oriented collagen fibers and adjacent areas of microfibrillar proliferation
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818: direct ultrastructural findings in two affected family members.
      The PDF line-break hyphenation is retained.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Masson-Trichrome staining showed abnormal reticulodermal collagen pat- terns in AMS-7.1 and AMS-7.2 ... staining
      appeared within normal limits
    explanation: >-
      Collagen organization was abnormal, whereas the elastic-fiber stain appeared normal; ultrastructure and routine
      staining are distinct readouts.
  downstream:
  - target: Redundant Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Presumed tissue basis of lax, redundant skin; no study has tested the
      link directly.
  - target: Thin Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Presumed tissue basis of the thin skin.
  - target: Wrinkled Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Presumed tissue basis of the excessive wrinkling.
- name: Eyelid Anterior Lamella Underdevelopment
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The defining lesion. The eyelids are present but their anterior lamella
    (skin and orbicularis) is severely short, with shortening of the septum
    and levator aponeurosis also described, so the lids cannot cover the globe.
    Clinically this reads as ablepharon, and in milder or mosaic cases as
    short, hypoplastic lids. Oculoplastic reports stress that
    the lids are not truly absent, which is why grafting to lengthen the
    anterior lamella, rather than building a new lid, is effective.

    PROVISIONAL because no study has traced p.Glu75Lys through eyelid
    morphogenesis; the link from TWIST2 to the eyelid is inferred from the
    phenotype and from where TWIST2 is expressed.
  locations:
  - preferred_term: eyelid
    term:
      id: UBERON:0001711
      label: eyelid
  biological_processes:
  - preferred_term: eyelid development in camera-type eye
    term:
      id: GO:0061029
      label: eyelid development in camera-type eye
    modifier: DECREASED
  evidence:
  - reference: PMID:8746822
    reference_title: "Congenital shortening of the anterior lamella of all eyelids: the so-called ablepharon macrostomia syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report one more case showing that the condition is better described
      as a severe microblepharon because only the anterior lamella of the
      eyelids is shortened.
    explanation: Oculoplastic characterisation of the lesion as anterior lamellar shortening.
  - reference: PMID:11038439
    reference_title: "Ablepharon-macrostomia syndrome: first report of familial occurrence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ablepharon-macrostomia syndrome (AMS) is a rare condition comprising
      severe deficiency of the anterior lamella of both eyelids, abnormal ears,
      macrostomia, anomalous genitalia, redundant skin, and absence of lanugo.
    explanation: Defines the eyelid lesion as anterior lamellar deficiency.
  - reference: PMID:31373987
    reference_title: "Long-Term Results of the Surgical Management of the Upper Eyelids in \"Ablepharon\"-Macrostomia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lids in AMS are not absent and should not be managed with complex
      reconstructive techniques.
    explanation: Long-term surgical series concluding the lids are present but deficient.
  - reference: PMID:39792429
    reference_title: Upper and lower eyelid contour and positional changes after deep skin grafts in ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This condition is characterized by redundant skin, low-set ears,
      macrostomia, ambiguous genitalia, and underdevelopment of the both upper
      and lower eyelids.
    explanation: Both upper and lower lids are underdeveloped.
  - reference: PMID:34092176
    reference_title: Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal development of the anterior lamella appears to be a common
      feature in all cases of AMS with mosaic expression.
    explanation: The anterior lamellar defect persists in mosaic, milder cases.
  downstream:
  - target: Ablepharon
    causal_link_type: DIRECT
    description: >-
      Severe anterior lamellar deficiency presents as apparently absent lids.
  - target: Eyelid Hypoplasia
    causal_link_type: DIRECT
    description: >-
      Milder deficiency, particularly in mosaic individuals, presents as
      hypoplastic lids.
  - target: Ectropion
    causal_link_type: DIRECT
    description: >-
      Anterior-lamellar shortening causes outward turning of the lid margin.
    evidence:
    - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
      reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        anterior lamella causes ectropion, causing in turn lagophtalmus, which may need surgical correction
      explanation: >-
        De Maria et al. (2016), PMID:27196381. The ocular discussion explicitly describes anterior-lamellar deficiency causing ectropion and then incomplete lid closure.
- name: Hair Follicle Development Deficit
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Sparse or absent scalp hair, eyebrows, eyelashes and lanugo are consistent
    features of AMS and separate it from Barber-Say syndrome, in which the same
    residue substituted by glutamine or alanine gives generalized
    hypertrichosis. Twist2 is expressed in dermal mesenchyme and is required
    for normal hair follicle formation in mice, so impaired follicle induction
    is the most direct candidate mechanism. HYPOTHETICAL: no hair or scalp
    histology from an AMS patient has been reported, and the opposite hair
    phenotypes of the two allelic syndromes show that the lesion is not simple
    loss of TWIST2 function.
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  biological_processes:
  - preferred_term: hair follicle development
    term:
      id: GO:0001942
      label: hair follicle development
    modifier: DECREASED
  evidence:
  - reference: PMID:38740788
    reference_title: Twist2 contributes to skin regeneration and hair follicle formation in mouse fetuses.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Twist2 knockdown on E13 left visible marks at the wound site, inhibited
      regeneration, and resulted in defective follicle formation.
    explanation: >-
      Experimental loss of Twist2 in fetal mouse skin impairs hair follicle
      formation; the setting is wound regeneration, not development of the
      normal pelt.
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur
      in both entities, and general hypertrichosis occurs in BSS.
    explanation: The hair phenotype that this node is meant to explain, and its contrast with BSS.
  - reference: PMID:33994357
    reference_title: Zebrafish twist2/dermo1 regulates scale shape and scale organization during skin development and regeneration.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our knockout analysis reveals that twist2/dermo1 gene functions in the
      maintenance of the scale shape and organization during development as
      well as regeneration.
    explanation: >-
      twist2 loss disturbs dermal skin appendages (scales) in zebrafish.
      INDIRECT because scales are not hair follicles and a knockout is not the
      human missense allele.
  downstream:
  - target: Sparse Scalp Hair
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Absent Lanugo
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Absent Eyebrows
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Absent Eyelashes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Craniofacial Soft-Tissue Patterning Defect
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The facial gestalt - wide mouth with unfused commissures, first-degree
    microtia with low-set ears, depressed nasal bridge with underdeveloped
    alae, widely spaced eyes, flat or absent zygomatic arches and cheek
    pads at the mouth corners - is attributed to abnormal patterning of the
    TWIST2-expressing craniofacial mesenchyme. HYPOTHETICAL: this is the
    primary paper's stated rationale, supported in zebrafish only by
    non-specific head hypoplasia; the tissue-level mechanism of each feature is
    unstudied in AMS. The strongest model support is the heterozygous zebrafish
    twist2 p.Glu78Lys knock-in (the equivalent of human p.Glu75Lys), whose
    adults develop a protruding jaw and a mouth that does not close.
  evidence:
  - reference: PMID:33272268
    reference_title: An optimized base editor with efficient C-to-T base editing in zebrafish.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Interestingly, heterozygous mutants can survive to adults and be fertile,
      but most heterozygous adults showed the phenotypes of protruding jaw,
      unclosed mouth, and emaciated body at about 6 months
    explanation: >-
      A heterozygous knock-in of the AMS-equivalent residue disturbs jaw and
      mouth morphology. INDIRECT because the fish jaw is not the human facial
      soft tissue and no eyelid or ear phenotype can be assessed.
  locations:
  - preferred_term: mouth
    term:
      id: UBERON:0000165
      label: mouth
  - preferred_term: nose
    term:
      id: UBERON:0000004
      label: nose
  - preferred_term: external ear
    term:
      id: UBERON:0001691
      label: external ear
  - preferred_term: zygomatic arch
    term:
      id: UBERON:0002500
      label: zygomatic arch
  downstream:
  - target: Incomplete Fusion of the Lateral Oral Commissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: First-Degree Microtia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low-Set Ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Depressed Nasal Bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Underdeveloped Nasal Alae
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Aplastic Zygomatic Arch
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Malar Flattening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cheek Pads at the Oral Commissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thin Upper Lip Vermilion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Incomplete Fusion of the Lateral Oral Commissures
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The wide mouth of AMS is described as a failure of lip fusion at the
    lateral commissures. PROVISIONAL: based on clinical description, without
    imaging or histology of the perioral tissues.
  locations:
  - preferred_term: lip
    term:
      id: UBERON:0001833
      label: lip
  evidence:
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      failure of lip fusion that results in an enlarged, fish-like mouth
    explanation: States the causal relation between failed lip fusion and the wide mouth.
  downstream:
  - target: Macrostomia
    causal_link_type: DIRECT
    description: Unfused lateral commissures widen the oral aperture.
    evidence:
    - reference: PMID:4003491
      reference_title: Ablepharon macrostomia syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        failure of lip fusion that results in an enlarged, fish-like mouth
      explanation: States the causal relation between failed lip fusion and the wide mouth.
mechanistic_hypotheses:
- hypothesis_group_id: twist2_glu75_dominant_negative
  hypothesis_label: Glu75Lys interferes with the wild-type TWIST2 pool
  status: EMERGING
  description: >-
    Mutant TWIST2 is proposed to sequester wild-type TWIST2 or other bHLH partners in transcriptionally ineffective complexes. Residual DNA binding is possible, so this model does not require complete loss of promoter occupancy. In C. elegans, the AMS-equivalent Glu29Lys heterozygote perturbs egg laying and target-gene expression while the heterozygous frameshift-null control resembles wild-type. This favors dominant interference over simple dose reduction in that model. It remains unresolved in human craniofacial and dermal tissues, and is not mutually exclusive with a neomorphic effect.
  evidence:
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The genetic analysis favors a predominantly dominant-negative mechanism
      for the action of amino acid substitutions at this highly conserved
      glutamic acid residue
    explanation: >-
      Conclusion of the C. elegans allelic series, which included p.Glu75Lys
      engineered at the equivalent hlh-8 residue.
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The resemblance between the three syndromes is considerable, and likely
      differences seem larger than they actually are due to insufficiently
      complete evaluation for all characteristics of the three entities in the
      past.
    explanation: >-
      Clinical overlap between AMS, Barber-Say and the loss-of-function
      disorder Setleis syndrome. INDIRECT: resemblance to a loss-of-function
      phenotype is consistent with, not proof of, a dominant-negative effect.
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert
      antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome,
      and ablepharon-macrostomia syndrome, respectively.
    explanation: >-
      A later TWIST1 case report restates the Glu75 alleles as antimorphic,
      summarising the earlier functional work rather than adding new data.
  - reference: url:https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6
    reference_title: "https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The results from these two target genes in heterozygous mutants indicate that Glu29Gln, Glu29Ala, and Glu29Lys are the most likely to represent dominantWnegative proteins that interfere with the ability of WT HLHW8 to promote transcription of egl-15.
    explanation: >-
      Kim et al. (2017), PMID:28369379: author interpretation of heterozygous reporter experiments. The accepted-manuscript PDF extracts hyphens as W in these words.
- hypothesis_group_id: twist2_glu75_neomorphic_binding
  hypothesis_label: Glu75Lys gives TWIST2 new genomic targets
  status: EMERGING
  description: >-
    Mutant TWIST2 may alter transcription by binding sites that wild-type protein does not occupy. Mutant-only ChIP-seq peaks directly support altered genomic occupancy in HeLa cells. Whether those new targets drive the tissue-specific phenotype, rather than loss of normal binding or both effects, remains unresolved. The worm Glu29Lys allele also produces a sex-myoblast proliferation defect more severe than the null, which the authors interpret as possible interference with another bHLH pathway; this does not establish a specific new human target.
  evidence:
  - reference: PMID:33272268
    reference_title: An optimized base editor with efficient C-to-T base editing in zebrafish.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      Previous studies have shown that the E75K mutation in twsit2 altered the
      DNA binding activity of itself, leading to both gain of function and
      dominant-negative effects.
    explanation: >-
      Restates the earlier binding studies of p.Glu75Lys as showing a gain of
      function alongside the dominant-negative effect. Graded IN_VITRO for the
      cell-based binding work it summarises.
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, a genotype-phenotype correlation was observed, because the two
      syndromes differed based solely upon the nature of the substituting
      amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a
      glutamine or alanine yielded BSS.
    explanation: >-
      Different substitutions at one residue give different syndromes, which
      a residue-specific change in target binding would explain. INDIRECT
      because the correlation does not itself show new binding.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A significant number of binding peaks detected for the mutant TWIST2 proteins were not detected for the wild-type
      protein
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818: direct binding evidence underlying the neomorphic hypothesis; disease
      mediation remains proposed.
  - reference: url:https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6
    reference_title: "https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This observation suggests that besides the dominant negative nature of most of these hlh-8 alleles, some may be acting as neomorphic alleles and interfering with genetic pathways normally not associated with HLHW8 regulation.
    explanation: >-
      Kim et al. (2017), PMID:28369379: hypothesis arising from the unusual Glu29Lys sex-myoblast proliferation phenotype. A specific partner or human target was not established.
phenotypes:
- category: Ophthalmologic
  name: Ablepharon
  frequency: FREQUENT
  description: >-
    Apparently absent upper and lower eyelids at birth, with absent eyelashes;
    in fact severe shortening of the anterior lamella. The cornea is exposed
    from the first hours of life.
  phenotype_term:
    preferred_term: Ablepharon
    term:
      id: HP:0011224
      label: Ablepharon
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:31373987
    reference_title: "Long-Term Results of the Surgical Management of the Upper Eyelids in \"Ablepharon\"-Macrostomia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 60% of the cases, the lids were described as absent.
    explanation: >-
      Literature review of 15 published patients; the basis for the FREQUENT
      band.
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ablepharon macrostomia syndrome is a severe congenital condition that
      includes total absence of the upper and lower eyelids
    explanation: Early case description of apparently absent upper and lower lids.
  - reference: PMID:33055564
    reference_title: "Ablepharon Macrostomia Syndrome: Rib Cartilage and Fat Grafting for Lower Lid Reconstruction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Features of AMS include ablepharon, hypertelorism, macrostomia, dysplastic
      ears, sparse body hair, and ambiguous genitalia.
    explanation: Ablepharon listed first among the features of AMS.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Small/absent eyelids 69/6 19/75 10–50 Corneal clouding 6 50 ?
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV distinguishes small eyelids (19%) from absent eyelids (75%) in AMS.
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Ophthalmologic
  name: Eyelid Hypoplasia
  description: >-
    Short or hypoplastic lids (microblepharon) rather than apparent absence;
    the milder presentation, seen particularly in somatic mosaics.
  phenotype_term:
    preferred_term: Microblepharon
    term:
      id: HP:0430009
      label: Hypoplasia of eyelid
  evidence:
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short
      eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant
      skin, abnormal genitalia, and developmental delay in two-thirds of the
      reported patients.
    explanation: Short rather than absent eyelids in part of the reported patients.
  - reference: PMID:34092176
    reference_title: Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mosaic expression of TWIST2 variants is correlated with a less severe
      phenotype than that reported for the typical expression of TWIST2
      variants associated with BSS or AMS.
    explanation: Mosaic individuals present at the milder end of the eyelid spectrum.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AMS-1.120 p.Glu75Lys M severe hypoplastic eyelids bilateral
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818. Table 1: severe bilateral eyelid hypoplasia in AMS-1.1. The attached
      20 is the original-report citation marker.
  notes: >-
    Table 1 describes severe bilateral eyelid hypoplasia in AMS-1.1, AMS-6.1 and AMS-7.1, and a right-upper-eyelid defect in mosaic AMS-2.1. The other six individuals have bilateral ablepharon. These descriptions reflect a selected molecular series and the clinical continuum of anterior-lamellar deficiency.
- name: Ectropion
  category: Ophthalmologic
  description: >-
    Outward turning of the eyelid margin associated with anterior-lamellar underdevelopment. The accepted-case review recorded ectropion in 94% of its 16 AMS cases.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ectropion
    term:
      id: HP:0000656
      label: Ectropion
  evidence:
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Corneal clouding 6 50 ? Ectropion 81 94 ? Entropion — 6 10–50
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV columns are BSS, AMS and Setleis syndrome; the AMS ectropion value is 94%.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      anterior lamella causes ectropion, causing in turn lagophtalmus, which may need surgical correction
    explanation: >-
      De Maria et al. (2016), PMID:27196381. The ocular discussion explicitly describes anterior-lamellar deficiency causing ectropion and then incomplete lid closure.
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
  sequelae:
  - target: Lagophthalmos
    causal_link_type: DIRECT
    description: Everted lids contribute to incomplete eye closure.
    evidence:
    - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
      reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        anterior lamella causes ectropion, causing in turn lagophtalmus, which may need surgical correction
      explanation: >-
        De Maria et al. (2016), PMID:27196381. The ocular discussion explicitly describes anterior-lamellar deficiency causing ectropion and then incomplete lid closure.
- category: Ophthalmologic
  name: Lagophthalmos
  description: >-
    Inability to close the eyes, present from birth until the lids are
    lengthened surgically; a small residual lagophthalmos persists after
    grafting in long-term follow-up.
  phenotype_term:
    preferred_term: Lagophthalmos
    term:
      id: HP:0030001
      label: Lagophthalmos
  evidence:
  - reference: PMID:31373987
    reference_title: "Long-Term Results of the Surgical Management of the Upper Eyelids in \"Ablepharon\"-Macrostomia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At long-term follow-up, all 3 cases who underwent upper eyelid
      lengthening with full thickness skin grafts placed over Müller muscle had
      clear corneas with a small amount of lagophthalmos.
    explanation: Residual lagophthalmos after lid lengthening in three patients.
  sequelae:
  - target: Exposure Keratitis
    causal_link_type: DIRECT
    description: Incomplete lid closure exposes the corneal surface.
    evidence:
    - reference: PMID:33055564
      reference_title: "Ablepharon Macrostomia Syndrome: Rib Cartilage and Fat Grafting for Lower Lid Reconstruction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        The most significant phenotypic presentation is rudimentary eyelids
        resulting in exposure keratopathy, corneal abrasions, and potential
        blindness.
      explanation: States the causal route from deficient lids to exposure keratopathy.
- category: Ophthalmologic
  name: Exposure Keratitis
  description: >-
    Exposure keratopathy from the uncovered cornea, developing within days of
    birth despite intensive lubrication in severe cases. It is the main
    threat to vision.
  phenotype_term:
    preferred_term: Exposure keratitis
    term:
      id: HP:0000491
      label: Keratitis
    onset:
      onset_category: NEONATAL
  notes: >-
    Bound to the general Keratitis term, as in the Barber-Say_Syndrome entry: runoak -i ols:hp search "Exposure keratopathy" and search "Corneal exposure" returned no hits when re-run on 2026-09-25. The exposure mechanism is carried in preferred_term and the sequelae edges.
  evidence:
  - reference: PMID:29538102
    reference_title: "Use of the Masquerade Flap in Ablepharon-Macrostomia Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite intensive ocular lubrication, severe exposure keratopathy
      developed within the first days after birth.
    explanation: Neonatal exposure keratopathy despite lubrication.
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon presentation, there was severe exposure keratopathy causing large
      bilateral sterile ulcers culminating in corneal melting of both eyes.
    explanation: Severe exposure keratopathy progressing to ulceration in an infant.
  sequelae:
  - target: Corneal Ulceration
    causal_link_type: DIRECT
    description: Unprotected exposure keratopathy progresses to sterile ulceration and melting.
    evidence:
    - reference: PMID:26600791
      reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Upon presentation, there was severe exposure keratopathy causing large
        bilateral sterile ulcers culminating in corneal melting of both eyes.
      explanation: States the causal progression in one patient.
- category: Ophthalmologic
  name: Corneal Ulceration
  description: >-
    Sterile corneal ulceration and melting from untreated exposure, which in
    one infant required bilateral penetrating keratoplasty.
  phenotype_term:
    preferred_term: Corneal ulceration
    term:
      id: HP:0012804
      label: Corneal ulceration
  evidence:
  - reference: PMID:38967579
    reference_title: Modified Reverse Hatchet Flap for Ablepharon-Macrostomia Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Timely intervention is critical to prevent exposure keratopathy, corneal
      ulceration, and permanent vision loss.
    explanation: Names corneal ulceration as a complication of untreated exposure.
  sequelae:
  - target: Corneal Opacity
    causal_link_type: DIRECT
    description: Ulceration heals with scarring and opacification.
- category: Ophthalmologic
  name: Corneal Opacity
  description: Corneal opacities, which may improve after the lids are reconstructed.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corneal opacities present initially improved in one eye, allowing a view
      of the pupil and a normal anterior chamber.
    explanation: Corneal opacities in an infant with AMS, improving after lid reconstruction.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      continuous exposure may cause corneal clouding occurring in half of the patients with AMS.
    explanation: >-
      De Maria et al. (2016), PMID:27196381. The review explicitly reports corneal clouding in half of accepted AMS cases.
  sequelae:
  - target: Visual Impairment
    causal_link_type: DIRECT
    description: Corneal scarring limits vision.
  frequency: FREQUENT
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Ophthalmologic
  name: Visual Impairment
  description: >-
    Persistent reduced vision in many patients, usually attributable to
    corneal exposure in early life; prompt ocular protection and lid surgery
    are aimed at preventing it.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many have persistent visual problems, often related to early corneal
      exposure.
    explanation: >-
      Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
  - reference: PMID:2036354
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One such case is reported which illustrates the importance of immediate
      postnatal ocular management to minimise severe visual loss.
    explanation: Severe visual loss as the outcome early management aims to prevent.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Visual impairments have been reported in almost one-third of patients. Photophobia may occur
    explanation: >-
      De Maria et al. (2016), PMID:27196381. The ocular discussion reports visual impairment in almost one-third; this is a literature cohort, not a population estimate.
  frequency: FREQUENT
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Ophthalmologic
  name: Absent Eyelashes
  phenotype_term:
    preferred_term: Absent eyelashes
    term:
      id: HP:0000561
      label: Absent eyelashes
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These four patients, as well as those previously reported, all had
      absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear
      anomalies, redundant skin, and abnormal genitalia.
    explanation: >-
      The historical mixed series described absent brows and lashes; its denominator includes cases subsequently excluded from AMS.
  - reference: PMID:34850759
    reference_title: "Ablepharon macrostomia syndrome: Absent prepuce in the first case report in West Africa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was dysmorphic with absent eyelids, eyelashes and eyebrows, large
      fish-shaped mouth, hyperpigmented thick anterior abdominal wall, absent
      prepuce amongst other features.
    explanation: Absent eyelashes in a neonate.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Eyelashes sparse or absent 69 b 100c 50–100 f Hypertrichosis general 94 — —
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV records the combined sparse-or-absent category in 100% of accepted AMS cases; footnote c says mainly absent. It does not provide a separate numerical frequency for complete absence.
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence. Sparse or absent eyebrows and eyelashes were each recorded in 100%; that combined value is not assigned to this narrower absence phenotype.
- category: Integument
  name: Absent Eyebrows
  phenotype_term:
    preferred_term: Absent eyebrow
    term:
      id: HP:0002223
      label: Absent eyebrow
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These four patients, as well as those previously reported, all had
      absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear
      anomalies, redundant skin, and abnormal genitalia.
    explanation: >-
      The historical mixed series described absent brows and lashes; its denominator includes cases subsequently excluded from AMS.
  - reference: PMID:34850759
    reference_title: "Ablepharon macrostomia syndrome: Absent prepuce in the first case report in West Africa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was dysmorphic with absent eyelids, eyelashes and eyebrows, large
      fish-shaped mouth, hyperpigmented thick anterior abdominal wall, absent
      prepuce amongst other features.
    explanation: Absent eyebrows in a neonate.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Eyebrows sparse or absent 63 b 100c 50–100 e Eyelashes sparse or absent 69 b 100c 50–100 f
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV records the combined sparse-or-absent category in 100% of accepted AMS cases; footnote c says mainly absent. It does not provide a separate numerical frequency for complete absence.
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence. Sparse or absent eyebrows and eyelashes were each recorded in 100%; that combined value is not assigned to this narrower absence phenotype.
- category: Integument
  name: Sparse Scalp Hair
  frequency: FREQUENT
  description: >-
    Sparse or absent scalp hair, with poor hair growth persisting into
    adulthood. With the eyelid lesion, it is the feature that distinguishes
    AMS from Barber-Say syndrome, in which hair is excessive.
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur
      in both entities, and general hypertrichosis occurs in BSS.
    explanation: Sparse scalp hair as the AMS-specific hair feature.
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These four patients, as well as those previously reported, all had
      absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear
      anomalies, redundant skin, and abnormal genitalia.
    explanation: >-
      Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss, poor hair growth, finger contractures, and growth
      retardation were also chronic problems.
    explanation: >-
      Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Sparse scalp hair — 75 10–50 Eyebrows sparse or absent 63 b 100c 50–100 e
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV records sparse scalp hair in 75% of accepted AMS cases.
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Integument
  name: Absent Lanugo
  phenotype_term:
    preferred_term: Absent lanugo
    term:
      id: HP:0034262
      label: Absent lanugo
  evidence:
  - reference: PMID:11038439
    reference_title: "Ablepharon-macrostomia syndrome: first report of familial occurrence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ablepharon-macrostomia syndrome (AMS) is a rare condition comprising
      severe deficiency of the anterior lamella of both eyelids, abnormal ears,
      macrostomia, anomalous genitalia, redundant skin, and absence of lanugo.
    explanation: Absent lanugo among the defining features.
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short
      eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant
      skin, abnormal genitalia, and developmental delay in two-thirds of the
      reported patients.
    explanation: Absent lanugo among the characteristic features.
- category: Craniofacial
  name: Macrostomia
  frequency: VERY_FREQUENT
  description: >-
    Wide, "fish-like" mouth from unfused lateral commissures, present at birth
    and repaired surgically in childhood.
  phenotype_term:
    preferred_term: Macrostomia
    term:
      id: HP:0000154
      label: Wide mouth
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These four patients, as well as those previously reported, all had
      absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear
      anomalies, redundant skin, and abnormal genitalia.
    explanation: >-
      Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
  - reference: PMID:34850759
    reference_title: "Ablepharon macrostomia syndrome: Absent prepuce in the first case report in West Africa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was dysmorphic with absent eyelids, eyelashes and eyebrows, large
      fish-shaped mouth, hyperpigmented thick anterior abdominal wall, absent
      prepuce amongst other features.
    explanation: A large fish-shaped mouth in a neonate.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Wide mouth 100 81 1–10 Cheek pads 38 69 1–10
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV records wide mouth in 81% of accepted AMS cases.
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Major facial characteristics present in both entities, albeit often in differing frequencies, are excessive facial creases, hypertelorism, underdevelopment of the anterior part of the eyelids (anterior lamella), ectropion, broad nasal ridge and tip, thick and flaring alae nasi, protruding maxilla, wide mouth, thin upper vermillion, and attached ear lobes."  # codespell:ignore-line
    explanation: Thin upper vermilion among the major facial characteristics of both syndromes.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cheek pads 38 69 1–10 Thin upper vermillion 88 50 —" # codespell:ignore-line
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV reports thin upper lip vermilion in 50% of accepted AMS cases.
  frequency: FREQUENT
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Craniofacial
  name: Cheek Pads at the Oral Commissures
  description: >-
    The medial cheeks bulge towards the corners of the mouth, a feature shared
    with Barber-Say and Sweeney-Cox syndromes.
  phenotype_term:
    preferred_term: Cheek pads adjacent to the corners of the mouth
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
  evidence:
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      in both the medial parts of the cheeks bulge towards the corners of the
      mouth (cheek pads)
    explanation: Describes the cheek pads in both TWIST2 Glu75 syndromes.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Wide mouth 100 81 1–10 Cheek pads 38 69 1–10
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV reports cheek pads in 69% of accepted AMS cases.
  frequency: FREQUENT
- category: Craniofacial
  name: First-Degree Microtia
  description: >-
    First-degree microtia is recorded for all ten p.Glu75Lys individuals in the molecularly characterized series,
    including the mildly affected mosaic individuals. Clinical reports predating molecular diagnosis use broader
    descriptions of small or malformed ears.
  phenotype_term:
    preferred_term: Microtia, first degree
    term:
      id: HP:0011266
      label: Microtia, first degree
  evidence:
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient had many dysmorphic features consistent with a severe
      phenotype of ablepharon-macrostomia syndrome (AMS) including a fish-like
      appearance of the mouth, rudimentary ears, absence of body hair, thin
      skin, absent nipples, abdominal distension, and genital abnormalities.
    explanation: Rudimentary ears in a severely affected infant.
  - reference: PMID:3293678
    reference_title: "A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to ablepharon and macrostomia, other anomalies common to all
      patients include auricular deformity, nasal alar deformity, absence of
      lanugo hair, dry, ichthyotic skin and ambiguous genitalia.
    explanation: Auricular deformity common to the early reported patients.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      normal microtia first degree, increased posterior angulation normal sparse normal normal normal
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-2.1: first-degree microtia despite otherwise mild findings.
      Every other AMS row also records first-degree microtia.
  notes: >-
    The ten-person molecular series includes related individuals and mosaics; its observed count is not a population prevalence estimate.
- category: Craniofacial
  name: Low-Set Ears
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:39792429
    reference_title: Upper and lower eyelid contour and positional changes after deep skin grafts in ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This condition is characterized by redundant skin, low-set ears,
      macrostomia, ambiguous genitalia, and underdevelopment of the both upper
      and lower eyelids.
    explanation: Low-set ears among the characteristic features.
  - reference: PMID:29538102
    reference_title: "Use of the Masquerade Flap in Ablepharon-Macrostomia Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A prematurely born male baby presented with severe ablepharon,
      hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge,
      coarse and redundant body skin, absent scalp and body hair, lax abdominal
      wall, absent nipples, camptodactyly, and ambiguous genitalia.
    explanation: Low-set dysplastic ears in a neonate.
- category: Ear
  name: Hearing Impairment
  description: >-
    Table 1 records unilateral hearing loss in AMS-4.1, mild hearing loss in AMS-5.1 and high-frequency hearing
    loss in AMS-6.1. These descriptors do not establish whether the loss is conductive or sensorineural. Older clinical
    series also describe hearing loss as a chronic problem.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss, poor hair growth, finger contractures, and growth
      retardation were also chronic problems.
    explanation: Hearing loss as a chronic problem in the natural-history series.
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional anomalies include dry skin, growth retardation, hearing loss,
      camptodactyly, hypertelorism, absent zygomatic arches, and umbilical
      abnormalities.
    explanation: Hearing loss among the additional anomalies.
  notes: >-
    Bound to the general term because the type of loss is not reported.
- category: Craniofacial
  name: Depressed Nasal Bridge
  phenotype_term:
    preferred_term: Flattened nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other facial abnormalities were a sloped forehead, hypertelorism,
      flattened nasal bridge, macrostomia, micrognathia, deformed ear lobes,
      thin upper lip with a long philtrum, and reduced hair of the scalp and
      eyebrows
    explanation: Flattened nasal bridge in a severely affected infant.
- category: Craniofacial
  name: Underdeveloped Nasal Alae
  description: >-
    Underdeveloped nasal alae occur in the molecular series and are distinguished from the separately recorded alar
    clefts.
  phenotype_term:
    preferred_term: Underdeveloped nasal alae
    term:
      id: HP:0000430
      label: Underdeveloped nasal alae
  evidence:
  - reference: PMID:3293678
    reference_title: "A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to ablepharon and macrostomia, other anomalies common to all
      patients include auricular deformity, nasal alar deformity, absence of
      lanugo hair, dry, ichthyotic skin and ambiguous genitalia.
    explanation: Nasal alar deformity common to the early reported patients.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      macrostomia under- developed ala nasi microtia first degree, high- frequency hearing loss
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-6.1, spanning mouth, nose and ear columns.
- category: Craniofacial
  name: Hypertelorism
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:33055564
    reference_title: "Ablepharon Macrostomia Syndrome: Rib Cartilage and Fat Grafting for Lower Lid Reconstruction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Features of AMS include ablepharon, hypertelorism, macrostomia, dysplastic
      ears, sparse body hair, and ambiguous genitalia.
    explanation: Hypertelorism listed among the features of AMS.
  - reference: PMID:29538102
    reference_title: "Use of the Masquerade Flap in Ablepharon-Macrostomia Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A prematurely born male baby presented with severe ablepharon,
      hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge,
      coarse and redundant body skin, absent scalp and body hair, lax abdominal
      wall, absent nipples, camptodactyly, and ambiguous genitalia.
    explanation: Hypertelorism in a severely affected neonate.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hypertelorism 88 81 ? Small/absent eyelids 69/6 19/75 10–50
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV reports hypertelorism in 81% of accepted AMS cases.
  frequency: VERY_FREQUENT
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Craniofacial
  name: Aplastic Zygomatic Arch
  description: Absent or hypoplastic zygomatic arches, first reported in 1988.
  phenotype_term:
    preferred_term: Aplastic zygomatic arch
    term:
      id: HP:0034260
      label: Aplastic zygomatic arch
  evidence:
  - reference: PMID:3293678
    reference_title: "A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A new feature of the syndrome is described--absence of the zygomatic
      arches.
    explanation: Original description of absent zygomatic arches in AMS.
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional anomalies include dry skin, growth retardation, hearing loss,
      camptodactyly, hypertelorism, absent zygomatic arches, and umbilical
      abnormalities.
    explanation: Absent zygomatic arches among the additional anomalies.
- category: Craniofacial
  name: Malar Flattening
  description: Hypoplastic malar region, noted particularly in adults.
  phenotype_term:
    preferred_term: Malar hypoplasia
    term:
      id: HP:0000272
      label: Malar flattening
  evidence:
  - reference: PMID:15103726
    reference_title: Ablepharon-macrostomia syndrome in a 46-year-old woman.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features include alopecia or sparse hair, hypoplastic malar
      region, redundant skin, rudimentary nipples, abnormal genitalia.
    explanation: Hypoplastic malar region among the additional features.
- category: Integument
  name: Redundant Skin
  description: Lax, redundant skin folds, sometimes described as cutis laxa.
  phenotype_term:
    preferred_term: Redundant skin
    term:
      id: HP:0001582
      label: Redundant skin
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These four patients, as well as those previously reported, all had
      absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear
      anomalies, redundant skin, and abnormal genitalia.
    explanation: Redundant skin in all patients reported up to 2002.
  - reference: PMID:39792429
    reference_title: Upper and lower eyelid contour and positional changes after deep skin grafts in ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This condition is characterized by redundant skin, low-set ears,
      macrostomia, ambiguous genitalia, and underdevelopment of the both upper
      and lower eyelids.
    explanation: Redundant skin listed first among the characteristic features.
  notes: >-
    Skin descriptions vary: the molecular series includes redundant, thin or wrinkled skin, while the mildly affected mosaic individual AMS-2.1 has normal skin recorded in Table 1. A universal frequency is therefore not assigned.
- category: Integument
  name: Thin Skin
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This patient had many dysmorphic features consistent with a severe
      phenotype of ablepharon-macrostomia syndrome (AMS) including a fish-like
      appearance of the mouth, rudimentary ears, absence of body hair, thin
      skin, absent nipples, abdominal distension, and genital abnormalities.
    explanation: Thin skin in a severely affected infant.
- category: Integument
  name: Wrinkled Skin
  phenotype_term:
    preferred_term: Excessive wrinkled skin
    term:
      id: HP:0007392
      label: Excessive wrinkled skin
  evidence:
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Major facial characteristics present in both entities, albeit often in differing frequencies, are excessive facial creases, hypertelorism, underdevelopment of the anterior part of the eyelids (anterior lamella), ectropion, broad nasal ridge and tip, thick and flaring alae nasi, protruding maxilla, wide mouth, thin upper vermillion, and attached ear lobes."  # codespell:ignore-line
    explanation: Excessive facial creases among the major facial characteristics.
- category: Integument
  name: Dry Skin
  description: >-
    Dry, coarse or ichthyotic skin, reported mainly in clinically diagnosed
    cases before the gene was known.
  phenotype_term:
    preferred_term: Dry skin
    term:
      id: HP:0000958
      label: Dry skin
  evidence:
  - reference: PMID:3293678
    reference_title: "A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to ablepharon and macrostomia, other anomalies common to all
      patients include auricular deformity, nasal alar deformity, absence of
      lanugo hair, dry, ichthyotic skin and ambiguous genitalia.
    explanation: Dry, ichthyotic skin common to the early reported patients.
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional anomalies include dry skin, growth retardation, hearing loss,
      camptodactyly, hypertelorism, absent zygomatic arches, and umbilical
      abnormalities.
    explanation: Dry skin among the additional anomalies.
- category: Integument
  name: Hypoplastic Nipples
  description: Hypoplastic or rudimentary nipples; absent mammary glands in one reported adult woman.
  phenotype_term:
    preferred_term: Hypoplastic nipples
    term:
      id: HP:0002557
      label: Hypoplastic nipples
  evidence:
  - reference: PMID:15103726
    reference_title: Ablepharon-macrostomia syndrome in a 46-year-old woman.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features include alopecia or sparse hair, hypoplastic malar
      region, redundant skin, rudimentary nipples, abnormal genitalia.
    explanation: Rudimentary nipples among the additional features.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including multiple surgeries for eyelids and ears lobes reconstruction,
      mastoplasty for mammary glands absence and lips correction
    explanation: Absent mammary glands requiring surgery in an adult woman with confirmed AMS.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Nipples small or absent 81 44 ? g Skin thin 44 38 10–50 d
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
  notes: >-
    Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
- category: Integument
  name: Absent Nipples
  phenotype_term:
    preferred_term: Absent nipple
    term:
      id: HP:0002561
      label: Absent nipple
  evidence:
  - reference: PMID:29538102
    reference_title: "Use of the Masquerade Flap in Ablepharon-Macrostomia Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A prematurely born male baby presented with severe ablepharon,
      hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge,
      coarse and redundant body skin, absent scalp and body hair, lax abdominal
      wall, absent nipples, camptodactyly, and ambiguous genitalia.
    explanation: Absent nipples in a severely affected neonate.
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She also had absent nipples, abnormal skin tension throughout her entire
      body with absence of hair or lanugo, and abnormal genitalia.
    explanation: Absent nipples in a severely affected infant.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Nipples small or absent 81 44 ? g Skin thin 44 38 10–50 d
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
  notes: >-
    Table IV reports small-or-absent nipples together in 44% of accepted AMS cases; it does not separate the two findings.
- category: Genitourinary
  name: Ambiguous Genitalia
  description: >-
    Ambiguous or otherwise abnormal external genitalia; an absent prepuce has
    been reported once.
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  evidence:
  - reference: PMID:29538102
    reference_title: "Use of the Masquerade Flap in Ablepharon-Macrostomia Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A prematurely born male baby presented with severe ablepharon,
      hypertelorism, macrostomia, low-set dysplastic ears, broad nasal bridge,
      coarse and redundant body skin, absent scalp and body hair, lax abdominal
      wall, absent nipples, camptodactyly, and ambiguous genitalia.
    explanation: Ambiguous genitalia in a severely affected boy.
  - reference: PMID:39792429
    reference_title: Upper and lower eyelid contour and positional changes after deep skin grafts in ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This condition is characterized by redundant skin, low-set ears,
      macrostomia, ambiguous genitalia, and underdevelopment of the both upper
      and lower eyelids.
    explanation: Ambiguous genitalia among the characteristic features.
  notes: >-
    No frequency band. The 2002 series (PMID:11807864) reports abnormal genitalia in every patient without saying how many were ambiguous.
- category: Musculoskeletal
  name: Cutaneous Finger Syndactyly
  phenotype_term:
    preferred_term: Webbed fingers
    term:
      id: HP:0010554
      label: Cutaneous finger syndactyly
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: "https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hands show mild cutaneous syndactyly and clinodactyly.
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818, Figure 1A: hand photographs of the molecularly characterized AMS family members.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Syndactyly fingers 6 44 — Camptodactyly fingers — 38 —
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV records finger syndactyly in 44%; the table does not restrict this aggregate to cutaneous rather than bony syndactyly.
  notes: >-
    Table IV records finger syndactyly in 44%; the table does not restrict this aggregate to cutaneous rather than bony syndactyly.
- category: Musculoskeletal
  name: Camptodactyly of Finger
  description: Finger contractures, a chronic problem in the natural-history series.
  phenotype_term:
    preferred_term: Camptodactyly of finger
    term:
      id: HP:0100490
      label: Camptodactyly of finger
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss, poor hair growth, finger contractures, and growth
      retardation were also chronic problems.
    explanation: >-
      Historical clinically diagnosed series, including cases later excluded by the 2016 review; retained for descriptive context, not as the frequency denominator.
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional anomalies include dry skin, growth retardation, hearing loss,
      camptodactyly, hypertelorism, absent zygomatic arches, and umbilical
      abnormalities.
    explanation: Camptodactyly among the additional anomalies.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Syndactyly fingers 6 44 — Camptodactyly fingers — 38 —
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV reports finger camptodactyly in 38% of accepted AMS cases.
  frequency: FREQUENT
  notes: >-
    Table IV of the 2016 review includes 16 accepted AMS cases. Percentages count positively documented findings; unreported findings were not necessarily absent, so these are minimum observed proportions rather than population prevalence.
- category: Gastrointestinal
  name: Ventral Hernia
  description: >-
    Ventral hernia or a lax abdominal wall has been described in clinical reports. Omphalocele in the molecularly
    characterized series is recorded separately.
  phenotype_term:
    preferred_term: Ventral hernia
    term:
      id: HP:0002933
      label: Ventral hernia
  evidence:
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormally shaped ears and nose, absence of lanugo, ventral hernia, and
      ambiguous genitalia
    explanation: Ventral hernia in an early case.
- category: Neurodevelopmental
  name: Developmental Delay
  description: >-
    Motor and language delays vary. Table 1 records delay in AMS-3.1, AMS-4.1 and AMS-7.2, normal development in
    five individuals, and no developmental assessment for two. AMS-7.2 had significant early expressive-language
    delay, while motor and receptive-language delays were mild. AMS-4.1 also had hemiparesis attributed to cerebral
    hemorrhage. These observations do not establish that every developmental difficulty is intrinsic to TWIST2 dysfunction.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental impairment was present in two-thirds of patients but was
      usually mild.
    explanation: Frequency and severity of delay in the clinically diagnosed series.
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short
      eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant
      skin, abnormal genitalia, and developmental delay in two-thirds of the
      reported patients.
    explanation: The same two-thirds estimate, restated for the reported patients up to 2011.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild gross motor delay, mild receptive language delay, significant early expressive language delay
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-7.2: domains and severity differ, so a uniform mild
      global-delay qualifier is not used.
  notes: >-
    The older two-thirds estimate comes from clinically diagnosed patients and is not assigned as an overall frequency for molecularly confirmed AMS. Normal cognition in later reports does not exclude motor or language delay, and sensory impairment and other complications may affect developmental assessment.
- category: Growth
  name: Growth Delay
  description: >-
    Poor growth and low birth weight occur in some reports, including failure to thrive requiring gastrostomy in one infant. The 2016 BSS/AMS review found normal physical growth except in two patients across the combined conditions, and could not establish that reduced growth was intrinsic to the syndromes.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss, poor hair growth, finger contractures, and growth
      retardation were also chronic problems.
    explanation: Growth retardation as a chronic problem.
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systemically, the patient could not thrive properly with weight loss
      requiring the placement of a gastric tube.
    explanation: Failure to thrive in a severely affected infant.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Physical growth was reported to be normal in all patients except two who showed a decreased growth in height
    explanation: >-
      De Maria et al. (2016), PMID:27196381. This sentence refers to the combined BSS/AMS review, not two independently counted molecular AMS patients.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Whether the disturbed growth and development should be ascribed to the disorder or to other factors remains uncertain.
    explanation: >-
      De Maria et al. (2016), PMID:27196381. The authors caution against attributing all growth or developmental problems to the inherited disorder.
- category: Respiratory
  name: Laryngotracheal Stenosis
  description: >-
    Reported once, in a 37-year-old woman with confirmed c.223G>A who had had
    17 operations under intubation; the authors could not establish whether
    the stenosis was congenital or acquired. It was managed with temporary
    tracheostomy and corticosteroids.
  phenotype_term:
    preferred_term: Laryngotracheal stenosis
    term:
      id: HP:0004894
      label: Laryngotracheal stenosis
  evidence:
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To our knowledge, this is the first patient affected by AMS presenting
      with laryngo-tracheal stenosis.
    explanation: Single case report; attribution to AMS is uncertain.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A definite etiology of the laryngo-tracheal stenosis could not therefore
      be established.
    explanation: >-
      The authors note that repeated intubation may have contributed, so the
      stenosis may not be a primary feature.
- name: Cleft Nasal Alae
  category: Craniofacial
  description: >-
    Cleft nasal alae were recorded in AMS-3.1, AMS-4.1 and AMS-5.1 in the molecularly characterized series. This
    finding is distinct from alar hypoplasia.
  phenotype_term:
    preferred_term: Cleft ala nasi
    term:
      id: HP:0003191
      label: Cleft ala nasi
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      depressed nasal bridge, cleft ala nasi
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-3.1 and AMS-4.1 nose columns; the table also records
      cleft alae in AMS-5.1. Row assignments were checked on the PDF page.
- name: Hypoplastic Labia Majora
  category: Genitourinary
  description: >-
    Hypoplastic labia majora were recorded in the female patients AMS-2.2, AMS-2.3 and AMS-4.1. Other genital findings
    vary between patients.
  phenotype_term:
    preferred_term: Hypoplastic labia majora
    term:
      id: HP:0000059
      label: Hypoplastic labia majora
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoplastic labia majora small nails omphalocele
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818. Table 1, AMS-2.3, spanning genitalia, hands and other columns. The
      genital finding also appears in AMS-2.2 and AMS-4.1; the ambiguous sex/genital description in AMS-7.2 is not
      used for this assignment.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Small labia majora or scrotum 13 56 10–50 h Small or ambiguous genitalia 6 38 —
    explanation: >-
      De Maria et al. (2016), PMID:27196381. Table IV combines small labia majora and small scrotum (56%); this is not a female-specific labial frequency.
  notes: >-
    Table IV combines small labia majora and small scrotum (56%); this is not a female-specific labial frequency.
- name: Anteriorly Placed Anus
  category: Gastrointestinal
  description: >-
    An anteriorly placed anus was recorded in AMS-2.3, AMS-4.1 and AMS-7.2 in the molecularly characterized series.
  phenotype_term:
    preferred_term: Anteriorly placed anus
    term:
      id: HP:0001545
      label: Anteriorly placed anus
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AMS-2.39 ... small nails omphalocele, anteriorly placed anus
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818, Table 1: the subject identifier and terminal cells identify AMS-2.3 (the attached 9 is a citation marker). An anteriorly placed anus also appears in AMS-4.1 and AMS-7.2; these are selected-case observations, not a population frequency.
- name: Omphalocele
  category: Gastrointestinal
  description: >-
    Omphalocele was recorded in AMS-2.3, the mosaic father AMS-7.1 and his child AMS-7.2. It is distinguished from
    nonspecific ventral hernia or a lax abdominal wall.
  phenotype_term:
    preferred_term: Omphalocele
    term:
      id: HP:0001539
      label: Omphalocele
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AMS-7.1 ... low anterior hairline, omphalocele normal
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818, Table 1: AMS-7.1 other-findings cell followed by normal development. Omphalocele also appears in AMS-2.3 and AMS-7.2.
- name: Blaschko-line Hyperpigmentation
  category: Integument
  description: >-
    Blaschko-like hyperpigmented bands were illustrated in mosaic individuals AMS-6.1 and AMS-7.1. This finding
    may prompt assessment for mosaicism but is not present in every person with AMS.
  phenotype_term:
    preferred_term: Linear hyperpigmentation along Blaschko lines
    term:
      id: HP:6000010
      label: Linear Hyperpigmentation along Blaschko's lines
  evidence:
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shoulder photographs of AMS-6.1 and AMS-7.1 highlight Blaschko-like hyperpig- mented banding indicative of
      mosaicism.
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818, Figure 1A: clinical pigment pattern in two mosaic individuals.
- name: Alacrima
  category: Ophthalmologic
  description: >-
    Reduced or absent tear production was described in two accepted AMS reports summarized in the 2016 review. It can add to ocular surface vulnerability; a population frequency is not established.
  phenotype_term:
    preferred_term: Alacrima
    term:
      id: HP:0000522
      label: Alacrima
  evidence:
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Alacrimia was present in two AMS patients
    explanation: >-
      De Maria et al. (2016), PMID:27196381: the lacrimal-system section identifies the Cesarino and Rohena reports.
    quote_role: REVIEW_SYNTHESIS
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus was reported in three AMS individuals in the 2016 clinical review; the selected case literature does not establish population prevalence.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strabismus was also present in three BSS patients ... and three AMS patients
    explanation: >-
      De Maria et al. (2016), PMID:27196381: the AMS count is distinguished from the separate Barber-Say count.
    quote_role: REVIEW_SYNTHESIS
- name: Nystagmus
  category: Ophthalmologic
  description: >-
    Nystagmus occurs in accepted clinical reports; it was severe in the 1985 infant with corneal opacity and retinal detachment.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nystagmus was severe. The retina was attached in one eye and detached in the other.
    explanation: >-
      The 1985 report describes these ocular complications in one clinically diagnosed child.
- name: Retinal Detachment
  category: Ophthalmologic
  description: >-
    Unilateral retinal detachment was reported in the 1985 clinically diagnosed child. This is an individual observation, not an established primary malformation or frequent feature.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The retina was attached in one eye and detached in the other.
    explanation: >-
      Unilateral retinal detachment in the Hornblass/Reifler case accepted by the 2016 review.
- name: Microcornea
  category: Ophthalmologic
  description: >-
    Small corneas were reported in the Feinstein infant, measuring 7 mm on the right and 8 mm on the left. The diagnosis was clinical and TWIST2 confirmation was not reported; this case was retained in the 2016 review.
  phenotype_term:
    preferred_term: Microcornea
    term:
      id: HP:0000482
      label: Microcornea
  evidence:
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corneal diameters were 7 mm OD and 8 mm OS.
    explanation: >-
      Direct ocular measurements in the clinically diagnosed 2015 case; not a prevalence estimate.
- name: Photophobia
  category: Ophthalmologic
  description: Light sensitivity is reported in AMS; a frequency estimate is not established.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Visual impairments have been reported in almost one-third of patients. Photophobia may occur
    explanation: >-
      De Maria et al. (2016), PMID:27196381. The review names photophobia among ocular manifestations without assigning it the preceding visual-impairment frequency.
genetic:
- name: TWIST2
  gene_term:
    preferred_term: TWIST2
    term:
      id: hgnc:20670
      label: TWIST2
  association: CAUSATIVE
  features: >-
    Heterozygous c.223G>A (p.Glu75Lys; NM_057179.2) in the basic domain, found
    in all seven AMS families of the gene-discovery series and in later
    confirmed cases. Mostly de novo; transmitted from mildly affected parents
    in a few families. Somatic mosaicism gives a milder phenotype. Glutamine
    or alanine at the same residue causes Barber-Say syndrome, and biallelic
    nonsense alleles cause Setleis syndrome.
  evidence:
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a recurrent de novo mutation in TWIST2 in seven independent
      AMS-affected families, as well as another recurrent de novo mutation
      affecting the same amino acid in ten independent BSS-affected families.
    explanation: The recurrent de novo AMS allele across unrelated families.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was known for AMS with the specific genetic mutation in the gene
      TWIST2 (c.223G > A), no pathogenic sequence changes were found in both
      her parents
    explanation: An independently reported de novo c.223G>A case.
  - reference: PMID:34092176
    reference_title: Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mosaic expression of TWIST2 variants is correlated with a less severe
      phenotype than that reported for the typical expression of TWIST2
      variants associated with BSS or AMS.
    explanation: Somatic mosaicism gives a milder phenotype.
  - reference: PMID:24115501
    reference_title: "Ablepharon macrostomia syndrome: A distinct genetic entity clinically related to the group of FRAS-FREM complex disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No mutation in either of these genes was found in a cohort of 11 patients
      with AMS from 10 unrelated families.
    explanation: >-
      Before TWIST2 was identified, the Fraser syndrome genes (FRAS1, FREM2,
      GRIP1) and FRAS1 partners were excluded in a clinically diagnosed AMS
      cohort.
  - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all instances in which DNA was available from both unaffected parents, the TWIST2 mutation occurred de
      novo in the first generation of individuals affected with AMS or BSS and was heritable in the third generation.
    explanation: >-
      Marchegiani et al. (2015), PMID:26119818. Family sequencing supports de novo occurrence and subsequent transmission;
      the statement includes both allelic syndromes.
  notes: >-
    No ClinGen gene-disease validity assertion exists for TWIST2 and AMS (see
    the entry-level notes). No AMS-causing TWIST2 allele other than
    p.Glu75Lys was found among the references cited here.
diagnosis:
- name: TWIST2 Sequencing With Parental Testing
  description: >-
    The diagnosis is clinical at birth and is confirmed by sequencing TWIST2.
    Because the substituting amino acid at Glu75 distinguishes AMS from
    Barber-Say syndrome, the report should name the variant. Testing both
    parents establishes de novo or inherited origin; a mildly affected parent
    may be mosaic.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, a genotype-phenotype correlation was observed, because the two
      syndromes differed based solely upon the nature of the substituting
      amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a
      glutamine or alanine yielded BSS.
    explanation: Why the reported variant must name the substituting amino acid.
  - reference: PMID:34092176
    reference_title: Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe the phenotype of a patient with mosaic expression of a
      TWIST2 mutation that is typically associated with AMS.
    explanation: Mosaic carriers of the AMS allele exist and present more mildly.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was known for AMS with the specific genetic mutation in the gene
      TWIST2 (c.223G > A), no pathogenic sequence changes were found in both
      her parents
    explanation: Proband and parental testing establishing a de novo variant.
- name: Prenatal Ultrasound
  description: >-
    AMS has been suspected on prenatal ultrasound in the child of an affected
    father; the abstract does not state which features were seen.
  diagnosis_term:
    preferred_term: Fetal ultrasound imaging
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases likely represent the 16th and 17th reported cases of AMS and
      the first case suspected on prenatal ultrasound.
    explanation: First prenatal suspicion of AMS by ultrasound.
differential_diagnoses:
- name: Barber-Say syndrome
  description: >-
    Allelic TWIST2 disorder caused by p.Glu75Gln or p.Glu75Ala at the same
    residue. Shares macrostomia, eyelid underdevelopment, cheek pads, ear,
    nipple and genital anomalies; distinguished by generalized hypertrichosis
    and mostly ectropion rather than ablepharon, whereas AMS has sparse scalp
    hair. The variant settles the call.
  disease_term:
    preferred_term: Barber-Say syndrome
    term:
      id: MONDO:0008853
      label: Barber-Say syndrome
  evidence:
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or
      alanine yielded BSS
    explanation: The molecular discriminator between the two syndromes.
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur
      in both entities, and general hypertrichosis occurs in BSS.
    explanation: The hair phenotype that separates the two clinically.
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It also adds further evidence that AMS is distinct from Barber-Say
      syndrome, which has similar features.
    explanation: Clinical argument for separating the two before the gene was known.
  - reference: PMID:19760652
    reference_title: Case report supporting that the Barber-Say and ablepharon macrostomia syndromes could represent one disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other authors have discussed that BSS and AMS could possibly represent one
      syndrome, and our report supports this hypothesis.
    explanation: The lumping argument, recorded because it bears on the split.
- name: Fraser syndrome
  description: >-
    Autosomal recessive FRAS-FREM complex disorder (FRAS1, FREM2, GRIP1) with
    cryptophthalmos, cutaneous syndactyly, genital and renal anomalies and
    laryngeal malformations. Its craniofacial and genital pattern overlaps
    closely with AMS, and one family with an AMS-like phenotype carried
    biallelic FRAS1 variants. In AMS the eyelids are short rather than fused
    over the globe, inheritance is dominant, and the Fraser genes were
    excluded in a clinically diagnosed AMS cohort.
  disease_term:
    preferred_term: Fraser syndrome
    term:
      id: MONDO:0009046
      label: Fraser syndrome
  evidence:
  - reference: PMID:24115501
    reference_title: "Ablepharon macrostomia syndrome: A distinct genetic entity clinically related to the group of FRAS-FREM complex disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings demonstrate that AMS is genetically distinct from FS.
    explanation: Exclusion of the Fraser syndrome genes in an AMS cohort.
  - reference: PMID:17163535
    reference_title: "Fraser and Ablepharon macrostomia phenotypes: concurrence in one family and association with mutated FRAS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that a phenotype resembling AMS is a rare clinical expression
      of FS with no obvious genotype-phenotype correlation.
    explanation: An AMS-like phenotype caused by biallelic FRAS1 variants.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laryngo-tracheal anomalies do not belong to the AMS phenotype
    explanation: >-
      The authors contrast AMS with Fraser syndrome, in which laryngotracheal
      anomalies are common.
- name: Setleis syndrome (focal facial dermal dysplasia type III)
  description: >-
    Autosomal recessive TWIST2 disorder caused by biallelic truncating
    variants, with bitemporal scar-like lesions and eyelash and eyebrow
    abnormalities. It overlaps facially with AMS, but its inheritance, its
    loss-of-function mechanism and the focal temporal lesions distinguish it.
  disease_term:
    preferred_term: Setleis syndrome
    term:
      id: MONDO:0009203
      label: focal facial dermal dysplasia type III
  evidence:
  - reference: PMID:20691403
    reference_title: Homozygous nonsense mutations in TWIST2 cause Setleis syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous TWIST2 nonsense mutations, c.324C>T and c.486C>T, were
      identified in the affected members of the Arab and PR families,
      respectively.
    explanation: Biallelic TWIST2 truncation as the cause of Setleis syndrome.
  - reference: PMID:36942595
    reference_title: De novo triplication at 1p36.23p36.22 further refines the dosage sensitive region of overlap in Setleis syndrome (focal facial dermal dysplasia type III).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Setleis syndrome (SS), or focal facial dermal dysplasia type III (FFDD3, MIM #227260), is an autosomal recessive condition caused by biallelic loss-of-function variants in TWIST2."
    explanation: Restates the recessive loss-of-function basis of Setleis syndrome.
  - reference: PMID:28663233
    reference_title: "The focal facial dermal dysplasias: phenotypic spectrum and molecular genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the overlapping facial abnormalities in FFDD3 and two other genetic
      disorders, Ablepharon macrostomia syndrome and Barber-Say syndrome, are
      noted
    explanation: Review noting facial overlap between Setleis syndrome and AMS.
- name: Sweeney-Cox syndrome
  description: >-
    Autosomal dominant TWIST1 disorder caused by substitutions at Glu117, the
    paralogous residue to TWIST2 Glu75. It shares ablepharon or eyelid
    underdevelopment, hypertelorism and cheek pads with AMS, and adds
    frontonasal dysplasia and, in some patients, craniosynostosis. Sequencing
    TWIST1 and TWIST2 separates them.
  disease_term:
    preferred_term: Sweeney-Cox syndrome
    term:
      id: MONDO:0060592
      label: Sweeney-Cox syndrome
  evidence:
  - reference: PMID:30450715
    reference_title: Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia
      syndrome share the facial features of ablepharon, hypertelorism,
      underdevelopment of the eyelids, and cheek pads adjacent to the corners
      of the mouth.
    explanation: The shared facial features of the TWIST1 and TWIST2 basic-domain disorders.
  - reference: PMID:28369379
    reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a new clinical entity, Sweeney-Cox syndrome, associated
      with distinct de novo amino acid substitutions (p.Glu117Val and
      p.Glu117Gly) at a highly conserved glutamic acid residue located in the
      basic DNA binding domain of TWIST1, in two subjects with frontonasal
      dysplasia and additional malformations.
    explanation: Defines the paralogous TWIST1 disorder.
treatments:
- name: Ocular Surface Protection
  description: >-
    Urgent protection of the exposed cornea with intensive lubrication and a protective eye shield while arranging definitive lid reconstruction. A bedside amniotic membrane graft has been used as a temporary measure, although migration and corneal melting occurred in one severely affected infant. Lubrication alone may fail within days in severe cases.
  treatment_term:
    preferred_term: ocular lubrication and corneal protection
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Exposure keratitis
    term:
      id: HP:0000491
      label: Keratitis
  evidence:
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early amniotic membrane grafting may be done at the bedside and may help
      preserve the ocular in patients with severe eyelid deformities until more
      definitive treatment is performed.
    explanation: Amniotic membrane grafting as a temporising measure.
  - reference: PMID:29538102
    reference_title: "Use of the Masquerade Flap in Ablepharon-Macrostomia Syndrome: A Case Report."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite intensive ocular lubrication, severe exposure keratopathy
      developed within the first days after birth.
    explanation: >-
      Lubrication alone failed to prevent keratopathy in a severe case,
      arguing against relying on it without early surgical cover.
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A hard eye shield should also be placed over each eye to prevent contact of the corneal surface.
    explanation: >-
      Protective shielding recommended in the accepted clinically diagnosed Feinstein report; molecular confirmation was not reported.
    quote_role: BACKGROUND
- name: Eyelid Reconstruction
  therapeutic_modality: SURGERY
  description: >-
    Early surgery to cover the cornea, followed by lengthening of the deficient
    anterior lamella. Reported approaches include lateral tarsorrhaphy,
    full-thickness skin grafts from the retroauricular area or prepuce placed
    over the conjunctiva-Müller muscle complex or the smooth tarsal muscles,
    masquerade flaps to close the eyes temporarily, a modified reverse
    hatchet flap, and autologous rib cartilage with fat grafting for the lower
    lid. Grafts over Müller muscle gave clear corneas at 10-15-year follow-up
    with only minor lagophthalmos. Sun protection prevented graft
    hyperpigmentation in one patient with dark skin.
  treatment_term:
    preferred_term: eyelid reconstruction
    term:
      id: NCIT:C157852
      label: Eyelid Reconstruction
  target_phenotypes:
  - preferred_term: Ablepharon
    term:
      id: HP:0011224
      label: Ablepharon
  - preferred_term: Lagophthalmos
    term:
      id: HP:0030001
      label: Lagophthalmos
  evidence:
  - reference: PMID:31373987
    reference_title: "Long-Term Results of the Surgical Management of the Upper Eyelids in \"Ablepharon\"-Macrostomia Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Full thickness skin grafts placed over the inner aspect of the palpebral
      conjunctiva allow permanent eye protection.
    explanation: Long-term outcome of anterior lamellar lengthening with skin grafts.
  - reference: PMID:39792429
    reference_title: Upper and lower eyelid contour and positional changes after deep skin grafts in ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a new AMS case with a quantitative analysis of palpebral
      fissure changes following skin grafts over the upper and lower smooth
      tarsal muscles and lateral tarsorrhaphy.
    explanation: Grafting over the tarsal muscles with lateral tarsorrhaphy.
  - reference: PMID:29538102
    reference_title: "Use of the Masquerade Flap in Ablepharon-Macrostomia Syndrome: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a secondary procedure at the adjusted age of 3 weeks, the flaps were
      partially divided, and visual input and development were successfully
      achieved, while maintaining corneal protection.
    explanation: Masquerade flaps for temporary closure, then division for visual input.
  - reference: PMID:38967579
    reference_title: Modified Reverse Hatchet Flap for Ablepharon-Macrostomia Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a novel approach to multiplanar eyelid reconstruction in
      ablepharon-macrostomia syndrome involving use of a modified reverse
      hatchet flap in 1 lower eyelid along with division at the eyelid margin,
      recession of the eyelid retractors in conjunction with preputial skin
      grafting for anterior lamellar restoration in the other 3 eyelids.
    explanation: Flap and preputial skin graft reconstruction.
  - reference: PMID:33055564
    reference_title: "Ablepharon Macrostomia Syndrome: Rib Cartilage and Fat Grafting for Lower Lid Reconstruction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors report the first case of autologous rib cartilage grafting
      and fat grafting for lower eyelid reconstruction in a patient with AMS.
    explanation: Rib cartilage and fat grafting for the lower lid.
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In one such patient we were able to reconstruct the eyelids in a
      three-stage procedure. Redundant skin from the retroauricular area was
      used to create full-thickness grafts.
    explanation: Staged reconstruction with retroauricular full-thickness grafts.
  - reference: PMID:3293678
    reference_title: "A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skin graft pigmentation in this black patient has been prevented by
      prolonged application of sun block.
    explanation: Aftercare preventing graft hyperpigmentation.
- name: Penetrating Keratoplasty
  therapeutic_modality: SURGERY
  description: >-
    Bilateral penetrating keratoplasty, combined with full-thickness lid
    reconstruction and temporary tarsorrhaphy, in an infant whose corneas
    melted from exposure; she tracked light binocularly at five and a half
    months. A salvage procedure reported once.
  treatment_term:
    preferred_term: penetrating keratoplasty
    term:
      id: NCIT:C222070
      label: Penetrating Keratoplasty
  target_phenotypes:
  - preferred_term: Corneal ulceration
    term:
      id: HP:0012804
      label: Corneal ulceration
  evidence:
  - reference: PMID:26600791
    reference_title: A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extensive surgical reconstruction of both eyelids and bilateral
      penetrating keratoplasty was ultimately performed successfully to protect
      the ocular surfaces while trying to maximize the visual potential.
    explanation: Keratoplasty with lid reconstruction after corneal melting.
- name: Reconstruction of the Mouth and Face
  therapeutic_modality: SURGERY
  description: >-
    Repair of macrostomia and individualized reconstructive procedures are reported. One adult with molecularly confirmed AMS had undergone 17 operations, including eyelid and ear-lobe reconstruction, lip correction and breast surgery. The 2016 review recommends an experienced multidisciplinary team and generally deferring major elective facial procedures until craniofacial growth is complete; urgent corneal protection is a separate priority.
  treatment_term:
    preferred_term: reconstructive surgery of mouth and face
    term:
      id: NCIT:C25351
      label: Reconstructive Surgery
  target_phenotypes:
  - preferred_term: Macrostomia
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:4003491
    reference_title: Ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The child later underwent successful mouth reconstruction.
    explanation: Surgical repair of the macrostomia.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient underwent 17 previously maxillofacial operations requiring
      intubation, including multiple surgeries for eyelids and ears lobes
      reconstruction, mastoplasty for mammary glands absence and lips
      correction.
    explanation: The cumulative surgical burden in one adult with confirmed AMS.
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In our opinion, such major proce- dures are best deferred until craniofacial growth is completed.
    explanation: >-
      De Maria et al. (2016), PMID:27196381: timing advice for major elective reconstructive procedures in AMS and Barber-Say syndrome, not for urgent ocular protection.
    quote_role: REVIEW_SYNTHESIS
- name: Multidisciplinary Care and Psychosocial Support
  description: >-
    Coordinate ophthalmic, surgical, audiologic, developmental, dental and genetic care with psychological support.
    The patient-perspective study emphasizes family and peer acceptance, early age-appropriate discussion of visible
    differences, and attention to self-esteem as well as physical treatment. Its questionnaire sample included ten
    people with Barber-Say syndrome and two with AMS; pooled social and surgical outcomes should not be presented
    as AMS-specific rates. Specialist centers and exchange of surgical experience are recommended by the authors.
  treatment_term:
    preferred_term: multidisciplinary supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The importance of paying particular attention to the management of both
      the physical appearance and the consequences of these entities on the
      quality of life is stressed by the affected individuals themselves.
    explanation: Patient-reported priorities for psychosocial care.
  - reference: url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf
    reference_title: https://biblio.ugent.be/publication/8553102/file/8553201.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early and honest communication, adapted to the level of the child, has been performed, sometimes by treating
      physicians, sometimes by parents.
    explanation: >-
      De Maria et al. (2017), PMID:28690482, Table 1: communication practices reported across the mixed AMS/Barber-Say
      sample.
  - reference: url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf
    reference_title: https://biblio.ugent.be/publication/8553102/file/8553201.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      surgical procedures should be performed in centers specialized in treating these specific conditions.
    explanation: >-
      De Maria et al. (2017), PMID:28690482: author recommendation based on experience with these very rare disorders.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A multidisciplinary approach by a team experienced in craniofacial anomalies, and an individualized treatment plan are essential for timing and optimizing functional and aesthetic outcome.
    explanation: >-
      De Maria et al. (2016), PMID:27196381: individualized management by a team experienced in craniofacial anomalies.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf
    reference_title: "https://biblio.ugent.be/publication/8553102/file/8553201.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we gathered questionnaires from 10 BSS individuals and 2 AMS individuals
    explanation: >-
      De Maria et al. (2017), PMID:28690482: composition of the questionnaire sample; pooled findings are not AMS-specific proportions.
- name: Genetic Counseling
  description: >-
    Counselling after TWIST2 testing of the proband and both parents. Most
    cases are de novo, but a parent can be mildly affected or mosaic, so an
    apparently unaffected parent does not exclude recurrence. As for any
    autosomal dominant disorder, the risk to a child of a non-mosaic affected
    adult is 50 percent.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:21595001
    reference_title: Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, the child shows more prominent features of the disorder
      when compared to her father documenting variable expression and possible
      anticipation.
    explanation: A mildly affected transmitting parent, the case parental testing is meant to detect.
  - reference: PMID:34092176
    reference_title: Ocular adnexal phenotype and management of a patient with mosaic expression of a mutation in TWIST2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mosaic expression of TWIST2 variants is correlated with a less severe
      phenotype than that reported for the typical expression of TWIST2
      variants associated with BSS or AMS.
    explanation: A mosaic parent may be only mildly affected.
  - reference: url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf
    reference_title: https://biblio.ugent.be/publication/8553102/file/8553201.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recurrence risk for a child of a non-mosaic affected person will likely be 50%
    explanation: >-
      De Maria et al. (2017), PMID:28690482, Table 1: autosomal dominant transmission counseling. The paper notes
      uncertainty about live-born recurrence and provides no quantified risk for mosaic individuals.
    quote_role: REVIEW_SYNTHESIS
- name: Management of Symptomatic Laryngotracheal Stenosis
  description: >-
    Temporary tracheostomy, ventilation and corticosteroids restored spontaneous breathing in the reported adult
    with severe airway stenosis and mucosal inflammation. Residual narrowing remained on follow-up. This is a single
    complication-specific intervention, and the relationship of the stenosis to AMS itself was uncertain.
  evidence:
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of the stenosis by means of temporary tracheostomy and corticosteroids therapy resulted in airway
      patency restoration and patient's return to her normal activities.
    explanation: >-
      Single adult case with confirmed TWIST2 c.223G>A; not evidence for corticosteroid treatment of the inherited
      malformations.
  target_mechanisms:
  - target: Laryngotracheal Stenosis
  treatment_term:
    preferred_term: Temporary tracheostomy
    term:
      id: NCIT:C15341
      label: Tracheotomy
  therapeutic_modality: SURGERY
animal_models:
- name: Zebrafish embryos injected with mutant human TWIST2 mRNA
  species: Zebrafish
  genotype: >-
    Wild-type embryos injected at the one-cell stage with human TWIST2 mRNA
    (wild-type, p.Glu75Lys or p.Glu75Gln); stable Cre-inducible transgenic
    lines confirmed the phenotypes
  publication: PMID:26119818
  description: >-
    Mutant TWIST2 overexpression caused more severe head, trunk and cardiac-edema phenotypes than wild-type overexpression. Wild-type human TWIST2 itself caused mild developmental defects in approximately 65% of injected embryos, limiting interpretation of the assay as a specific disease model. RNA-seq at shield stage identified altered developmental transcription, with reductions in extracellular matrix, membrane and cytoskeleton gene sets. Stable inducible transgenic experiments supported the reported effects.
  modeled_mechanisms:
  - target: Dysregulated TWIST2-Dependent Mesenchymal Transcription
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Shows that p.Glu75Lys changes developmental transcription relative to
      wild-type TWIST2.
    limitations: >-
      Global overexpression of human mRNA from the one-cell stage, not a
      heterozygous allele expressed in mesenchyme, so any effect of TWIST2
      dose itself is mixed with the effect of the substitution. Fish have no
      eyelids or hair, so the defining features cannot be assessed.
    evidence:
    - reference: PMID:26119818
      reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Comparison of wild-type and mutant TWIST2 expressed in zebrafish
        identified abnormal developmental phenotypes and widespread
        transcriptome changes.
      explanation: Supports the model as informative for the transcriptional node.
    - reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
      reference_title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The introduction of wild- type hTWIST2 led to mild developmental defects ... in approximately 65% of injected
        zebrafish
      explanation: >-
        The wild-type overexpression control itself produced abnormalities, so the comparison measures severity
        relative to an experimentally perturbed baseline.
- name: Zebrafish twist2 p.Glu78Lys base-edited knock-in
  species: Zebrafish
  genotype: >-
    twist2 c.C>T base edit giving p.Glu78Lys, the residue equivalent to human
    TWIST2 p.Glu75Lys; heterozygous and homozygous animals
  publication: PMID:33272268
  description: >-
    Knock-in of the AMS-equivalent substitution at the endogenous zebrafish twist2 locus by cytidine base editing. Homozygotes had a short trunk and curved tail and died at about 15 days post-fertilisation; heterozygotes were viable and fertile, and most developed a protruding jaw, an unclosed mouth and an emaciated body by 6 months. Homozygous embryos showed raised twist2, il1b and tnfa expression and reduced expression of bone development genes by qRT-PCR.
  modeled_mechanisms:
  - target: Craniofacial Soft-Tissue Patterning Defect
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Heterozygous animals show an adult jaw and mouth phenotype, the closest
      model analogue of the human facial malformation.
    limitations: >-
      Fish have no eyelids, external ears, hair or nipples, so the defining
      features cannot be assessed; the jaw phenotype appears in adults rather
      than at hatching, and the report is a methods paper that describes the
      phenotype qualitatively without penetrance figures or histology.
    evidence:
    - reference: PMID:33272268
      reference_title: An optimized base editor with efficient C-to-T base editing in zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        zAncBE4max successfully generated the Twist2 p.E78K mutation in
        zebrafish, recapitulating pathological features of human ablepharon
        macrostomia syndrome (AMS).
      explanation: The authors' claim that the knock-in models AMS.
    - reference: PMID:30076894
      reference_title: Programmable base editing in zebrafish using a modified CRISPR-Cas9 system.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here we describe a protocol for using the base editing system in
        zebrafish and its application to reproduce a single base mutation
        observed in human Ablepharon-Macrostomia Syndrome.
      explanation: Methods paper from the same group describing the base-editing route to the AMS allele.
- name: hlh-8 Glu29 allelic series (C. elegans)
  species: Caenorhabditis elegans
  genotype: hlh-8 Glu29 substitutions equivalent to the five human TWIST1/TWIST2 disease alleles
  publication: PMID:28369379
  description: >-
    CRISPR-engineered endogenous hlh-8 Glu29 substitutions model the conserved TWIST1/TWIST2 residue. The AMS-equivalent Glu29Lys heterozygotes retained embryos and had markedly reduced egl-15 reporter expression, whereas the heterozygous frameshift-null control resembled wild-type. Homozygous Glu29Lys additionally impaired sex-myoblast proliferation more severely than the null allele. These readouts support dominant interference and a possible additional neomorphic effect, without modeling human eyelids or skin.
  modeled_mechanisms:
  - target: Dysregulated TWIST2-Dependent Mesenchymal Transcription
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Models the molecular character of the residue substitution in a
      single-Twist background, separating interference with the wild-type
      product from loss of dose.
    limitations: >-
      C. elegans has one Twist homolog and none of the affected human tissues;
      the M-lineage cellular readout speaks to allele behaviour and relative
      severity, not to skin, hair or eyelid development. Binding sites were
      not mapped in this model.
    evidence:
    - reference: PMID:28369379
      reference_title: Localized TWIST1 and TWIST2 basic domain substitutions cause four distinct human diseases that can be modeled in Caenorhabditis elegans.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This allelic series revealed that different substitutions exhibit
        graded severity, in terms of both gene expression and cellular
        phenotype, which we incorporate into a model explaining the various
        human disease phenotypes.
      explanation: Grades the Glu75-equivalent alleles in vivo.
    - reference: url:https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6
      reference_title: "https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast the Glu29†/+ animals exhibited a range of defects with Glu29Lys/+ the most defective with nearly 100% of the population not expressing the reporter at all
      explanation: >-
        Kim et al. (2017), PMID:28369379: egl-15::gfp expression in heterozygotes compared with a recessive frameshift-null control. This is a transcriptional reporter assay, not a DNA-binding map.
experimental_models:
- name: HeLa ChIP-seq of wild-type and mutant FLAG-TWIST2
  experimental_model_type: CELL_LINE
  publication: PMID:26119818
  description: >-
    Tetracycline-inducible T-REx HeLa lines overexpressing FLAG-HA-tagged
    wild-type TWIST2 or each disease allele, including p.Glu75Lys, profiled by
    anti-FLAG ChIP-seq.
  modeled_mechanisms:
  - target: Altered TWIST2 Genomic DNA-Binding Pattern
    relationship: MEASURES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Direct measurement of genome-wide binding of the AMS mutant protein
      against wild-type.
    limitations: >-
      Overexpression in a cervical cancer cell line without a wild-type allele
      co-expressed at physiological ratio, and not in craniofacial or dermal
      mesenchyme, so which peaks are relevant in patient tissue is unknown.
    evidence:
    - reference: PMID:26119818
      reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        All identified mutations fell in the basic domain of TWIST2 and altered
        the DNA-binding pattern of Flag-TWIST2 in HeLa cells.
      explanation: The measurement this model provides.
discussions:
- discussion_id: ams_residue_specific_phenotype_gap
  prompt: >-
    Why does lysine at TWIST2 residue 75 give ablepharon with sparse hair,
    when glutamine or alanine at the same residue gives ectropion with
    generalized hypertrichosis?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Sparse Scalp Hair
  - pathophysiology#Hair Follicle Development Deficit
  - mechanistic_hypotheses#twist2_glu75_neomorphic_binding
  rationale: >-
    The two allelic syndromes differ most in hair and in eyelid severity, yet
    no study among the references cited here has examined hair follicles,
    eyelid mesenchyme or target genes in either. The binding comparison of the
    alleles was done in HeLa cells. The hair follicle node in this entry is
    therefore hypothetical, and a residue-specific difference in target
    binding is the leading but untested explanation.
  evidence:
  - reference: PMID:27196381
    reference_title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Scalp hair is sparse in AMS only, but sparse eyebrows and eyelashes occur
      in both entities, and general hypertrichosis occurs in BSS.
    explanation: The opposite hair phenotypes of the two allelic syndromes.
- discussion_id: ams_developmental_outcome_gap
  prompt: >-
    How often does molecularly confirmed AMS cause developmental delay, and is
    any delay intrinsic to TWIST2 p.Glu75Lys or secondary to visual and hearing
    impairment and prolonged hospitalisation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Developmental Delay
  rationale: >-
    Older clinically diagnosed series reported delay in about two-thirds of patients. The molecular series documents
    variable motor and language delays alongside normal development, with two individuals unassessed and one delayed
    individual having cerebral hemorrhage. Later patient-perspective reports largely describe normal cognition.
    These are different outcomes and ascertainment frames; sensory impairment and prolonged hospitalization may
    also affect development. A systematic prospective assessment of genotyped patients is lacking.
  evidence:
  - reference: PMID:11807864
    reference_title: Ablepharon-macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental impairment was present in two-thirds of patients but was
      usually mild.
    explanation: The higher estimate from a clinically diagnosed series.
  - reference: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both are characterized by abnormalities in ectoderm-derived structures
      and cause a very unusual morphology of mainly the face in individuals
      with otherwise normal cognition and normal physical functioning.
    explanation: The later view, from contact with affected individuals, that cognition is normal.
  - reference: PMID:31462237
    reference_title: Laryngo-tracheal stenosis in a woman with ablepharon macrostomia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her intellectual and motor development was normal.
    explanation: Normal development in an adult with molecularly confirmed AMS.
- discussion_id: ams_model_fidelity_gap
  prompt: >-
    Would a heterozygous Twist2 Glu75Lys knock-in mouse reproduce the eyelid,
    skin and hair phenotype, and which mesenchymal targets would it show to be
    lost or newly bound?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Zebrafish twist2 p.Glu78Lys base-edited knock-in
  - pathophysiology#Altered TWIST2 Genomic DNA-Binding Pattern
  - pathophysiology#Craniofacial Soft-Tissue Patterning Defect
  rationale: >-
    The functional results for p.Glu75Lys come from overexpressed human
    protein (zebrafish mRNA injection, tagged protein in HeLa cells), from
    engineered alleles in the single C. elegans Twist homolog, and from one
    heterozygous zebrafish twist2 knock-in whose phenotype (jaw and mouth,
    emaciation) was described qualitatively in a methods paper. None of these
    organisms has eyelids, hair or mammalian dermis. Twist2 knockout mice
    model loss of function, which corresponds to Setleis syndrome rather than
    to this dominant allele. Whether the mechanism is dominant-negative,
    neomorphic or both cannot be settled until the allele is studied in
    mammalian mesenchyme. No mammalian knock-in model was found among the
    references cited here.
  evidence:
  - reference: PMID:20691403
    reference_title: Homozygous nonsense mutations in TWIST2 cause Setleis syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, Setleis syndrome patients and Twist2 knockout mice have similar
      facial features, indicating the gene's conserved role in mammalian
      development.
    explanation: >-
      The knockout mouse matches the recessive loss-of-function disorder, not
      AMS.
- discussion_id: ams_historical_case_reclassification
  prompt: Which older reports should be excluded from the AMS phenotype spectrum?
  kind: INTERPRETATION
  status: RESOLVED
  rationale: >-
    The 2016 critical review excluded the Pellegrino chromosome-18q case (PMID:8834257), the Amor/Savarirayan CNS case (PMID:11746001), the Kallish limb-anomaly case (PMID:22002929), and the Larumbe dental/skin case (PMID:23198177). The authors considered the Kallish phenotype an acrofacial dysostosis, possibly Nager syndrome, and the Larumbe phenotype severe congenital ichthyosis. The Amor/Savarirayan and Kallish cases tested negative for TWIST2 mutations. These exclusions limit the use of older clinically assembled series for phenotype frequencies and prevent transferring case-specific findings or interventions to molecularly defined AMS.
  evidence:
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient reported by Kallish et al. ... showed the phenotype of an acrofacial dysostosis, possibly Nager syndrome, and the differences to AMS were too significant to allow inclusion.
    explanation: >-
      De Maria et al. (2016), PMID:27196381: differential reassessment of the Kallish report.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lastly, the patient reported by Larumbe et al. ... clearly had severe congenital ichthyosis.
    explanation: >-
      De Maria et al. (2016), PMID:27196381: the dental/skin case is excluded from AMS.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This chromosome imbalance, the less marked eye signs, the pres- ence of supernumerary nipples, cutis laxa, widely spread joint contractures, edema, and marked developmental delay and seiz- ures make it unlikely that this patient should be diagnosed as having AMS.
    explanation: >-
      De Maria et al. (2016), PMID:27196381: reasons for excluding the Pellegrino 18q-rearrangement case.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
    reference_title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The latter two patients ... tested negatively for TWIST2 mutations
    explanation: >-
      De Maria et al. (2016), PMID:27196381: negative TWIST2 testing in two excluded cases. The review prints 2011 for Amor/Savarirayan here; the indexed report and bibliography are from 2001.
    quote_role: REVIEW_SYNTHESIS
references:
- reference: PMID:26119818
  title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
- reference: PMID:27196381
  title: "Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview."
- reference: PMID:11807864
  title: Ablepharon-macrostomia syndrome.
- reference: PMID:31373987
  title: "Long-Term Results of the Surgical Management of the Upper Eyelids in \"Ablepharon\"-Macrostomia Syndrome."
- reference: PMID:28690482
  title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
- reference: url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
  title: https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
- reference: url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf
  title: https://biblio.ugent.be/publication/8553102/file/8553201.pdf
- reference: url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
  title: "https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf"
- reference: url:https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6
  title: "https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6"
📚

References & Deep Research

References

9
PMID:26119818
Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
No top-level findings curated for this source.
PMID:27196381
Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview.
No top-level findings curated for this source.
PMID:11807864
Ablepharon-macrostomia syndrome.
No top-level findings curated for this source.
PMID:31373987
Long-Term Results of the Surgical Management of the Upper Eyelids in "Ablepharon"-Macrostomia Syndrome.
No top-level findings curated for this source.
PMID:28690482
Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View.
No top-level findings curated for this source.
url:https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
https://repository.ubn.ru.nl/bitstream/handle/2066/153827/153827.pdf
No top-level findings curated for this source.
url:https://biblio.ugent.be/publication/8553102/file/8553201.pdf
https://biblio.ugent.be/publication/8553102/file/8553201.pdf
No top-level findings curated for this source.
url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf
No top-level findings curated for this source.
url:https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6
https://ora.ox.ac.uk/objects/uuid%3A0b9cf8b9-01b4-43b7-95b4-b9c68ea74406/files/mf135269e0a132704a438813780ba4af6
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 (1)

Create: Ablepharon Macrostomia Syndrome · 2026-09-25T14:49:19Z · View source

Created the Ablepharon-Macrostomia Syndrome entry (MONDO:0008693; TWIST2 p.Glu75Lys, autosomal dominant). Sources: the OpenScientist deep-research report research/Ablepharon_Macrostomia_Syndrome-deep-research-openscientist.md (25/25 references resolved; two flagged off topic; term validation flagged HP:0011500 as Polycoria, so Ablepharon is bound to HP:0011224 after an OLS lookup), plus a PubMed title/abstract search for "ablepharon". just preflight-dr returned WARN only because the report also cites OMIM 227260 (Setleis syndrome) as a differential; the report header, causal gene (TWIST2, 50 mentions) and OMIM 200110 match the intended disease. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER) and ClinGen has no TWIST2 gene-validity row. Frequency bands are assigned only where a cited abstract states a proportion (for example the 2002 series and a 2019 literature review). The pathograph runs from the Glu75Lys substitution through altered DNA binding and dysregulated mesenchymal transcription to eyelid anterior-lamella, dermal matrix, hair-follicle, craniofacial and oral-commissure nodes, with the dominant-negative and neomorphic models kept as parallel mechanistic hypotheses as in the Barber-Say entry; 24 of 35 phenotypes are causally connected. Added the heterozygous zebrafish twist2 p.Glu78Lys knock-in (PMID:33272268) from the report. Report references not used: PMID:20980404 and PMID:18231602 (Wnt/beta-catenin control of Dermo1 expression and mesenchymal lineages, upstream of the lesion rather than part of it), PMID:19609939 (TWIST genes in adult mesenchymal stem cells), PMID:21109964 (TWIST2 promoter methylation in cancer lines), PMID:37493047 (cryptophthalmos cohort that does not mention AMS). Three AMS papers cached without quotable text (PMID:10721975, 11746001, 33689605) and are named in notes as leads. Full-text quotes: the reference validator currently refuses the cached full text of PMID:26119818 and PMID:28690482 (issue #12672), so every evidence item quoting their full text was either re-cited to a sentence from the same paper's abstract, re-cited to another cached paper, or removed. This removed the clinical-table frequency bands, the phenotypes supported only by that table (cleft ala nasi, hypoplastic labia majora, anteriorly placed anus, Blaschko-line pigmentation in mosaic fathers), the skin electron microscopy behind the dermal matrix node (now HYPOTHETICAL), and the ChIP-seq peak counts; omphalocele was replaced by ventral hernia, which an abstract supports. Validation: schema and term validation pass, count-verified-snippets reports 155/155, and validate-disorders reports 0 issues.

OpenScientist ▸
Ablepharon-Macrostomia Syndrome (AMS): Comprehensive Disease Characteristics Report
openscientist-autonomous 25 citations 2026-09-25T14:44:38.020257

Ablepharon-Macrostomia Syndrome (AMS): Comprehensive Disease Characteristics Report

Disease: Ablepharon-Macrostomia Syndrome MONDO ID: MONDO:0008693 OMIM: #200110 Category: Mendelian (autosomal dominant, de novo) Causal gene: TWIST2 (a.k.a. DERMO1), HGNC:20670, chromosome 2q37.3

Summary

Ablepharon-Macrostomia Syndrome (AMS) is an ultra-rare congenital ectodermal dysplasia (fewer than ~20 well-documented cases worldwide since its first description in 1977) defined by a nearly pathognomonic combination of ablepharon (absent or severely foreshortened eyelids with anterior-lamellar dysgenesis) and macrostomia (an abnormally wide, "fish-shaped" mouth), accompanied by absent eyebrows/eyelashes, external-ear malformations, malar/zygomatic hypoplasia, sparse hair/alopecia, dry ichthyotic redundant skin, rudimentary nipples, and ambiguous or abnormal genitalia. The disorder is caused by a recurrent de novo heterozygous missense mutation in TWIST2, c.223G>A (p.Glu75Lys / E75K), located in the basic DNA-binding domain of this basic helix-loop-helix (bHLH) transcription factor (PMID: 26119818). Remarkably, mutation of the same codon to glutamine or alanine (E75Q/E75A) produces the allelic Barber-Say syndrome (BSS) rather than AMS, one of the cleanest genotype–phenotype correlations in dysmorphology.

Mechanistically, the E75K substitution does not eliminate the protein (that would cause a different, recessive disease — Setleis syndrome); instead it alters the DNA-binding specificity of TWIST2, producing a dominant antimorphic/neomorphic effect that dysregulates the Wnt-downstream TWIST2/DERMO1 mesenchymal transcriptional program that governs dermal, craniofacial, and skin-appendage development. The result is faulty specification and differentiation of cranial-neural-crest- and mesoderm-derived mesenchymal progenitors, producing the characteristic eyelid, malar, ear, skin, and genital defects. The disorder is faithfully modeled in zebrafish (a base-edited twist2 p.E78K knock-in) and in C. elegans (an allelic series engineered into the single Twist homolog hlh-8).

There is no disease-modifying pharmacologic or gene therapy. Management is multidisciplinary, supportive, and surgical: urgent neonatal corneal protection (intensive lubrication, masquerade flaps) to prevent exposure keratopathy and blindness, followed by staged anterior-lamellar eyelid reconstruction (e.g., full-thickness skin grafts over the Müller-muscle/conjunctiva complex, rib-cartilage/fat grafting, reverse hatchet flaps), plus reconstructive surgery for macrostomia, ear, skin, and genital anomalies. Cognition and lifespan are generally normal; the major morbidity is ophthalmic. Both sexes are affected, there is no known population/founder enrichment, and there is no known non-genetic (environmental, infectious, lifestyle) contribution or prevention beyond genetic counseling.

1. Disease Information

Overview. AMS is an extremely rare congenital malformation syndrome of ectoderm- and mesenchyme-derived structures. It is characterized by absent/short eyelids (ablepharon), a wide fish-shaped mouth (macrostomia), external ear abnormalities, absent eyebrows/eyelashes, and a range of skin, skeletal, and genital anomalies (PMID: 15103726). It was first described by McCarthy and West in 1977.

Key identifiers. | Resource | Identifier | |---|---| | MONDO | MONDO:0008693 | | OMIM | #200110 (Ablepharon-Macrostomia Syndrome) | | Orphanet | ORPHA:920 | | MeSH | Ablepharon macrostomia syndrome (within "Ectodermal Dysplasia" tree) | | Gene | TWIST2 / DERMO1, HGNC:20670, NCBI Gene 117581 | | ICD-10 | Q18.8 / Q10.3 (other congenital malformations of face/eyelid) — no specific code | | ICD-11 | LD2F.1Y (other specified developmental anomalies) — no dedicated code |

Synonyms / alternative names. Ablepharon-macrostomia syndrome; AMS. It is closely related to (and allelic with) Barber-Say syndrome (BSS), and both belong to the TWIST2-related craniofacial/ectodermal dysplasia spectrum.

Data provenance. The disease-level knowledge base for AMS is derived almost entirely from aggregated case reports and small case series (individual patients described in the published literature) plus functional/molecular studies, rather than from large EHR cohorts or registries. Given fewer than ~20 reported cases, all epidemiologic and clinical statements are based on this aggregated case literature.

2. Etiology

Disease causal factors — genetic. AMS is a monogenic Mendelian disorder. The primary and essentially sole cause is a de novo heterozygous missense mutation in TWIST2, specifically c.223G>A, p.Glu75Lys (E75K) in the basic DNA-binding domain (PMID: 26119818; PMID: 28369379). Inheritance is autosomal dominant; most cases are sporadic (de novo), with rare familial transmission and rare mosaic cases.

Genetic risk factors. The single causal variant is the risk factor. There are no known susceptibility loci or modifier genes established for AMS beyond the allelic-series relationship at codon 75 that determines AMS vs BSS. No GWAS/polygenic contribution applies to this Mendelian condition.

Environmental risk factors. None identified. No toxins, teratogens, infections, parental age effects, occupational exposures, diet, or lifestyle factors have been implicated. The de novo mutations arise spontaneously.

Protective factors. None identified (neither genetic protective alleles nor environmental/dietary protective exposures are described for this single-gene disorder).

Gene–environment interactions. Not applicable / none reported. AMS is a fully penetrant consequence of the causal genotype; there is no evidence of environmental modulation.

3. Phenotypes

AMS phenotypes are congenital (present at birth), non-progressive/stable structural malformations (the ophthalmic complications, however, can progress if untreated), and highly consistent across reported patients for the two cardinal features. Frequencies below are qualitative given the tiny case literature.

Phenotype Type HPO term (suggested) Onset Frequency Notes
Ablepharon / absent or short eyelids (anterior-lamellar dysgenesis) Physical/structural HP:0011500 (Ablepharon) Congenital Cardinal (~100%; "absent" lids in ~60% of reports) Sight-threatening; anterior lamella specifically deficient (PMID: 34092176)
Macrostomia (wide fish-shaped mouth) Physical/structural HP:0000154 (Macrostomia) Congenital Cardinal (~100%)
Absent eyebrows and eyelashes Physical HP:0002223 (Absent eyebrow); HP:0000561 (Absent eyelashes) Congenital Very frequent
External ear abnormalities / dysplastic ears Physical HP:0000356 (Abnormal outer ear morphology) Congenital Frequent
Malar/zygomatic hypoplasia; zygomatic-arch absence Skeletal HP:0000272 (Malar flattening) Congenital Frequent Zygomatic arch absence reported (PMID: 3293678)
Alopecia / sparse hair; absent lanugo Ectodermal HP:0001596 (Alopecia); HP:0008070 (Sparse hair) Congenital Frequent
Dry, ichthyotic, redundant skin Ectodermal/skin HP:0008064 (Ichthyosis); HP:0001582 (Redundant skin) Congenital Frequent
Rudimentary/absent nipples Physical HP:0002557 (Rudimentary/absent nipples) Congenital Reported
Ambiguous / abnormal genitalia (e.g., absent prepuce) Physical HP:0000078 (Abnormality of the genital system) Congenital Frequent in both sexes Absent prepuce reported (PMID: 34850759)
Hypertelorism Physical HP:0000316 (Hypertelorism) Congenital Reported (PMID: 33055564)
Exposure keratopathy / corneal ulceration → vision loss Ophthalmic complication (secondary) HP:0000508 / HP:0000481 Neonatal onset, progressive if untreated Major morbidity Preventable with early intervention (PMID: 38967579)
Laryngo-tracheal malacia / stenosis Visceral (rare) HP:0001601 (Laryngomalacia) Variable Rare First stenosis case: PMID: 31462237

Canonical description (F003): "AMS is characterized by absent or short eyelids, absent eyebrows and eyelashes, macrostomia, and external ear abnormalities. Additional features include alopecia or sparse hair, hypoplastic malar region, redundant skin, rudimentary nipples, abnormal genitalia" (PMID: 15103726).

Severity/expressivity. Variable; mosaic TWIST2 expression yields a milder phenotype, with anterior-lamella abnormality remaining a common feature (PMID: 34092176).

Quality-of-life impact. The dominant QoL burden is ophthalmic — the eyelid defect causes lagophthalmos and exposure keratopathy that, untreated, leads to corneal ulceration and blindness (PMID: 38967579). Facial dysmorphism (macrostomia, ear, malar) carries psychosocial and functional (feeding, speech) impact requiring multidisciplinary reconstruction (PMID: 33689605). Cognition is generally normal. A patient's-view account underscores the lived experience of AMS/BSS (PMID: 28690482). No standardized EQ-5D/SF-36 QoL data exist for this ultra-rare disorder.

4. Genetic / Molecular Information

Causal gene. TWIST2 (also DERMO1), a bHLH transcription factor gene on chromosome 2q37.3 (HGNC:20670; OMIM *607556). UniProt Q8WVJ9.

Pathogenic variant. - AMS-specific variant: c.223G>A, p.Glu75Lys (E75K) — a missense change in the basic DNA-binding domain (PMID: 26119818). - Classification: Pathogenic (recurrent de novo, robust genotype–phenotype correlation, functional evidence) per ACMG/AMP criteria (PS2, PS1/PM5 at codon, PM1 in critical domain, PP3). - Allele frequency: Absent from population databases (gnomAD) — de novo, not a population polymorphism. - Origin: Germline de novo (germline/somatic mosaicism described in rare milder cases, PMID: 34092176). Not somatic/cancer-associated. - Functional consequence: Altered DNA binding — a dominant antimorphic/neomorphic effect, not simple loss of function or haploinsufficiency. "All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells" (PMID: 26119818); basic-domain substitutions "exert antimorphic effects" (PMID: 30450715).

The TWIST2 allelic series (F002) — a key organizing principle:

Variant Residue Disease Inheritance Mechanism
TWIST2 p.Glu75Lys E75 (basic domain) AMS (this disease) AD, de novo Altered DNA binding (antimorph)
TWIST2 p.Glu75Gln / Ala E75 (basic domain) Barber-Say syndrome AD, de novo Altered DNA binding (antimorph)
TWIST2 biallelic loss-of-function — Setleis syndrome / FFDD3 (MIM#227260) AR Loss of function
TWIST1 p.Glu117 (paralogous residue) basic domain Sweeney-Cox syndrome AD Altered DNA binding
TWIST1 haploinsufficiency — Saethre-Chotzen syndrome AD Loss of function (+ craniosynostosis)

"a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS" (PMID: 26119818). "subjects with Barber-Say and Ablepharon-Macrostomia syndromes were found to harbor heterozygous missense substitutions in the paralogous glutamic acid residue in TWIST2 (p.Glu75Ala, p.Glu75Gln and p.Glu75Lys)" and "This allelic series revealed that different substitutions exhibit graded severity, in terms of both gene expression and cellular phenotype" (PMID: 28369379). "Setleis syndrome (SS), or focal facial dermal dysplasia type III (FFDD3, MIM #227260), is an autosomal recessive condition caused by biallelic loss-of-function variants in TWIST2" (PMID: 36942595).

Modifier genes. None established. The E→ (K vs Q/A) identity at codon 75 is itself the principal genotype-driven modifier of phenotype (AMS vs BSS).

Epigenetic information. No disease-specific methylation signature is described for AMS. Of note, in cancer cell lines the DERMO1/TWIST2 promoter can be silenced by CpG-island hypermethylation (PMID: 21109964) — relevant to TWIST2 biology as a tumor-suppressor context but not to AMS pathogenesis.

Chromosomal abnormalities. None cause AMS; karyotype/CMA are normal in AMS and serve mainly to exclude CNV mimics. (By contrast, a 1p36.23p36.22 dosage change relates to the Setleis/FFDD3 spectrum, PMID: 36942595.)

5. Environmental Information

  • Environmental factors: None known. AMS is not caused or triggered by toxins, radiation, pollution, or occupational exposure.
  • Lifestyle factors: Not applicable — no smoking/diet/alcohol association (congenital de novo genetic disorder).
  • Infectious agents: None. AMS is not infectious in origin and has no known infectious trigger.

This section is essentially "not applicable" for AMS: it is a purely genetic, de novo Mendelian disorder.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A de novo heterozygous mutation TWIST2 c.223G>A (p.Glu75Lys) arises in the germline, placing a lysine in the basic DNA-binding domain of the TWIST2 (DERMO1) bHLH transcription factor. → leads to
  2. Altered DNA-binding specificity of the mutant TWIST2 protein (demonstrated: altered binding of Flag-TWIST2 in HeLa cells), producing a dominant antimorphic/neomorphic activity rather than loss of function. → results in
  3. Dysregulation of the TWIST2/DERMO1 transcriptional program in mesenchymal progenitor cells. TWIST2 normally dimerizes with E-proteins, binds E-box DNA, and acts downstream of canonical Wnt/β-catenin signaling as a master regulator of dermal/mesenchymal lineage identity. → leads to
  4. Impaired specification and differentiation of cranial-neural-crest- and mesoderm-derived mesenchymal progenitors (dermal fibroblasts, cranial mesenchyme, chondrogenic/osteogenic and adipogenic precursors). → results in
  5. Faulty morphogenesis of ectoderm-associated mesenchymal structures: eyelid anterior lamella, malar/zygomatic bone, auricular cartilage, hair follicles, skin, nipples, and genitalia. → manifests as
  6. Clinical phenotype: ablepharon, macrostomia, malar/zygomatic hypoplasia, ear dysplasia, sparse hair, redundant/ichthyotic skin, rudimentary nipples, ambiguous genitalia.
  7. [Downstream / inferred, secondary] Anterior-lamella deficiency → lagophthalmos → corneal exposure → exposure keratopathy → corneal ulceration → blindness if untreated.

Branch note: Steps 1–3 are demonstrated in vitro and in animal models; steps 4–5 are inferred from TWIST2/DERMO1 developmental biology; step 7 is a well-documented secondary mechanical consequence.

Supporting detail by category

  • Molecular pathways. Canonical Wnt/β-catenin → DERMO1/TWIST2 axis. "Wnt signaling/β-catenin is absolutely required and sufficient for Dermo1 expression and dermal cell identity in the cranium" (PMID: 20980404). In zebrafish skin-appendage development, "the expression of twist2/dermo1 and twist3 is regulated by Wnt signaling" (PMID: 33994357). GO suggestions: GO:0016055 (Wnt signaling pathway), GO:0006357 (regulation of transcription by RNA Pol II), GO:0003700 (DNA-binding transcription factor activity).
  • Cellular processes. Mesenchymal stem-cell self-renewal and lineage commitment; suppression of osteogenesis and promotion of adipogenesis via Id genes. "implicate the TWIST gene family members as potential mediators of MSC self-renewal and lineage commitment in postnatal skeletal tissues" (PMID: 19609939). GO: GO:0060485 (mesenchyme development), GO:0001837 (EMT), GO:0030154 (cell differentiation).
  • Protein dysfunction. bHLH transcription factor with altered DNA-binding; gain-of-abnormal-function/antimorph, not misfolding/aggregation. Basic-domain substitutions "exert antimorphic effects" (PMID: 30450715).
  • Metabolic changes / immune involvement / oxidative injury: Not primary to AMS. (Twist2-null mice — a loss-of-function context distinct from AMS — show elevated proinflammatory cytokines and perinatal death, illustrating TWIST2's role restraining inflammation, but this is not the AMS mechanism.)
  • Biochemical abnormality. Transcription-factor DNA-binding defect (no enzyme/ion-channel deficiency).
  • Molecular profiling. Mutant TWIST2 expressed in zebrafish embryos causes widespread transcriptome changes and abnormal developmental phenotypes (PMID: 26119818); the C. elegans hlh-8 allelic series shows graded gene-expression changes (PMID: 28369379). No human patient transcriptomic/proteomic/metabolomic datasets exist.

Cell types (CL suggestions): dermal fibroblast (CL:0000057), mesenchymal stem cell (CL:0000134), cranial neural crest cell (CL:0000333), chondrocyte (CL:0000138). GO biological processes: mesenchyme development (GO:0060485), skin development (GO:0043588), palate development, hair follicle morphogenesis (GO:0031069).

7. Anatomical Structures Affected

Organ level (primary). - Eyelids / anterior lamella (UBERON:0000014 skin of eyelid; UBERON:0001711 eyelid) — cardinal. - Mouth / oral opening (UBERON:0000165 mouth) — macrostomia. - External ear / auricle (UBERON:0001757 pinna). - Malar/zygomatic bone (UBERON:0001683 zygomatic bone) — hypoplasia/arch absence. - Skin (UBERON:0002097) — ichthyotic, redundant. - Hair follicles (UBERON:0002073) — sparse hair/alopecia. - Nipple/breast (UBERON:0002030) — rudimentary nipples. - External genitalia (UBERON:0000990 reproductive system) — ambiguous/abnormal.

Secondary organ involvement. - Cornea/ocular surface (UBERON:0000964) — exposure keratopathy, ulceration (mechanical consequence of eyelid defect). - Larynx/trachea (UBERON:0001737 / UBERON:0003126) — rare malacia/stenosis (PMID: 31462237).

Body systems: integumentary (skin/hair/nails), musculoskeletal (craniofacial bone/cartilage), ocular/adnexal, reproductive/genitourinary, and (rarely) respiratory.

Tissue/cell level. Predominantly mesenchyme-derived connective tissue (dermis, cranial mesenchyme, cartilage/bone precursors) and their epithelial appendages. Targeted cell populations: dermal fibroblasts (CL:0000057), mesenchymal stem cells (CL:0000134), cranial neural crest cells (CL:0000333), chondrocytes (CL:0000138).

Subcellular level. The molecular lesion resides in the nucleus (GO:0005634) — a DNA-binding transcription factor acting on chromatin (GO:0003700 DNA-binding TF activity; GO:0000981).

Localization / lateralization. Craniofacial midline and paired bilateral structures; the eyelid, ear, and malar defects are typically bilateral (e.g., "bilateral absence or hypoplasia of lower eyelids," PMID: 3293678).

8. Temporal Development

  • Onset: Congenital — all structural features are present at birth; the disorder is fully developmental. Onset pattern is fixed/congenital rather than acute or progressive.
  • Progression: The malformations themselves are stable/non-progressive (structural). The ophthalmic complication is time-critical: exposure keratopathy can develop within the first days of life and progress to corneal ulceration and permanent vision loss without intervention (PMID: 29538102; PMID: 38967579).
  • Disease course / duration: Chronic/lifelong structural condition; managed by staged reconstruction over childhood into adulthood. Patients survive into adulthood (reported at ages 37 and 46 years: PMID: 31462237; PMID: 15103726).
  • Critical periods: The neonatal period is the key window of vulnerability (corneal protection) and of intervention opportunity. Staged eyelid reconstruction thereafter shows durable results at 10–15 year follow-up (PMID: 31373987).
  • Remission: Not applicable (structural congenital malformation); surgical correction is the only route to functional improvement.

9. Inheritance and Population

Epidemiology. Ultra-rare. "Only 15 patients with AMS have been described in 12 articles" (PMID: 31373987); "fewer than 20 cases being reported in the literature" (PMID: 33055564). Prevalence/incidence are not formally quantifiable but far below 1/1,000,000. No population-based registry data exist.

Genetic etiology. - Inheritance pattern: Autosomal dominant, almost always de novo; rare familial transmission and rare mosaic cases (PMID: 31462237; PMID: 39792429; PMID: 34092176). - Penetrance: Complete for the constitutional E75K genotype (mosaicism attenuates severity). - Expressivity: Variable; mosaic expression → milder phenotype (PMID: 34092176). - Anticipation: Not applicable (not a repeat-expansion disorder). - Germline/somatic mosaicism: Reported in rare milder cases. - Founder effects / consanguinity: None described; parents typically unrelated (PMID: 34850759). (Consanguinity is relevant to the recessive Setleis syndrome, not AMS.) - Carrier frequency: Not applicable (dominant, de novo).

Population demographics. - Affected populations: Worldwide, no ethnic enrichment; cases reported across regions including the first West African report (PMID: 34850759). - Geographic distribution: None (sporadic, global). - Sex ratio: Both sexes affected; ambiguous genitalia reported in both males and females (no strong sex bias). - Age distribution: Diagnosed at birth; patients span neonates to at least the fifth decade.

10. Diagnostics

Diagnostic approach (F008). Diagnosis is clinical gestalt — the pathognomonic combination of ablepharon + macrostomia with ectodermal/craniofacial/genital features at birth — confirmed by molecular testing.

  • Genetic testing:
  • Single-gene TWIST2 sequencing for the recurrent c.223G>A (p.Glu75Lys) is the confirmatory test of choice; the specific codon-75 substitution also distinguishes AMS (E75K) from allelic BSS (E75Q/E75A) (PMID: 26119818).
  • Whole-exome/whole-genome sequencing is useful when the diagnosis is uncertain or for gene discovery.
  • Chromosomal microarray / karyotype are typically normal; their role is to exclude CNV/aneuploidy mimics.
  • Mitochondrial DNA, repeat-expansion, and FISH testing are not indicated.
  • Clinical tests / imaging: Skull radiography/CT can demonstrate malar/zygomatic hypoplasia or zygomatic-arch absence (PMID: 3293678; PMID: 34850759). Ophthalmic slit-lamp examination assesses corneal integrity/exposure. Bronchoscopy is used if airway symptoms suggest laryngo-tracheal malacia/stenosis (PMID: 31462237).
  • Laboratory/biomarkers: No specific biochemical biomarker; diagnosis is molecular. Endocrine/genital work-up may be needed for ambiguous genitalia.
  • Omics-based diagnostics: Not used clinically for AMS.

Clinical criteria. No formal consensus diagnostic criteria; diagnosis rests on the characteristic phenotype + TWIST2 variant.

Differential diagnosis. | Condition | Gene/mechanism | Distinguishing feature | |---|---|---| | Barber-Say syndrome (allelic) | TWIST2 E75Q/E75A | Hypertrichosis (vs sparse hair in AMS); codon-75 substitution differs (PMID: 28680619) | | Saethre-Chotzen syndrome | TWIST1 haploinsufficiency | Craniosynostosis — a cardinal feature absent in AMS (PMID: 30450715) | | Sweeney-Cox syndrome | TWIST1 Glu117 | Paralogous TWIST1 basic-domain substitution (PMID: 28369379) | | Setleis syndrome / FFDD3 | TWIST2 biallelic LoF (AR) | Recessive; focal facial dermal dysplasia (PMID: 36942595) | | Fraser / cryptophthalmos spectrum | FRAS1 / FREM2 / GRIP1 | Cryptophthalmos (skin covering eye), syndactyly (PMID: 37493047) |

"craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome" — its absence is a key discriminator for AMS (PMID: 30450715).

Screening. No population newborn screening exists (ultra-rare, clinically obvious at birth). Cascade/carrier screening is generally unnecessary given de novo origin, but molecular confirmation informs recurrence-risk counseling.

11. Outcome / Prognosis

  • Survival / mortality: Generally normal life expectancy; cognition typically normal. AMS is not intrinsically lethal — patients reach adulthood (documented at 37 and 46 years). Rare life-threatening events are secondary (e.g., acute airway compromise from laryngo-tracheal stenosis requiring tracheostomy, PMID: 31462237).
  • Morbidity / function: Dominated by ophthalmic morbidity — untreated exposure keratopathy can cause permanent vision loss/blindness (PMID: 38967579; PMID: 33055564). Facial dysmorphism affects feeding, speech, and psychosocial function.
  • Disease course / complications: Exposure keratopathy, corneal ulceration; feeding/airway issues; psychosocial impact. Surgical reconstruction substantially improves function and appearance.
  • Recovery potential: Structural defects are surgically correctable with good durability — full-thickness skin grafts over Müller muscle gave clear corneas at 10–15 year follow-up (PMID: 31373987).
  • Prognostic factors: Timeliness of neonatal corneal protection is the principal determinant of visual outcome. Mosaic cases have milder overall prognosis (PMID: 34092176).
  • Prognostic biomarkers: None molecular; genotype (E75K constitutional vs mosaic) predicts severity.

12. Treatment

No disease-modifying pharmacotherapy or gene/RNA/cell therapy exists. Management is supportive, surgical, and multidisciplinary (F004).

Urgent supportive care (neonatal). Intensive ocular lubrication to prevent exposure keratopathy; "Despite intensive ocular lubrication, severe exposure keratopathy developed within the first days after birth. The eyes were closed using masquerade flaps" (PMID: 29538102). NCIT suggestions: ocular lubricant therapy, supportive care (NCIT:C15277).

Surgical / interventional — eyelid (anterior-lamella) reconstruction. The eyelids are not truly absent but foreshortened with anterior-lamellar dysgenesis; staged reconstruction is the standard:

Technique Evidence Outcome
Full-thickness skin grafts over Müller-muscle/conjunctiva complex PMID: 31373987 "all 3 cases who underwent upper eyelid lengthening with full thickness skin grafts placed over Müller muscle had clear corneas"; durable at 10–15 yr
Masquerade flaps (urgent), then staged division PMID: 29538102 Emergency corneal protection in severe neonates
Autologous rib cartilage + fat grafting (lower lid) PMID: 33055564 First reported use for lower-lid reconstruction
Modified reverse hatchet flap + preputial skin graft PMID: 38967579 Corneal protection / lid lengthening
Deep skin grafts adjusting eyelid contour/position PMID: 39792429 Improved eyelid contour and position

Other reconstructive surgery. Macrostomia repair (commissuroplasty), ear reconstruction, malar augmentation, skin and genital surgery, all coordinated multidisciplinarily (PMID: 33689605). Airway stenosis managed by temporary tracheostomy + corticosteroids (PMID: 31462237). NCIT suggestions: reconstructive surgical procedure, skin graft (NCIT:C15325), tracheostomy (NCIT:C51796).

Supportive/rehabilitative. Feeding support, speech therapy, and psychosocial support as needed.

Experimental / advanced therapeutics. None; no ClinicalTrials.gov interventional trials for AMS. Pharmacogenomics, targeted therapy, and immunotherapy are not applicable.

Treatment strategy. Algorithm: (1) immediate corneal protection at birth → (2) staged anterior-lamellar eyelid reconstruction → (3) sequential correction of macrostomia, ear, malar, skin, and genital anomalies, timed to growth and function.

13. Prevention

  • Primary prevention: None possible — de novo mutation; not preventable by risk-factor modification, vaccination, or lifestyle change.
  • Secondary prevention: Early recognition and immediate neonatal corneal protection is the critical "secondary prevention" that prevents the major preventable complication (blindness) (PMID: 29538102; PMID: 38967579).
  • Tertiary prevention: Staged reconstruction and ongoing ophthalmic/multidisciplinary follow-up to prevent complications and disability.
  • Genetic screening / counseling: For families with an affected child, recurrence risk is low (de novo) but non-zero due to possible germline mosaicism; genetic counseling and, where desired, prenatal/preimplantation testing for the known TWIST2 variant are appropriate. Prenatal ultrasound may detect facial anomalies.
  • Immunization, public-health, environmental, behavioral, prophylactic measures: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy / natural disease: No naturally occurring AMS-equivalent disease is reported in companion animals or wildlife (OMIA has no AMS entry). AMS is a human de novo disorder; there is no zoonotic or cross-species transmission (not applicable).
  • Orthologous genes: TWIST2/DERMO1 is evolutionarily conserved — zebrafish twist2/dermo1 (and twist3), C. elegans single Twist homolog hlh-8 (residue Glu29), and mouse Twist2/Dermo1. The disease-critical glutamic-acid residue (human Glu75) is conserved across paralogs and orthologs (PMID: 28369379).
  • Comparative biology: The graded-severity allelic series across TWIST1/TWIST2 basic-domain substitutions is conserved and reproducible in C. elegans, demonstrating deep evolutionary conservation of the Twist-family transcription-factor mechanism (PMID: 28369379).

15. Model Organisms

AMS is well-modeled experimentally (F006):

Model Construct Recapitulation Reference
Zebrafish (Danio rerio) CRISPR base-edited twist2 p.E78K knock-in (paralogous to human E75K) "recapitulating pathological features of human ablepharon macrostomia syndrome (AMS)" PMID: 33272268; protocol PMID: 30076894
Zebrafish (overexpression) Mutant TWIST2 mRNA in embryos Abnormal developmental phenotypes + widespread transcriptome changes PMID: 26119818
C. elegans All five TWIST1/TWIST2 disease alleles engineered into hlh-8 Glu29 Graded severity of gene-expression and M-lineage/muscle cellular phenotypes PMID: 28369379
In vitro (HeLa) Flag-TWIST2 mutants Altered DNA-binding pattern PMID: 26119818
Mouse (Twist2/Dermo1) Knockout / Dermo1-Cre lineage tools Developmental biology of Wnt/β-catenin–Dermo1 mesenchyme; Twist2-null → perinatal death with elevated proinflammatory cytokines PMID: 20980404, PMID: 18231602

"zAncBE4max successfully generated the Twist2 p.E78K mutation in zebrafish, recapitulating pathological features of human ablepharon macrostomia syndrome (AMS)" (PMID: 33272268). "we engineered all five disease-associated alleles into the equivalent Glu29 residue encoded by hlh-8, the single Twist homolog present in Caenorhabditis elegans" (PMID: 28369379).

Applications: These models enable study of the antimorphic DNA-binding mechanism, the allelic-series severity gradient (AMS vs BSS vs Sweeney-Cox), and downstream transcriptional dysregulation. Limitations: Invertebrate/fish models incompletely capture human craniofacial/ectodermal complexity; no mouse knock-in of the exact E75K antimorph is reported for full AMS phenotype recapitulation. Resources: ZFIN (zebrafish), WormBase (C. elegans), MGI (mouse Twist2).

Mechanistic Model / Interpretation

    de novo TWIST2 c.223G>A (p.Glu75Lys) — basic DNA-binding domain
                   |  [demonstrated]
                   v
 Altered TWIST2 DNA-binding specificity
 (dominant ANTIMORPH — not loss of function)
                   |  [demonstrated: HeLa; zebrafish transcriptome]
                   v
       Wnt/beta-catenin --> DERMO1/TWIST2 transcriptional program DYSREGULATED
                   |  [inferred from developmental biology]
                   v
      Impaired specification/differentiation of mesenchymal progenitors
      (dermal fibroblasts, cranial NCC-derived mesenchyme, cartilage/bone)
                   |
+--------------+----------+-----------+-------------+-----------+
v              v                      v             v           v
   eyelid anterior  malar/zygomatic      auricular      hair/skin   genital/
   lamella defect     hypoplasia          cartilage    (ichthyosis, nipple
|            (arch absence)        dysplasia    alopecia)    anomalies
v
   ABLEPHARON --> lagophthalmos --> corneal exposure --> exposure keratopathy
                   [secondary/mechanical] --> ulceration --> BLINDNESS (if untreated)

   MACROSTOMIA (wide fish-shaped mouth) — parallel branch of oral mesenchyme defect

Key interpretive points. (1) The allele identity at codon 75 determines the disease (K→AMS, Q/A→BSS), while the mechanism determines the axis (dominant antimorph → AMS/BSS; recessive LoF → Setleis) — a textbook demonstration of how different mutation types in one gene yield distinct diseases. (2) The mechanism is a transcription-factor DNA-binding perturbation upstream of a broad developmental program, explaining the pleiotropic, multi-structure phenotype. (3) The most clinically actionable step is downstream and mechanical (eyelid → cornea), which is why timely surgical/supportive intervention — not molecular therapy — currently drives outcomes.

Evidence Base

PMID Contribution Supports
26119818 Landmark: recurrent basic-domain TWIST2 mutations; E75K→AMS, E75Q/A→BSS; altered DNA binding in HeLa; zebrafish transcriptome F001, F002, F007, F008 (core causal + mechanism)
28369379 TWIST1/TWIST2 allelic series; C. elegans hlh-8 modeling; graded severity F002, F006
36942595 Recessive LoF TWIST2 → Setleis/FFDD3 (contrasts dominant AMS) F002, F008
30450715 Antimorphic effect of basic-domain substitutions; craniosynostosis distinguishes Saethre-Chotzen from AMS F002, F005, F007, F008
15103726 Canonical clinical feature list (46-yr-old patient) F003
3293678 Zygomatic-arch absence; bilateral lid involvement F003, F007
34092176 Mosaic TWIST2 → milder phenotype; anterior-lamella hallmark F003, F005
34850759 First West African case; absent prepuce; unrelated parents F003, F005
31462237 Laryngo-tracheal stenosis; AD mutation; adult survival F003, F005
38967579 Sight-threatening keratopathy; reverse hatchet flap F003, F004
31373987 Definitive skin-graft-over-Müller technique; 10–15 yr outcomes; "only 15 patients" F004, F005
29538102 Masquerade flap; urgent neonatal corneal protection F004
33055564 Rib-cartilage/fat grafting; "<20 cases" F004, F005
39792429 Deep skin grafts; AD inheritance statement F004, F005
33689605 Multidisciplinary care F004
33272268 Zebrafish twist2 E78K knock-in recapitulates AMS F006
30076894 Base-editing protocol reproducing the AMS mutation in zebrafish F006
20980404 Wnt/β-catenin required/sufficient for Dermo1 + cranial dermal identity F007
33994357 twist2/dermo1 Wnt-regulated in skin-appendage development F007
19609939 TWIST family mediates MSC self-renewal/lineage commitment F007
28680619 Barber-Say (hypertrichosis) differential F008
37493047 Cryptophthalmos/Fraser differential F008
28690482 Patient's-view QoL perspective Section 3
21109964 DERMO1 promoter methylation (cancer context) Section 4 (epigenetics, non-AMS)
18231602 Dermo1-Cre/β-catenin mesenchymal lineage biology Section 6/15

Evidence-type mix: human clinical (case reports/series), in vitro (HeLa DNA-binding), and model organism (zebrafish, C. elegans, mouse). There are no large human -omics cohort datasets for AMS.

Limitations and Knowledge Gaps

  1. Tiny evidence base. Fewer than ~20 reported patients; all clinical/epidemiologic claims rest on aggregated case reports — no registries, no prevalence/incidence figures, no controlled QoL data.
  2. Mechanism partly inferred. Steps 1–3 (mutation → altered DNA binding → transcriptome change) are demonstrated; steps 4–5 (tissue-specific developmental failure) are inferred from TWIST2/DERMO1 biology, not directly from AMS patient tissue.
  3. No exact mammalian knock-in. The zebrafish E78K and C. elegans hlh-8 models are informative but phylogenetically distant; no mouse Twist2 E75K knock-in recapitulating the full craniofacial AMS phenotype has been reported.
  4. No molecular therapy. No pharmacologic, gene-editing, or ASO approach is in development; the antimorphic/dominant mechanism (rather than simple LoF) complicates gene-replacement strategies.
  5. Genotype–phenotype nuance unresolved. Why lysine (E75K) specifically yields AMS while glutamine/alanine yield BSS — i.e., the precise altered DNA-binding readout — is not fully mapped at the level of target genes.
  6. Under-characterized systemic involvement. Rare visceral features (airway, genital) are described anecdotally; their true frequency and natural history are unknown.

Proposed Follow-up Experiments / Actions

  1. Patient-derived iPSC / organoid models: Generate TWIST2 E75K iPSCs and differentiate into cranial-neural-crest and dermal mesenchyme to directly map the dysregulated transcriptional program (RNA-seq + CUT&RUN/ChIP-seq for mutant vs WT TWIST2 genome-wide binding).
  2. Precise mouse knock-in: Create a conditional Twist2 E75K knock-in mouse to test craniofacial/eyelid/skin phenotype recapitulation and to serve as a preclinical platform.
  3. Define the altered-binding "neo-target" set: Comparative genome-wide binding of E75K vs E75Q/A vs WT to explain the AMS-vs-BSS divergence mechanistically.
  4. Allele-selective silencing proof-of-concept: Given the dominant antimorph, test allele-specific ASO/siRNA or base-editing correction in the zebrafish E78K model as a therapeutic feasibility study.
  5. International registry + natural-history study: Pool the ultra-rare cases to quantify feature frequencies, ophthalmic outcomes, and standardized QoL (validated instruments), and to formalize diagnostic/management guidelines.
  6. Standardize surgical outcome reporting: Prospective, multi-center comparison of eyelid-reconstruction techniques (skin-graft-over-Müller vs rib-cartilage/fat vs flaps) with corneal and cosmetic endpoints at ≥10 years.

Report compiled from 8 confirmed findings and 29 reviewed papers over a 5-iteration autonomous investigation. Evidence types: human clinical case literature, in vitro DNA-binding assays, and zebrafish/C. elegans/mouse model-organism studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 25
On topic 15
Off topic 2

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:20980404 (6 mentions) - Role of canonical Wnt signaling/ß-catenin via Dermo1 in cranial dermal cell development.
  • shared terms: dermo1
  • PMID:19609939 (4 mentions) - TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment.
  • shared terms: gene

Weighed against this report's own most characteristic terms: ams, twist2, phenotype, skin, dna-binding, gene, dermo1, dominant, novo, corneal, disease, e75k, exposure, eyelid, bss, mutation, mechanism, macrostomia, patient, syndrome.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome Count
Terms checked 48
Resolved 46
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 14
Terms named correctly 6
Terms named as a different term 2
Terms whose name is worth a second look 6

Terms the report names something else

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

  • MONDO:0008693 (2 mentions) - the report calls it "MONDO"; MONDO calls it ablepharon macrostomia syndrome
  • HP:0011500 (1 mention) - the report calls it "Ablepharon"; HP calls it Polycoria

Terms whose name is worth a second look

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

  • HP:0000154 (1 mention) - the report calls it "Macrostomia"; HP calls it Wide mouth, and lists "Macrostomia" among its other names
  • HP:0000356 (1 mention) - the report calls it "Abnormal outer ear morphology"; HP calls it Abnormality of the outer ear
  • HP:0002557 (1 mention) - the report calls it "Rudimentary/absent nipples"; HP calls it Hypoplastic nipples, and lists "Small nipples" among its other names
  • UBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other names
  • UBERON:0002030 (1 mention) - the report calls it "Nipple/breast"; UBERON calls it nipple
  • UBERON:0000964 (1 mention) - the report calls it "Cornea/ocular surface"; UBERON calls it cornea, and lists "cornea of camera-type eye" among its other names

Prefixes with no resolver

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