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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous TWIST2 basic-domain variants cause autosomal dominant disease. De novo origin was demonstrated when both unaffected parents were available in the discovery study. Father-to-daughter transmission is documented, including BSS-4.1, a mildly affected mosaic father of two affected daughters. The reported three transmitting mosaic parents in the discovery paper refer to the combined AMS/BSS series, not three Barber-Say fathers. A 1999 mother-to-son report was subsequently reassessed: the mother remained a convincing case, but the son's diagnosis was insufficiently documented. Parental testing informs recurrence counseling; mild parental features and tissue-dependent mosaicism complicate interpretation.

Autosomal dominant inheritance

Show evidence (5 references)

PMID:10440829 SUPPORT Human Clinical

"We report on a mother-to-son transmission of the Barber-Say syndrome, a finding that strongly supports dominant inheritance of this rare disorder."

Historical report of proposed mother-to-son transmission. The 2016 critical review accepted the mother but excluded the son from its confirmed series because available data were insufficient; this report alone does not establish the son as an affected case.

PMID:20799330 SUPPORT Human Clinical

"We report on a father to daughter transmission of Barber-Say syndrome (BSS)"

A second vertically transmitting family.

PMID:26119818 SUPPORT Human Clinical

"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."

Establishes de novo origin in simplex families and subsequent transmission.

+ 2 more references

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Mechanistic Hypotheses

2

Glu75 substitutions interfere with the wild-type TWIST2 pool

twist2_glu75_dominant_negative EMERGING

Evidence balance 4 support

Under this model the mutant subunit still enters TWIST2 homodimers and bHLH heterodimers but those complexes fail to bind the normal E-box targets, so the wild-type protein is inactivated along with it. Support comes from the ChIP-seq loss of wild-type peaks, from the C. elegans hlh-8 allelic series, which favours a predominantly dominant-negative mechanism for the TWIST1/TWIST2 residue substitutions, and from phenotypic overlap with Setleis syndrome, which is caused by biallelic loss of TWIST2 function. Not mutually exclusive with the neomorphic model.

Pathograph links

Altered TWIST2 Genomic DNA-Binding Pattern -> Dysregulated TWIST2-Dependent Mesenchymal Transcription INDIRECT UNKNOWN INTERMEDIATES Altered target occupancy could change transcription through interference with normal TWIST2 complexes or acquisition of new targets. The proportion of dysfunctional dimers in patient tissue was not measured.

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 the TWIST2 Glu75 alleles engineered at the equivalent hlh-8 residue.

PMID:26119818 SUPPORT Human Clinical

"Supporting a contribution by the first mechanism is the phenotypic overlap with Setleis syndrome"

The primary paper's argument for the dominant-negative model from phenotypic overlap with the recessive loss-of-function allelic disorder.

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

Glu75 substitutions give TWIST2 new genomic targets

twist2_glu75_neomorphic_binding EMERGING

Evidence balance 2 support

Under this model the disease-relevant effect is the binding of mutant TWIST2 to sites the wild-type protein does not occupy, changing expression of genes TWIST2 does not normally regulate. The observation behind it is the large set of mutant-only ChIP-seq peaks. It would also offer an explanation for why lysine at the same residue (AMS) and glutamine or alanine (BSS) give different syndromes, but no study has tested that target-set difference in a relevant tissue.

Pathograph links

Altered TWIST2 Genomic DNA-Binding Pattern -> Dysregulated TWIST2-Dependent Mesenchymal Transcription INDIRECT UNKNOWN INTERMEDIATES Altered target occupancy could change transcription through interference with normal TWIST2 complexes or acquisition of new targets. The proportion of dysfunctional dimers in patient tissue was not measured.

Show evidence (2 references)

PMID:26119818 SUPPORT In Vitro

"two possible mechanisms: a dominant-negative effect due to loss of binding to the normal contingent of TWIST2 DNA binding sites or a neomorphic mechanism due to binding of the mutant TWIST2 to extraneous promoter sites"

The primary functional study states the neomorphic mechanism as an alternative to the dominant-negative one.

PMID:26119818 SUPPORT In Vitro

"A significant number of binding peaks detected for the mutant TWIST2 proteins were not detected for the wild-type protein"

The mutant-only binding peaks the neomorphic model rests on.

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Discussions and Knowledge Gaps

2

How do the Glu75Gln and Glu75Ala substitutions produce generalized hypertrichosis, when Glu75Lys at the same residue gives sparse scalp hair?

KNOWLEDGE GAP OPEN bss_hypertrichosis_mechanism_gap

Attached to

phenotypes#Congenital Generalized Hypertrichosis mechanistic_hypotheses#twist2_glu75_neomorphic_binding

The opposing hair distributions in Barber-Say and ablepharon-macrostomia syndromes remain unexplained by the cited functional studies. Clinical skin biopsies have examined follicles, but the studies do not establish how these alleles alter the signaling that controls hair growth. HeLa binding differences suggest a testable hypothesis, not a demonstrated follicular mechanism.

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.

Would a heterozygous Twist2 Glu75Gln 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 bss_model_fidelity_gap

Attached to

animal_models#Zebrafish pathophysiology#Altered TWIST2 Genomic DNA-Binding Pattern

The cited Barber-Say functional studies use human TWIST2 overexpression in zebrafish or HeLa cells, or conserved-residue substitutions in C. elegans. The worm study does include endogenous heterozygotes with a wild-type allele, unlike the overexpression assays, but cannot reproduce mammalian skin, hair and eyelid anatomy. The cited studies do not include a Barber-Say knock-in mammalian model or identify the patient-tissue targets responsible for each manifestation.

Show evidence (1 reference)

PMID:26119818 SUPPORT Model Organism

"Simple overexpression of the wild-type protein in zebrafish caused a mild developmental phenotype."

Shows that the zebrafish system responds to TWIST2 dose itself, limiting what it can say about the heterozygous allele.

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Pathophysiology

6

TWIST2 Basic-Domain Variant

Mechanism confidence: Established

Heterozygous variants alter the DNA-contacting basic domain of TWIST2. The discovery series contained p.Glu75Gln, p.Glu75Ala and p.Gln77_Arg78dup. The p.Glu75Lys substitution instead segregated with ablepharon-macrostomia syndrome. Structural modeling predicted altered DNA interaction rather than a gross change in protein fold; that prediction is distinct from the measured binding changes in HeLa cells.

TWIST2 hgnc:20670

Genetic context TWIST2 hgnc:20670 zygosity: HETEROZYGOUS

Heterozygous missense substitutions p.Glu75Gln and p.Glu75Ala and the in-frame duplication p.Gln77_Arg78dup, including de novo, inherited and mosaic presentations. Dominant-negative and neomorphic mechanisms are recorded as hypotheses because binding changes alone do not establish their relative contribution in human tissue.

Downstream

Altered TWIST2 Genomic DNA-Binding Pattern The substituted basic domain changes where TWIST2 binds the genome.

Show evidence (4 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."

Identifies the recurrent causal residue across unrelated BSS families.

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 ablepharon-macrostomia syndrome.

PMID:26119818 SUPPORT Human Clinical

"A 12th individual with BSS, BSS-1.1, carried a heterozygous c.229_234dupCAGCGC (p.Gln77_Arg78dup) mutation"

The one non-Glu75 allele in the series, also in the basic domain.

+ 1 more reference

Altered TWIST2 Genomic DNA-Binding Pattern

Mechanism confidence: Provisional

ChIP-seq in T-REx HeLa cells overexpressing tagged TWIST2 compared wild-type protein with p.Glu75Lys, p.Glu75Gln, p.Glu75Ala and p.Gln77_Arg78dup. Wild-type TWIST2 had 630 binding peaks. The paper reports that p.Glu75Ala and p.Gln77_Arg78dup shared only 25 peaks with wild-type, and that mutant proteins also occupied sites not detected for wild-type. These findings support altered target occupancy in this assay. Their relevance to endogenous TWIST2 binding in affected human craniofacial or dermal mesenchyme remains provisional.

Glu75 substitutions give TWIST2 new genomic targets Glu75 substitutions interfere with the wild-type TWIST2 pool

E-box binding GO:0070888 ↓ DECREASED DNA-binding transcription factor activity GO:0003700 ↕ DYSREGULATED

Experimental models

HeLa ChIP-seq of wild-type and mutant FLAG-TWIST2 CELL LINE Direct measurement of genome-wide binding of the Barber-Say mutant proteins against wild-type.

Downstream

Dysregulated TWIST2-Dependent Mesenchymal Transcription Altered target occupancy could change transcription through interference with normal TWIST2 complexes or acquisition of new targets. The proportion of dysfunctional dimers in patient tissue was not measured.

Show evidence (4 references)

PMID:26119818 SUPPORT In Vitro

"We identified 630 binding peaks associated with wild-type TWIST2."

The wild-type binding baseline in the same assay.

PMID:26119818 SUPPORT In Vitro

"p.Glu75Ala and p.Gln77_Arg78dup TWIST2, both associated with BSS, shared only 25 binding peaks in common with the wild-type"

Loss of normal binding sites for the BSS alleles.

PMID:26119818 SUPPORT In Vitro

"A significant number of binding peaks detected for the mutant TWIST2 proteins were not detected for the wild-type protein"

Gain of binding at sites the wild-type protein does not occupy.

+ 1 more reference

Dysregulated TWIST2-Dependent Mesenchymal Transcription

Mechanism confidence: Provisional

TWIST2 is expressed in craniofacial mesenchyme and chondrogenic precursors during embryonic development and is thought to direct development of dermal and chondrogenic tissue. Expressing the Barber-Say (p.Glu75Gln) or AMS (p.Glu75Lys) protein in zebrafish embryos produced more severe developmental defects than wild-type TWIST2 and down-regulated genes for extracellular matrix, membrane and cytoskeletal components. PROVISIONAL: the tissue-expression premise comes from the background of the primary paper, and the transcriptome is from zebrafish embryos injected with human mRNA at the one-cell stage, which over-expresses TWIST2 globally rather than modelling a heterozygous allele in mesenchyme. The cited studies do not provide a patient-cell transcriptome for a Barber-Say allele.

mesenchymal cell CL:0008019 fibroblast of dermis CL:0002551

extracellular matrix organization GO:0030198 ↕ DYSREGULATED skin development GO:0043588 ⚠ ABNORMAL

Animal models

Zebrafish embryos injected with mutant human TWIST2 mRNA Zebrafish partially recapitulates Shows that the Barber-Say allele changes developmental transcription and head development more than wild-type TWIST2 does.

hlh-8 Glu29 allelic series (C. elegans) Caenorhabditis elegans partially recapitulates BSS-equivalent substitutions impair target-gene reporter expression in endogenous heterozygous worms, contrasting with the recessive null control and supporting dominant-negative activity.

Downstream

Dermal Extracellular Matrix Disorganization Aberrant TWIST2 target expression is proposed to disturb the dermal extracellular matrix.

Eyelid Anterior Lamella Underdevelopment Disturbed TWIST2-directed mesenchymal development is proposed to underlie the facial and eyelid malformations; the steps in eyelid morphogenesis are not established.

Craniofacial Soft-Tissue Patterning Defect The same disturbance is proposed to produce the facial patterning defects of the mouth, nose and ears.

Show evidence (3 references)

PMID:26119818 SUPPORT BACKGROUND Other

"During embryonic development, TWIST2 is highly expressed in the craniofacial mesenchyme and in chondrogenic precursors."

Places TWIST2 in the tissues affected in this syndrome. The sentence is introduction material restating earlier work and names no species, so it is graded OTHER with quote_role BACKGROUND.

PMID:26119818 SUPPORT BACKGROUND Other

"Previous studies suggest that TWIST2 regulates mesenchymal stem cell differentiation and directs the development of dermal and chondrogenic tissues."

The developmental role of TWIST2 in dermis on which this node rests, stated as background from earlier studies.

PMID:26119818 SUPPORT Model Organism

"Gene ontology (GO) analyses revealed the greatest reduction in the expression of genes related to extracellular matrix (ECM), membrane components, and cytoskeleton (fibrils)"

Transcriptional consequence of mutant TWIST2 expression in zebrafish embryos, the only transcriptome available for a Barber-Say allele.

Dermal Extracellular Matrix Disorganization

Mechanism confidence: Provisional

Skin electron microscopy in BSS-3.1 showed thin, long elastic fibers, disordered collagen fibers of variable diameter, microfibrillar proliferation and amorphous deposits. A second individual, BSS-5.1, had reduced elastic fibers on biopsy. These are tissue observations; neither the rate of elastic-fiber assembly nor a direct causal link to each cutaneous feature was measured. The broader clinical review records normal biopsies in some other patients.

collagen fibril organization GO:0030199 ⚠ ABNORMAL

dermis UBERON:0002067

Downstream

Redundant Skin Disorganised dermal elastic and collagen fibres are the observed tissue correlate of lax, redundant skin; no study has tested the link directly.

Thin Skin Thin dermis with disordered fibres is the tissue correlate of the thin skin.

Wrinkled Skin Loss of dermal fibre organisation is the tissue correlate of the excessive wrinkling and facial creases.

Atrophic Skin Atrophic skin, one of the four features in the original descriptive name, is the clinical expression of the thin, disorganised dermis.

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"Electron microscopy of the skin biopsy of BSS-3.1 showed findings similar to those of AMS, i.e., thin and long elastic fibers, abnormally oriented collagen fibers, and areas of microfibrillar proliferation and amorphous deposits"

Ultrastructural dermal findings in a Barber-Say patient.

PMID:26119818 SUPPORT Human Clinical

"clubfeet, reduced elastic fibers on skin biopsy"

Table 1 entry for a second Barber-Say individual (BSS-5.1) with reduced elastic fibres on biopsy.

Eyelid Anterior Lamella Underdevelopment

Mechanism confidence: Provisional

Underdevelopment of the anterior lamella of the eyelid contributes to ectropion and incomplete lid closure. The degree of eyelid hypoplasia varies across Barber-Say and ablepharon-macrostomia syndromes. Clinical anatomy supports the local sequence from lamellar deficiency to corneal exposure; the molecular steps linking a specific TWIST2 allele to eyelid morphogenesis remain provisional.

eyelid development in camera-type eye GO:0061029 ↓ DECREASED

eyelid UBERON:0001711

Downstream

Ectropion A deficient anterior lamella everts the lid margin.

Eyelid Hypoplasia Reduced development of the anterior eyelid produces a smaller eyelid; the review describes minor size reduction in Barber-Say syndrome.

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..."

Critical review of published patients listing anterior lamellar underdevelopment.

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"

The critical review connects anterior lamellar deficiency, ectropion and incomplete closure.

Craniofacial Soft-Tissue Patterning Defect

Mechanism confidence: Hypothetical

The facial gestalt - macrostomia, a broad bulbous nasal tip with thick alae, first-degree microtia with narrow ear canals, widely spaced eyes 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 Barber-Say syndrome.

mouth UBERON:0000165 nose UBERON:0000004 external ear UBERON:0001691

Downstream

Macrostomia

Bulbous Nose

Thick Nasal Alae

First-Degree Microtia

Narrow External Auditory Canals

Hypertelorism

Cheek Pads at the Oral Commissures

Low-Set Ears

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Histopathology

1

Abnormal Dermal Elastic and Collagen Fibers

Electron microscopy in molecularly confirmed BSS-3.1 showed thin elongated elastic fibers, abnormal collagen orientation, microfibrillar proliferation and amorphous deposits. Reduced elastic fibers were recorded separately in BSS-5.1. Findings vary among patients and are not established as diagnostic.

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"Electron microscopy of the skin biopsy of BSS-3.1 showed findings similar to those of AMS, i.e., thin and long elastic fibers, abnormally oriented collagen fibers, and areas of microfibrillar proliferation and amorphous deposits"

Ultrastructural dermal findings in a Barber-Say patient.

PMID:26119818 SUPPORT Human Clinical

"clubfeet, reduced elastic fibers on skin biopsy"

Table 1 entry for a second Barber-Say individual (BSS-5.1) with reduced elastic fibres on biopsy.

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Pathograph

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

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Phenotypes

67

Breast 5

Hypoplastic Nipples FREQUENT HP:0002557

Frequency basis: Table 1 of PMID:26119818 records hypoplastic nipples in 9 of 12 BSS individuals, inverted nipples in 4 (three of them also hypoplastic) and absent nipples in 1. Counted from the table rows.

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"The BSS-affected individuals exhibited ectropion, macrostomia, bulbous noses, malformed ears in the spectrum of microtia first degree, thin, redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and development, together with other variable features"

Hypoplastic nipples in the molecularly confirmed BSS series.

Inverted Nipples HP:0003186

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"marked hypertrichosis | inverted, hypoplastic | normal | normal | low anterior hair line"

Table 1 records inversion and hypoplasia separately in BSS-4.1; the family clustering limits population-frequency inference.

Absent Nipples HP:0002561

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"marked hypertrichosis, lanugo hair, sparse eyebrows | absent | normal | normal"

Table 1 nipple column for molecularly confirmed BSS-7.1.

Breast Aplasia HP:0100783

Show evidence (1 reference)

PMID:9674915 SUPPORT Human Clinical

"We present a girl with lax, redundant skin, ectropion, bulbous nose, macrostomia, and absence of mammary glands."

A clinical report retained in the 2016 critical review; nipple size is a separate observation.

Breast Hypoplasia HP:0003187

Show evidence (1 reference)

PMID:20830793 SUPPORT Human Clinical

"A 7-year-old female with multiple congenital anomalies such mammary gland hypoplasia, hypertrichosis, ectropion, and redundant skin"

Mammary hypoplasia was specifically described in this dental case report, rather than inferred from hypoplastic nipples.

Cardiovascular 1

Telangiectasia HP:0001009

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"parental consanguinity, telengectasias, hypdontia malocculusion"

Table 1 lists telengectasias among BSS-7.1 findings; the source spelling is retained in the quotation.

Digestive 3

Feeding Difficulties HP:0011968

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"Due to feeding difficulties and intermittent stridor, ENT recommended a frenulectomy and a sleep study that showed abnormal sleep architecture, obstructive sleep apnea, and micrognathia."

Infant feeding difficulties in a p.Glu75Gln-confirmed case.

Diastasis Recti HP:0001540

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"Also observed were hypoplastic nipples, diastasis recti, and hypertrichosis on the back"

Direct neonatal examination in a molecularly confirmed case.

Gastroesophageal Reflux HP:0002020

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"He continues to follow with ophthalmology, ENT for observation of cleft palate, gastroenterology for reflux, and pulmonology for obstructive sleep apnea."

Follow-up describes reflux in this patient; not assumed universal.

Ear 5

First-Degree Microtia FREQUENT Microtia, first degree HP:0011266

Frequency basis: Table 1 of PMID:26119818 records first-degree microtia in 8 of 12 BSS individuals; most of the rest had other ear anomalies (small or low-set ears, narrow canals). Counted from the table rows.

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"The BSS-affected individuals exhibited ectropion, macrostomia, bulbous noses, malformed ears in the spectrum of microtia first degree, thin, redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and development, together with other variable features"

First-degree microtia in the molecularly confirmed BSS series.

Narrow External Auditory Canals FREQUENT Stenosis of the external auditory canal HP:0000402

Frequency basis: Table 1 of PMID:26119818 records hypoplastic, small or narrow external auditory canals in 6 of 12 BSS individuals (BSS-1.1, 2.1, 3.1, 4.2, 8.1, 10.1). Counted from the table rows.

Sequelae: Conductive Hearing Impairment

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"cup-shaped, hypoplastic external auditory canals, hearing loss"

Table 1 entry for BSS-1.1, with hypoplastic canals and hearing loss.

Conductive Hearing Impairment HP:0000405

Show evidence (3 references)

PMID:10440829 SUPPORT Human Clinical

"The mother also had cleft palate and mild conductive hearing loss."

Conductive hearing loss in the mother retained as Barber-Say syndrome by the subsequent critical review; no inference is made from her incompletely documented son.

PMID:19760652 SUPPORT Human Clinical

"She also demonstrated conductive hearing impairment and microblepharon."

Conductive hearing impairment in a 7-year-old with BSS.

PMID:28680619 REFUTE Human Clinical

"Laboratory tests, echocardiogram, head MRI, voiding cystourethrogram, and hearing screen were normal."

A normal neonatal hearing screen in a molecularly confirmed case argues against hearing impairment being universal or necessarily present at birth.

Low-Set Ears OCCASIONAL HP:0000369

Frequency basis: Table 1 of PMID:26119818 records low-set ears in 3 of 12 BSS individuals (BSS-4.2, 4.3, 7.1), 25 percent; two of the three are sisters. Counted from the table rows.

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"low-set ears, microtia first degree, concha extra fold"

Table 1 ear entry for BSS-4.3.

PMID:28680619 SUPPORT Human Clinical

"low set posteriorly rotated ears, redundant skin on the neck"

Low-set, posteriorly rotated ears in a p.Glu75Gln-confirmed boy.

Attached Earlobes HP:0009907

Show evidence (1 reference)

PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical

"broad nasal ridge and tip, thick and flaring alae nasi, protruding maxilla, wide mouth, thin upper vermillion, and attached ear lobes."

The review identifies attached lobes in the overlapping facial phenotype.

Eye 3

Exposure Keratitis HP:0000491

Bound to the general Keratitis term because HPO has no exposure-keratitis or exposure-keratopathy term (runoak -i ols:hp search "Exposure keratopathy" and search "Corneal exposure" returned no hits on 2026-09-23); the exposure mechanism is carried in preferred_term and the sequelae edges.

Show evidence (1 reference)

PMID:29329175 SUPPORT Human Clinical

"The authors present the case of a pediatric patient with a clinical diagnosis of Barber-Say syndrome with ocular symptoms related to exposure keratitis."

Exposure keratitis in a child with Barber-Say syndrome.

Hypertelorism FREQUENT HP:0000316

Frequency basis: Table 1 of PMID:26119818 records hypertelorism in 4 of 12 BSS individuals (BSS-3.1, 8.1, 9.1, 10.1), 33 percent. Counted from the table rows.

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..."

Hypertelorism among the major facial characteristics.

PMID:30455119 SUPPORT Human Clinical

"The case is presented of a 2-day-old male child in whom ectropion, hypertelorism, hypertrichosis and other dysmorphic features led to the clinical diagnosis of Barber-Say syndrome, which was later confirmed with genetic tests."

Hypertelorism in a neonate with confirmed BSS.

Strabismus HP:0000486

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"

The review identifies the three BSS reports separately from AMS reports. The small literature series is not a population prevalence estimate.

Genitourinary 7

Genital Anomalies FREQUENT Abnormal external genitalia morphology HP:0000811

Frequency basis: Table 1 of PMID:26119818 records a genital anomaly in 6 of 12 BSS individuals (ambiguous genitalia, shawl scrotum, bilateral cryptorchidism, hypoplastic or "snout-shaped" labia). Counted from the table rows. The individual anomalies with their own citations are curated below.

Show evidence (1 reference)

PMID:19760652 SUPPORT Human Clinical

"generalized hypertrichosis especially at the back, dry lax skin, macrostomia, thin lips, cup-shaped ears, bulbous nose, hypoplastic nipples, and abnormal external genitalia"

Abnormal external genitalia in a girl with BSS.

Shawl Scrotum HP:0000049

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"Patient also had a shawl scrotum concealing an anatomically normal shaft and glans of the penis"

Shawl scrotum in a p.Glu75Gln-confirmed boy.

Ambiguous Genitalia HP:0000062

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"marked hypertrichosis | normal | ambiguous | normal | parental consanguinity"

Table 1 row for BSS-2.1 (p.Glu75Gln, de novo), recording ambiguous genitalia in a molecularly confirmed individual.

Bilateral Cryptorchidism HP:0008689

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"hypoplastic | bilateral cryptorchidism | normal | hypertelorism | normal"

The genital column of Table 1 for BSS-8.1 records bilateral cryptorchidism.

Hypoplastic Labia Majora HP:0000059

Severity: MILD

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"hypoplastic | mild hypoplasia of labia majora | brachydacytly and clinodactyly f5 prominent digit pads"

Table 1 genital findings in the p.Glu75Ala individual BSS-6.1.

Hypoplastic Labia Minora HP:0000064

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"hypoplastic | hypoplastic labia minora | normal | hypertelorism, delayed eruption of teeth"

Table 1 genital findings in BSS-10.1.

Hydronephrosis HP:0000126

Laterality: RIGHT Severity: MILD

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"Ultrasound of the abdomen showed mild right hydronephrosis."

Case-specific imaging finding with no syndrome-wide frequency inferred.

Head and Neck 26

Ectropion VERY_FREQUENT HP:0000656

Onset: CONGENITAL

Frequency basis: Table 1 of PMID:26119818 records ectropion in 11 of 12 BSS individuals; the exception (BSS-4.1) is a mildly affected mosaic father. Counted from the table rows.

Sequelae: Lagophthalmos Exposure Keratitis

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"The BSS-affected individuals exhibited ectropion, macrostomia, bulbous noses, malformed ears in the spectrum of microtia first degree, thin, redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and development, together with other variable features"

Ectropion in the molecularly confirmed BSS series.

PMID:30455119 SUPPORT Human Clinical

"The case is presented of a 2-day-old male child in whom ectropion, hypertelorism, hypertrichosis and other dysmorphic features led to the clinical diagnosis of Barber-Say syndrome, which was later confirmed with genetic tests."

Ectropion recognised in the neonatal period.

Eyelid Hypoplasia OCCASIONAL Hypoplasia of eyelid HP:0430009

Frequency basis: Table 1 of PMID:26119818 records hypoplastic eyelids or microblepharon in 3 of 12 BSS individuals (BSS-1.1, 6.1, 7.1). Counted from the table rows.

Show evidence (2 references)

PMID:19760652 SUPPORT Human Clinical

"This is the first report of microblepharon in BSS."

Microblepharon in a patient with Barber-Say syndrome.

PMID:28680619 SUPPORT Human Clinical

"At 7 months of age, patient had eye surgery with ophthalmology and plastic surgery to correct hypoplastic eyelids with skin grafting."

Hypoplastic eyelids in a p.Glu75Gln-confirmed infant.

Lagophthalmos HP:0030001

Sequelae: Exposure Keratitis

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"recommended vigorous eye lubrication due to the hypoplastic eyelids and inability to close eyes"

Neonatal inability to close the eyes in a confirmed case.

Macrostomia VERY_FREQUENT Wide mouth HP:0000154

Onset: CONGENITAL

Frequency basis: Table 1 of PMID:26119818 records macrostomia in all 12 BSS individuals. Counted from the table rows.

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"The BSS-affected individuals exhibited ectropion, macrostomia, bulbous noses, malformed ears in the spectrum of microtia first degree, thin, redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and development, together with other variable features"

Macrostomia in the molecularly confirmed BSS series.

PMID:8368246 SUPPORT Human Clinical

"presented with a multiple congenital anomalies (MCA) pattern consisting of severe hypertrichosis, macrostomia, ectropion, and atrophic skin"

The four features that gave the syndrome its descriptive name.

Bulbous Nose VERY_FREQUENT HP:0000414

Frequency basis: Table 1 of PMID:26119818 records a bulbous nose in all 12 BSS individuals. Counted from the table rows.

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"The BSS-affected individuals exhibited ectropion, macrostomia, bulbous noses, malformed ears in the spectrum of microtia first degree, thin, redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and development, together with other variable features"

Bulbous nose in the molecularly confirmed BSS series.

PMID:27196381 SUPPORT REVIEW SYNTHESIS Human Clinical

"In BSS a remarkable extension of the columella on the philtrum can be seen"

Columellar extension as a BSS-specific nasal feature.

Thick Nasal Alae HP:0009928

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..."

Lists thick and flaring alae nasi among the major facial characteristics.

Telecanthus OCCASIONAL HP:0000506

Frequency basis: Table 1 of PMID:26119818 records telecanthus in 3 of 12 BSS individuals, all in one family (BSS-4.1, 4.2, 4.3). Counted from the table rows.

Show evidence (1 reference)

PMID:20799330 SUPPORT Human Clinical

"a rare, congenital disorder characterized by severe generalized hypertrichosis, macrostomia, ocular telecanthus, bulbous nose and atrophic skin"

Lists ocular telecanthus among the defining features.

Low Anterior Hairline FREQUENT HP:0000294

Frequency basis: Table 1 of PMID:26119818 records a low anterior hairline in 4 of 12 BSS individuals (BSS-3.1, 4.1, 4.2, 4.3). Counted from the table rows.

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"low anterior hairline, sparse eyebrows, hypertelorism, hypoplastic maxilla, gum hypertrophy, widely spaced teeth"

Table 1 entry for BSS-3.1.

Sparse Eyebrows OCCASIONAL HP:0045075

Frequency basis: Table 1 of PMID:26119818 records sparse eyebrows in 2 of 12 BSS individuals (BSS-3.1, 7.1). Counted from the table rows.

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."

Sparse eyebrows occur in BSS despite generalized hypertrichosis.

Sparse Eyelashes OCCASIONAL HP:0000653

Frequency basis: Table 1 of PMID:26119818 records sparse lashes in 2 of 12 BSS individuals (BSS-5.1, 10.1). Counted from the table rows.

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."

Sparse eyelashes occur in BSS.

Thin Upper Lip Vermilion HP:0000219

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..."

Thin upper vermilion among the major facial characteristics.

Micrognathia HP:0000347

The two sisters are BSS-4.2 and BSS-4.3 in Table 1 of PMID:26119818 ("macrostomia, mild micrognathia").

Sequelae: Obstructive Sleep Apnea

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"Due to feeding difficulties and intermittent stridor, ENT recommended a frenulectomy and a sleep study that showed abnormal sleep architecture, obstructive sleep apnea, and micrognathia."

Micrognathia in a p.Glu75Gln-confirmed infant.

Epiblepharon HP:0011225

Table 1 of PMID:26119818 records epiblepharon in 2 of 12 BSS individuals, both daughters of one mosaic father (BSS-4.2, 4.3). No frequency band is assigned because the two observations are not independent.

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"ectropion, ocular telecanthus, epiblepharon | macrostomia, mild micrognathia"

Table 1 eyelid entry for BSS-4.3.

PMID:26119818 SUPPORT Human Clinical

"ectropion, telecanthus, epiblepharon | macrostomia, mild micrognathia"

Table 1 eyelid entry for BSS-4.2, the sister of BSS-4.3.

High Palate HP:0000218

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"high palate, lumbar flat angioma"

Table 1 "other" entry for BSS-6.1 (p.Glu75Ala, de novo).

Velopharyngeal Insufficiency HP:0000220

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"normal | velopharyngeal incompetence | delayed language development"

Table 1 row for BSS-1.1.

Cleft Palate HP:0000175

Show evidence (2 references)

PMID:10440829 SUPPORT Human Clinical

"The mother also had cleft palate and mild conductive hearing loss."

Cleft palate in an affected mother.

PMID:28680619 SUPPORT Human Clinical

"ENT evaluation showed a soft palate cleft."

Soft palate cleft in a p.Glu75Gln-confirmed infant.

Gingival Overgrowth Gingival fibromatosis HP:0000169

Show evidence (1 reference)

PMID:20830793 SUPPORT Human Clinical

"Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion."

Gingival fibromatosis in a 7-year-old with BSS.

Delayed Eruption of Teeth HP:0000684

Show evidence (1 reference)

PMID:20830793 SUPPORT Human Clinical

"Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion."

Delayed tooth eruption in a child with BSS.

Taurodontia HP:0000679

Show evidence (1 reference)

PMID:20830793 SUPPORT Human Clinical

"Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion."

Taurodontism in a single reported child.

Maxillary Hypoplasia Hypoplasia of the maxilla HP:0000327

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"low anterior hairline, sparse eyebrows, hypertelorism, hypoplastic maxilla, gum hypertrophy, widely spaced teeth"

The individual finding is documented in the primary table, not extrapolated from other craniofacial syndromes.

Widely Spaced Teeth HP:0000687

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"hypoplastic maxilla, gum hypertrophy, widely spaced teeth"

Table 1 oral findings in BSS-3.1.

Hypodontia HP:0000668

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"parental consanguinity, telengectasias, hypdontia malocculusion"

Table 1 lists hypdontia, a typographical form of hypodontia, in BSS-7.1.

Dental Malocclusion HP:0000689

Show evidence (1 reference)

PMID:20830793 SUPPORT Human Clinical

"Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion."

Direct oral examination in a 7-year-old girl.

Bitemporal Narrowing Narrow forehead HP:0000341

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

"Bitemporal narrowing and ﬂat malae are present in both syndromes"

The full clinical review documents narrowing between the temporal regions.

Lacrimal Duct Stenosis HP:0007678

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

"lacrimal duct stenosis in two BSS patients"

The review separates BSS lacrimal stenosis from AMS alacrimia.

Absent Eyebrows HP:0002223

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"hypoplastic eyelids, ectropion, sparse eyelashes, absent eyebrows, low set posteriorly rotated ears"

The case explicitly distinguishes absent eyebrows from sparse eyelashes.

Integument 7

Congenital Generalized Hypertrichosis VERY_FREQUENT HP:0004540

Onset: CONGENITAL

Frequency basis: Table 1 of PMID:26119818 records marked hypertrichosis in all 12 molecularly confirmed BSS individuals (VERY_FREQUENT rather than OBLIGATE, given the small series). The count is taken from the table rows; no single sentence states it.

Show evidence (3 references)

ORPHA:1231 SUPPORT Other

"A rare congenital malformation syndrome with neonatal onset characterized by congenital generalized hypertrichosis, redundant skin and facial dysmorphism such as ectropion and macrostomia."

Orphanet definition lists congenital generalized hypertrichosis first.

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."

Hypertrichosis as the BSS-specific feature relative to AMS.

PMID:26119818 SUPPORT Human Clinical

"The BSS-affected individuals exhibited ectropion, macrostomia, bulbous noses, malformed ears in the spectrum of microtia first degree, thin, redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and development, together with other variable features"

Cohort-level summary of the molecularly confirmed BSS series.

Redundant Skin FREQUENT HP:0001582

Frequency basis: Table 1 of PMID:26119818 describes the skin as redundant or lax in 8 of 12 BSS individuals; the other four are described as thin or wrinkled. Counted from the table rows.

Show evidence (2 references)

ORPHA:1231 SUPPORT Other

"A rare congenital malformation syndrome with neonatal onset characterized by congenital generalized hypertrichosis, redundant skin and facial dysmorphism such as ectropion and macrostomia."

Redundant skin in the Orphanet definition.

PMID:9674915 SUPPORT Human Clinical

"We present a girl with lax, redundant skin, ectropion, bulbous nose, macrostomia, and absence of mammary glands."

Lax, redundant skin in a reported patient.

Thin Skin HP:0000963

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"The BSS-affected individuals exhibited ectropion, macrostomia, bulbous noses, malformed ears in the spectrum of microtia first degree, thin, redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and development, together with other variable features"

Thin skin in the molecularly confirmed BSS series.

Wrinkled Skin Excessive wrinkled skin HP:0007392

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 FREQUENT HP:0000958

Frequency basis: Table 1 of PMID:26119818 records dry skin in 4 of 12 BSS individuals (BSS-1.1, 4.1, 4.2, 4.3), 33 percent; three of the four are one family (a mosaic father and his two daughters). Counted from the table rows.

Show evidence (3 references)

PMID:26119818 SUPPORT Human Clinical

"hearing loss | wrinkled, dry | marked hypertrichosis"

Table 1 row for BSS-1.1, recording wrinkled, dry skin.

PMID:26119818 SUPPORT Human Clinical

"redundant, dry skin, lipodystrophy | marked hypertrichosis"

Table 1 skin entry shared by the sisters BSS-4.2 and BSS-4.3.

PMID:19760652 SUPPORT Human Clinical

"generalized hypertrichosis especially at the back, dry lax skin, macrostomia, thin lips, cup-shaped ears, bulbous nose, hypoplastic nipples, and abnormal external genitalia"

Dry, lax skin in the 2009 Haensel case, subsequently included as BSS-1.1 in the discovery series; this is not an independent additional patient.

Atrophic Skin Dermal atrophy HP:0004334

Show evidence (2 references)

PMID:8368246 SUPPORT Human Clinical

"presented with a multiple congenital anomalies (MCA) pattern consisting of severe hypertrichosis, macrostomia, ectropion, and atrophic skin"

Atrophic skin as a core feature of an early case.

PMID:20799330 SUPPORT Human Clinical

"a rare, congenital disorder characterized by severe generalized hypertrichosis, macrostomia, ocular telecanthus, bulbous nose and atrophic skin"

Atrophic skin in a father-daughter pair.

Prominent Digit Pads HP:0011298

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"brachydacytly and clinodactyly f5 prominent digit pads"

Table 1 hand findings include prominent digit pads; no persistence from fetal life is inferred.

Limbs 3

Clubfoot Talipes equinovarus HP:0001762

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"shawl scrotum | normal | clubfeet, reduced elastic fibers on skin biopsy"

Table 1 records clubfeet in BSS-5.1.

Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"brachydacytly and clinodactyly f5 prominent digit pads"

The source table uses the misspelling brachydacytly in its hand findings for BSS-6.1.

Fifth-Finger Clinodactyly Clinodactyly of the 5th finger HP:0004209

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"brachydacytly and clinodactyly f5 prominent digit pads"

Table 1 specifies fifth-finger clinodactyly in BSS-6.1; direction is not stated.

Musculoskeletal 1

Lipodystrophy HP:0009125

Table 1 of PMID:26119818 records lipodystrophy in 2 of 12 BSS individuals, both daughters of one mosaic father (BSS-4.2, 4.3). No frequency band is assigned because the two observations are not independent, and the table does not say whether the lipodystrophy is generalized or partial, so the general term is bound.

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"redundant, dry skin, lipodystrophy | marked hypertrichosis"

Table 1 skin entry shared by the sisters BSS-4.2 and BSS-4.3.

Nervous System 2

Delayed Speech and Language Development OCCASIONAL HP:0000750

Frequency basis: Table 1 of PMID:26119818 records language delay in 2 of 12 BSS individuals (BSS-1.1, 10.1) and "mild delay" without further detail in one more (BSS-3.1). Counted from the table rows.

Show evidence (2 references)

PMID:26119818 SUPPORT Human Clinical

"delayed language development, dyslalia, dysgrammatism"

Table 1 entry for BSS-1.1.

PMID:28680619 REFUTE Human Clinical

"At 1 year of age, patient was meeting all developmental milestones."

Normal cognition or early milestones in this source argue against a universal developmental phenotype; they do not exclude language delay in other individuals.

Obstructive Sleep Apnea HP:0002870

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"Due to feeding difficulties and intermittent stridor, ENT recommended a frenulectomy and a sleep study that showed abnormal sleep architecture, obstructive sleep apnea, and micrognathia."

Sleep-study-documented obstructive sleep apnea in an infant.

Respiratory 1

Stridor HP:0010307

Show evidence (1 reference)

PMID:28680619 SUPPORT Human Clinical

"Due to feeding difficulties and intermittent stridor, ENT recommended a frenulectomy and a sleep study"

Direct clinical observation in the confirmed infant; no specific laryngeal lesion was established.

Neoplasm 1

Rhabdomyomatous Mesenchymal Hamartomas HP:0010566

Bound to the general Hamartoma term; rhabdomyomatous mesenchymal hamartoma has no HPO term (runoak -i ols:hp search "Hamartoma" on 2026-09-23 returned HP:0010566 and organ-specific hamartoma terms only). No malignancy is reported in any reference cited in this entry, but no study has looked for tumour risk, so absence of reports is not evidence of no risk.

Show evidence (1 reference)

PMID:37817291 SUPPORT Human Clinical

"We describe a 9-year-old boy with congenital generalized hypertrichosis and multiple rhabdomyomatous mesenchymal hamartomas (RMHs) on his nose and periocular region."

The single report of these hamartomas in BSS.

Other 2

Cheek Pads at the Oral Commissures

Left unbound, as in the Sweeney-Cox_Syndrome entry: HPO has no term for localised pads at the oral commissures, and HP:0000293 Full cheeks describes generalised fullness, a different finding.

Show evidence (1 reference)

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.

Protruding Premaxilla

OLS HP searches for protruding premaxilla, maxillary protrusion and maxillary prognathism returned no exact match; Overjet describes a dental relationship and Hyperplasia of the maxilla asserts increased size rather than the reported position. The observed premaxillary protrusion is retained without either binding.

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

"protrusion of the maxilla (Fig. 5) occurs in three-quarters of all BSS patients, and becomes frequently more pronounced after infancy."

The review describes the location and age-related prominence of the finding. Its selected literature cases should not be treated as a prospective population sample.

🧬

Genetic Associations

1

TWIST2 (CAUSATIVE)

Gene: TWIST2 hgnc:20670

Show evidence (3 references)

PMID:26119818 SUPPORT Human Clinical

"nine had a c.223G>C (p.Glu75Gln) mutation (GenBank: NM_057179.2) and two had c.224A>C (p.Glu75Ala) mutations"

Allele counts in the Glu75 BSS individuals of the discovery series.

PMID:28680619 SUPPORT Human Clinical

"TWIST2 sequencing showed a pathogenic mutation: c.223G>C (p.Glu75Gln)."

Independent confirmation of the recurrent allele in a later case.

PMID:37817291 SUPPORT Human Clinical

"Therefore, we consider this variant as de novo mosaicism."

De novo mosaic TWIST2 variant in a proband.

Variants (3)

NM_057179.2:c.223G>C (p.Glu75Gln)

Gene: TWIST2 hgnc:20670

Recurrent missense variant, including de novo, inherited and mosaic individuals.

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"nine had a c.223G>C (p.Glu75Gln) mutation"

Variant identified in the molecularly characterized discovery series.

NM_057179.2:c.224A>C (p.Glu75Ala)

Gene: TWIST2 hgnc:20670

Missense variant found in two discovery-series individuals.

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"two had c.224A>C (p.Glu75Ala) mutations"

Variant identified in the molecularly characterized discovery series.

NM_057179.2:c.229_234dupCAGCGC (p.Gln77_Arg78dup)

Gene: TWIST2 hgnc:20670

In-frame basic-domain duplication, identified in BSS-1.1.

Show evidence (1 reference)

PMID:26119818 SUPPORT Human Clinical

"A 12th individual with BSS, BSS-1.1, carried a heterozygous c.229_234dupCAGCGC (p.Gln77_Arg78dup) mutation"

Variant identified in the molecularly characterized discovery series.

💊

Medical Actions

9

Ocular Surface Protection

Action: ocular lubrication and corneal protection Ontology label: Supportive Care NCIT:C15747

Platform: Other

Ophthalmic assessment and lubrication with artificial tears or ointment when eyelid closure is incomplete. Topical antibiotics were used in one clinically diagnosed neonate; that case does not establish routine prophylaxis for every patient. Severe exposure may require eyelid surgery.

Target Phenotypes: Exposure keratitis HP:0000491

Show evidence (2 references)

PMID:30984591 SUPPORT Human Clinical

"Eye care with artificial tear, eye lubricant and local antibiotics were started for the patient."

Neonatal ocular surface protection in a one-day-old.

PMID:28680619 SUPPORT Human Clinical

"recommended vigorous eye lubrication due to the hypoplastic eyelids and inability to close eyes"

Lubrication recommended for lagophthalmos in a neonate.

Eyelid Reconstruction

Action: eyelid reconstruction Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

For clinically significant corneal exposure, reported approaches include tarsorrhaphy, eyelid reconstruction with skin grafts and autologous fat grafting. Donor sites in one confirmed case included forearm, retroauricular and supraclavicular skin. Surgery restored lid closure or relieved ocular symptoms in reported cases; timing and technique depend on the individual anatomy and exposure severity.

Target Phenotypes: Ectropion HP:0000656 Lagophthalmos HP:0030001

Show evidence (4 references)

PMID:30984591 SUPPORT Human Clinical

"Tarsoraphy was done on the second day of admission"

Neonatal tarsorrhaphy for severe ectropion.

PMID:30455119 SUPPORT Human Clinical

"The approach in this case included a lateral tarsorrhaphy and skin grafts taken from the volar surface of the forearm, retroauricular area and supraclavicular fossa, as well as autologous lipografts from the inner side of both thighs for palpebral reconstruction."

Staged eyelid reconstruction in an infant.

PMID:28680619 SUPPORT Human Clinical

"Following this procedure, he was able to fully close the eyes."

Restored lid closure after skin grafting at 7 months.

+ 1 more reference

Oral Commissure Repair for Macrostomia

Action: oral commissure repair Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Cheiloplasty can form part of an individualized facial reconstruction plan. The patient-perspective study illustrates staged reconstruction in an adult woman with Barber-Say syndrome, including two cheiloplasties. Major elective craniofacial procedures are generally considered after growth, balancing function and the person's priorities.

Target Phenotypes: Macrostomia HP:0000154

Show evidence (1 reference)

PMID:28690482 SUPPORT Human Clinical

"Cheiloplasty was performed twice to obtain a better vermilion exposure together with upper lip shortening, blepharoplasty, and correction of the eyelid position."

Figure 2 describes cheiloplasty in an adult woman with Barber-Say syndrome.

Dental and Gingival Management

Action: gingivoplasty and orthodontic treatment Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Gingivoplasty for gingival fibromatosis and orthodontic treatment for malocclusion and delayed eruption, reported in a 7-year-old.

Target Phenotypes: Gingival fibromatosis HP:0000169

Show evidence (1 reference)

PMID:20830793 SUPPORT Human Clinical

"Dental treatment included gingivoplasty and orthodontic treatment."

Reported dental management in a child with BSS.

Multidisciplinary Care and Psychosocial Support

Action: multidisciplinary supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Multidisciplinary care addresses ophthalmic, craniofacial, dental, genetic and developmental needs. The patient-perspective study emphasizes acceptance by family and peers, age-appropriate explanation of the condition and access to psychological support. Decisions about appearance-related procedures should reflect the person's preferences and functional needs. The study included both Barber-Say and ablepharon-macrostomia participants and did not establish a population-level quality-of-life effect.

Show evidence (3 references)

PMID:20799330 SUPPORT Human Clinical

"Treatment is challenging for both patients and doctors, requiring a multidisciplinary approach."

Multidisciplinary management.

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.

PMID:28690482 SUPPORT Human Clinical

"Acceptance by family and peers is absolutely essential. Psychological support is useful at various ages."

The mixed AMS/BSS patient-perspective study identifies family/peer acceptance and psychological support as priorities.

Genetic Counseling

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counseling incorporates proband and parental testing, variable expressivity and possible parental mosaicism. The patient-perspective review gives a likely 50% transmission risk for a non-mosaic affected parent, while noting uncertainty about live-born recurrence. Mosaicism requires individualized counseling rather than applying that figure automatically.

Show evidence (3 references)

PMID:26119818 SUPPORT Human Clinical

"Three disease-transmitting fathers with mild AMS or BSS and variable skin pigmentation were mosaic for a TWIST2 mutation"

Parental mosaicism is the counselling-relevant finding.

PMID:28680619 SUPPORT Human Clinical

"Genetic counseling was provided pre- and posttesting."

Counselling given around TWIST2 testing in a confirmed case.

PMID:28690482 SUPPORT REVIEW SYNTHESIS Human Clinical

"The recurrence risk for a child of a non-mosaic affected person will likely be 50%"

The shared AMS/BSS counseling discussion gives an expected risk for non-mosaic parents, with uncertainty about live-born recurrence; it does not quantify risk from mosaic parents.

Laser Hair Removal

Action: Laser Hair Removal Ontology label: Laser Therapy NCIT:C15466

Platform: Device

Laser therapy has been used for hypertrichosis in Barber-Say syndrome, with favorable results reported especially for dark hair. Multiple sessions are required because of hair growth cycles. The review notes that treatment can be painful and children may require general anesthesia; this is a procedural consideration for an elective, preference-sensitive treatment.

Target Phenotypes: Congenital, generalized hypertrichosis HP:0004540

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

"Hypertrichosis in BSS can be treated with laser therapy with good results, especially in patients with dark hair"

This passage concerns laser treatment specifically in Barber-Say syndrome.

url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"The disadvantages are that multiple sessions are needed due to the growth cycles of hairs and that general anesthesia is needed in children as laser therapy can be very painful."

The review describes repeated sessions and general anesthesia in children as treatment burdens.

Breast Reconstruction

Action: Breast Reconstruction Ontology label: Mammoplasty NCIT:C15354

Platform: Surgery

Reconstruction for absent or underdeveloped breasts is an elective option discussed after puberty. The mixed AMS/BSS literature and patient-perspective reports describe favorable experiences, without comparative outcome data or a requirement for surgery.

Target Phenotypes: Breast aplasia HP:0100783 Breast hypoplasia HP:0003187

Show evidence (2 references)

PMID:28690482 SUPPORT REVIEW SYNTHESIS Human Clinical

"Can cosmetic surgery be done because of the small breasts? At what age? | This has been done several times with good success. It can be done at the end of puberty but also at any age thereafter."

The source addresses optional breast surgery after puberty in its shared counseling table.

url:https://pure.amsterdamumc.nl/ws/files/159999289/Barber-say-syndrome-and-ablepharon-macrostomia-syndrome-an-overview.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Cosmetic mamma reconstructions using prostheses have been performed with good results"

The critical review reports favorable experience with prosthetic breast reconstruction, without comparative outcome data.

Individualized Facial Reconstruction

Action: facial reconstruction Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

An adult woman with Barber-Say syndrome underwent staged maxillomandibular advancement, genioplasty, malar implants, rhinoplasty and soft-tissue procedures. The shared clinical review advises individualized planning, generally deferring major elective procedures until craniofacial growth is complete. This describes reported practice rather than a standardized surgical regimen. Botulinum toxin injections are also listed as an adjunct in the shared AMS/BSS review, without a Barber-Say-specific regimen or efficacy estimate.

Show evidence (2 references)

PMID:28690482 SUPPORT Human Clinical

"she underwent malar implants and rhinoplasty."

Figure 2 records additional facial reconstruction in a woman with Barber-Say syndrome.

PMID:28690482 SUPPORT REVIEW SYNTHESIS Human Clinical

"Surgical procedures have included nasal reconstruction with rib cartilage grafts, orthognathic surgery, cheiloplasty, local skin flaps, and botox injections."

The treatment is explicitly listed in the shared review-synthesis table; no efficacy estimate is assigned.

🔬

Diagnosis

2

TWIST2 Sequencing With Parental Testing

The characteristic congenital phenotype prompts TWIST2 sequencing. Interpretation must distinguish disease-associated basic-domain alleles from variants of uncertain significance and from alleles associated with other TWIST2 disorders. Testing both parents can establish inheritance or support de novo origin; testing a single tissue may miss mosaicism.

Genetic Testing NCIT:C15709

Show evidence (2 references)

PMID:28680619 SUPPORT Human Clinical

"Genetic testing is recommended in patients presenting with these phenotypic abnormalities, along with their parents, to establish de novo or inherited mutations."

Recommends proband and parental TWIST2 testing.

PMID:28680619 SUPPORT Human Clinical

"Paternal testing would have helped to clarify whether this finding is paternally inherited or de novo. Additionally, it would clarify recurrence risks for the patient's family."

Parental testing informs recurrence risk.

Assessment for Tissue-Dependent TWIST2 Mosaicism

A negative result from one sampled tissue may not exclude mosaicism when the phenotype is suggestive. In one child, sequencing detected the variant in blood and rhabdomyomatous mesenchymal hamartoma tissue but not saliva or parental samples. This observation supports considering specimen choice and assay sensitivity in an individualized genetics assessment; it is not a validated universal testing algorithm.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:37817291 SUPPORT Human Clinical

"Next-generation sequencing, performed in DNA from a blood sample, and RMH tissue, revealed a pathogenic variant in the TWIST2 gene, which was not detected in a salivary sample of the patient, nor in his parents."

Direct evidence of tissue-dependent detection in one mosaic proband.

📊

Prevalence

1

Worldwide

Cases In Literature

A 2016 critical review of the published literature accepted 16 individuals as reliably diagnosed with Barber-Say syndrome, excluding earlier reports it judged misdiagnosed or insufficiently documented. Case reports published after that review are cited elsewhere in this entry.

Show evidence (1 reference)

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.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Barber-Say Syndrome:

Ablepharon-macrostomia syndrome MONDO:0008693

Overlapping Features Allelic TWIST2 disorder caused by p.Glu75Lys at the same residue. Shares macrostomia, eyelid underdevelopment, cheek pads, ear, nipple and genital anomalies; distinguished by absent or severely hypoplastic eyelids (ablepharon) and sparse scalp hair, whereas Barber-Say syndrome has generalized hypertrichosis and mostly ectropion. The known alleles and the clinical phenotype support the distinction; an uncharacterized TWIST2 variant alone does not settle it.

Show evidence (3 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:19760652 SUPPORT Human Clinical

"Other authors have discussed that BSS and AMS could possibly represent one syndrome, and our report supports this hypothesis."

The lumping argument, recorded because it bears on the split.

Setleis syndrome (focal facial dermal dysplasia type III) Not Yet Curated MONDO:0009203

Overlapping Features TWIST2-related Setleis syndrome is recessive and associated with biallelic loss-of-function alleles, bitemporal scar-like lesions and eyelash/eyebrow abnormalities. Temporal lesions can also occur in Barber-Say syndrome, so they are not an absolute discriminator. Genotype, inheritance and the full clinical pattern must be considered together; Setleis-like phenotypes are genetically heterogeneous.

Show evidence (2 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: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 BSS.

🧫

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, 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 Barber-Say mutant proteins 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

2

Zebrafish embryos injected with mutant human TWIST2 mRNA

Overexpression model used to compare wild-type and mutant TWIST2 in vivo. Mutant protein caused more severe head hypoplasia and trunk defects than wild-type, and RNA-seq at shield stage showed down-regulation of extracellular matrix, membrane and cytoskeletal gene sets.

Species

Zebrafish

Genotype

Wild-type embryos injected at the one-cell stage with human TWIST2 mRNA (wild-type, p.Glu75Gln or p.Glu75Lys); 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 the Barber-Say allele changes developmental transcription and head development more than wild-type TWIST2 does.

Limitations: Global overexpression of human mRNA from the one-cell stage, not a heterozygous allele expressed in mesenchyme; wild-type TWIST2 overexpression alone produced a phenotype, so the comparison is between two gain-of-dose conditions. 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

hlh-8 Glu29 allelic series (C. elegans)

CRISPR/Cas9 substitutions at endogenous hlh-8 Glu29 model the conserved human TWIST1/TWIST2 residue. BSS-equivalent Glu29Ala and Glu29Gln were examined as homozygotes and heterozygotes, with a frameshift-null control. Homozygotes had egg-laying and M-lineage defects, with residual tissue-specific reporter expression. Heterozygotes showed reduced vulval-muscle egl-15 reporter expression despite a wild-type allele; null heterozygotes resembled wild-type. Embryo retention was assessed in a sensitized multicopy reporter background.

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 BSS-equivalent substitutions impair target-gene reporter expression in endogenous heterozygous worms, contrasting with the recessive null control and supporting dominant-negative activity.

Limitations: The worm has a single Twist homolog and no mammalian eyelids or hair. Reporter transgenes contain multiple promoter copies; the embryo-retention assay uses a sensitized background. These assays address allele behavior rather than the specific human mesenchymal transcriptome, and do not map DNA-binding sites. Inferred sequestration into nonproductive dimers was not directly measured.

Show evidence (3 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.

+ 2 more references

{ }

Source YAML

click to show

name: Barber-Say Syndrome
creation_date: '2026-09-23T00:00:00Z'
category: Mendelian
synonyms:
- Barber Say syndrome
- BBRSAY
- hypertrichosis-atrophic skin-ectropion-macrostomia syndrome
- hypertrichosis, atrophic skin, ectropion, and macrostomia
description: >-
  Barber-Say syndrome is a congenital ectodermal dysplasia characterized by generalized hypertrichosis, thin,
  wrinkled and redundant skin, ectropion with eyelid anterior lamellar underdevelopment, macrostomia, a bulbous
  nose, ear anomalies and hypoplastic nipples. Cognition and motor development are usually normal, although
  developmental difficulties have been reported. Incomplete eyelid closure can expose the cornea from birth;
  lubrication and, when exposure is severe, early eyelid surgery are important components of care. Heterozygous
  TWIST2 basic-domain variants cause autosomal dominant disease: p.Glu75Gln and p.Glu75Ala substitutions and
  an in-frame p.Gln77_Arg78dup duplication were identified in the discovery series. De novo, inherited and
  mosaic variants have been documented. The allelic p.Glu75Lys substitution causes ablepharon-macrostomia syndrome,
  while biallelic loss-of-function variants cause TWIST2-related Setleis syndrome. Mutant TWIST2 shows altered
  genomic binding in HeLa cells. Worm genetics favor a dominant-negative mechanism, while mutant-only binding
  sites also support a possible neomorphic contribution; their relative contributions in affected human tissues
  remain unresolved.
disease_term:
  preferred_term: Barber-Say syndrome
  term:
    id: MONDO:0008853
    label: Barber-Say syndrome
parents:
- ectodermal dysplasia syndrome
- TWIST2-related disorder
notes: >-
  Lump/split. Barber-Say syndrome is curated as its own Disease entry, with ablepharon-macrostomia syndrome
  (AMS, MONDO:0008693) as an allelic differential rather than a subtype. The reasons are that MONDO, OMIM (209885
  versus 200110) and Orphanet keep the two separate, and that the molecular split is clean at the residue level:
  in the gene-discovery series every AMS family carried p.Glu75Lys and every BSS family carried p.Glu75Gln,
  p.Glu75Ala or p.Gln77_Arg78dup, with no allele shared between the two phenotypes (PMID:26119818). The opposing
  view is documented: a 2009 case report of microblepharon in BSS argued the two could be one disorder (PMID:19760652),
  and a 2016 critical review of all published patients expected BSS, AMS and Setleis syndrome eventually to
  be regarded as a continuum (PMID:27196381). If a future entry lumps AMS and BSS 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, has its own entry (Sweeney-Cox_Syndrome). The synonym list
  omits "BSS" and "Bss". In the curation queue these had been attached to Brown-Sequard syndrome, an unrelated
  spinal cord hemisection lesion, and the abbreviation is ambiguous with it. Name collision: Say-Barber-Biesecker-Young-Simpson
  syndrome (entry Say-Barber-Biesecker-Young-Simpson_Syndrome) shares two eponyms with this disease but is
  unrelated: it is caused by KAT6B truncating variants and is a blepharophimosis and intellectual disability
  syndrome. It is not listed as a differential diagnosis because the defining features differ (narrow, ptotic
  palpebral fissures and severe developmental delay there; macrostomia, ectropion and hypertrichosis with usually
  normal cognition here), though non-specific features such as cleft palate, hearing loss and cryptorchidism
  occur in both. The note is here so that literature or database records for one are not attached to the other.
  The MONDO:0008853 textual definition (sourced to Orphanet:1231) says "microstomia". The current Orphanet
  definition in ORPHA:1231 and every clinical report cited here describe macrostomia, so the MONDO wording
  appears to be an error in the imported definition; macrostomia is curated. No GeneReviews chapter exists
  for this disease (just check-genereviews --online, Bookshelf index snapshot 2026-09-10: NO_CHAPTER). The
  ClinGen gene-disease validity download (search.clinicalgenome.org, retrieved 2026-09-23) has no TWIST2 row,
  so there is no CGGV assertion to cite. Source reassessment: the 2016 critical review (PMID:27196381; full
  text cached under its Amsterdam UMC PDF URL) excluded Suga 2014 (PMID:25614816) as likely another disorder
  after negative TWIST2 testing, and excluded Ng and Rajguru 2006 (PMID:16714944) and the son in Dinulos and
  Pagon 1999 (PMID:10440829) for diagnostic uncertainty. The anesthesia report PMID:29497666 identifies its
  patient as the same first Japanese case reported by Suga; its anesthesia observations therefore are not used
  here to establish Barber-Say-specific risks. The mother's phenotype in PMID:10440829 remains usable. PMID:34092176
  describes mosaic AMS, so it is not primary Barber-Say patient evidence. The Oxford PDF is the full text corresponding
  to PMID:28369379, and the Amsterdam UMC PDF corresponds to PMID:27196381.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous TWIST2 basic-domain variants cause autosomal dominant disease. De novo origin was demonstrated
    when both unaffected parents were available in the discovery study. Father-to-daughter transmission is
    documented, including BSS-4.1, a mildly affected mosaic father of two affected daughters. The reported
    three transmitting mosaic parents in the discovery paper refer to the combined AMS/BSS series, not three
    Barber-Say fathers. A 1999 mother-to-son report was subsequently reassessed: the mother remained a convincing
    case, but the son's diagnosis was insufficiently documented. Parental testing informs recurrence counseling;
    mild parental features and tissue-dependent mosaicism complicate interpretation.
  evidence:
  - reference: PMID:10440829
    reference_title: Autosomal dominant inheritance of Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a mother-to-son transmission of the Barber-Say syndrome, a
      finding that strongly supports dominant inheritance of this rare
      disorder.
    explanation: >-
      Historical report of proposed mother-to-son transmission. The 2016 critical review accepted the mother
      but excluded the son from its confirmed series because available data were insufficient; this report
      alone does not establish the son as an affected case.
  - reference: PMID:20799330
    reference_title: Barber-Say syndrome in a father and daughter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a father to daughter transmission of Barber-Say syndrome
      (BSS)
    explanation: A second vertically transmitting family.
  - 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: >-
      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: >-
      Establishes de novo origin in simplex families and subsequent
      transmission.
  - 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: >-
      Three disease-transmitting fathers with mild AMS or BSS and variable skin
      pigmentation were mosaic for a TWIST2 mutation
    explanation: >-
      Mosaic transmission in the combined AMS/BSS series. Table 1 identifies BSS-4.1 and his two daughters;
      the count of three is not a Barber-Say-specific count.
  - 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 description and pictures of patient 1 are ﬁtting well the diagnosis BSS but data on the child were
      insufﬁcient to allow for a diagnosis
    explanation: >-
      The critical review retained the mother and excluded the incompletely documented son from Dinulos and
      Pagon 1999.
    quote_role: REVIEW_SYNTHESIS
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    A 2016 critical review of the published literature accepted 16 individuals
    as reliably diagnosed with Barber-Say syndrome, excluding earlier reports it
    judged misdiagnosed or insufficiently documented. Case reports published
    after that review are cited elsewhere in this entry.
  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.
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:29329175
      reference_title: Clinical Description, Molecular Analysis of TWIST2 Gene, and Surgical Treatment in a Patient With Barber-Say Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Barber-Say syndrome is a rare autosomal dominant disease characterized
        by dysmorphic features, mainly of the eyelids and skin.
      explanation: A single-gene autosomal dominant malformation syndrome.
pathophysiology:
- name: TWIST2 Basic-Domain Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Heterozygous variants alter the DNA-contacting basic domain of TWIST2. The discovery series contained p.Glu75Gln,
    p.Glu75Ala and p.Gln77_Arg78dup. The p.Glu75Lys substitution instead segregated with ablepharon-macrostomia
    syndrome. Structural modeling predicted altered DNA interaction rather than a gross change in protein fold;
    that prediction is distinct from the measured binding changes in HeLa cells.
  gene:
    preferred_term: TWIST2
    term:
      id: hgnc:20670
      label: TWIST2
  genetic_context:
    gene:
      preferred_term: TWIST2
      term:
        id: hgnc:20670
        label: TWIST2
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous missense substitutions p.Glu75Gln and p.Glu75Ala and the in-frame duplication p.Gln77_Arg78dup,
      including de novo, inherited and mosaic presentations. Dominant-negative and neomorphic mechanisms are
      recorded as hypotheses because binding changes alone do not establish their relative contribution in
      human tissue.
  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: Identifies the recurrent causal residue across unrelated BSS families.
  - 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 ablepharon-macrostomia syndrome.
  - 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 12th individual with BSS, BSS-1.1, carried a heterozygous
      c.229_234dupCAGCGC (p.Gln77_Arg78dup) mutation
    explanation: The one non-Glu75 allele in the series, also in the basic domain.
  - reference: PMID:26119818
    reference_title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      In silico TWIST2 modeling suggests that mutations affecting the p.Glu75
      residue do not alter global protein structure but could alter DNA binding
    explanation: Structural modelling result from the same paper, graded COMPUTATIONAL.
  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 directly to altered DNA binding in
        a cell system.
- name: Altered TWIST2 Genomic DNA-Binding Pattern
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    ChIP-seq in T-REx HeLa cells overexpressing tagged TWIST2 compared wild-type protein with p.Glu75Lys, p.Glu75Gln,
    p.Glu75Ala and p.Gln77_Arg78dup. Wild-type TWIST2 had 630 binding peaks. The paper reports that p.Glu75Ala
    and p.Gln77_Arg78dup shared only 25 peaks with wild-type, and that mutant proteins also occupied sites
    not detected for wild-type. These findings support altered target occupancy in this assay. Their relevance
    to endogenous TWIST2 binding in affected human craniofacial or dermal mesenchyme remains provisional.
  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: >-
      We identified 630 binding peaks associated with wild-type TWIST2.
    explanation: The wild-type binding baseline in the same assay.
  - 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: >-
      p.Glu75Ala and p.Gln77_Arg78dup TWIST2, both associated with BSS, shared
      only 25 binding peaks in common with the wild-type
    explanation: Loss of normal binding sites for the BSS alleles.
  - 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: >-
      A significant number of binding peaks detected for the mutant TWIST2
      proteins were not detected for the wild-type protein
    explanation: Gain of binding at sites the wild-type protein does not occupy.
  - 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: >-
      Mutations in the basic domain of TWIST2 drastically altered the spectrum
      of DNA binding, reducing normal binding and increasing binding to
      off-target sites.
    explanation: The authors' summary of the ChIP-seq result.
  downstream:
  - target: Dysregulated TWIST2-Dependent Mesenchymal Transcription
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - twist2_glu75_dominant_negative
    - twist2_glu75_neomorphic_binding
    description: >-
      Altered target occupancy could change transcription through interference with normal TWIST2 complexes
      or acquisition of new targets. The proportion of dysfunctional dimers in patient tissue was not measured.
    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: IN_VITRO
      snippet: >-
        The dominant nature of the mutations, then, could be explained by the
        abnormal 50% of TWIST2 homodimers and bHLH heterodimers that either
        reduced binding to the normal contingent of DNA binding sites or
        conferred a neomorphic function by binding to other sites.
      explanation: >-
        The authors' proposed route from altered binding to a dominant
        transcriptional effect. INDIRECT because it is an interpretation of
        the binding data, not a measurement of target-gene expression in
        human tissue.
- name: Dysregulated TWIST2-Dependent Mesenchymal Transcription
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    TWIST2 is expressed in craniofacial mesenchyme and chondrogenic precursors during embryonic development
    and is thought to direct development of dermal and chondrogenic tissue. Expressing the Barber-Say (p.Glu75Gln)
    or AMS (p.Glu75Lys) protein in zebrafish embryos produced more severe developmental defects than wild-type
    TWIST2 and down-regulated genes for extracellular matrix, membrane and cytoskeletal components. PROVISIONAL:
    the tissue-expression premise comes from the background of the primary paper, and the transcriptome is
    from zebrafish embryos injected with human mRNA at the one-cell stage, which over-expresses TWIST2 globally
    rather than modelling a heterozygous allele in mesenchyme. The cited studies do not provide a patient-cell
    transcriptome for a Barber-Say allele.
  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: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DYSREGULATED
  - 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: >-
      During embryonic development, TWIST2 is highly expressed in the
      craniofacial mesenchyme and in chondrogenic precursors.
    explanation: >-
      Places TWIST2 in the tissues affected in this syndrome. The sentence is
      introduction material restating earlier work and names no species, so
      it is graded OTHER with quote_role BACKGROUND.
  - 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: >-
      Previous studies suggest that TWIST2 regulates mesenchymal stem cell
      differentiation and directs the development of dermal and chondrogenic
      tissues.
    explanation: >-
      The developmental role of TWIST2 in dermis on which this node rests,
      stated as background from earlier studies.
  - 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: >-
      Gene ontology (GO) analyses revealed the greatest reduction in the
      expression of genes related to extracellular matrix (ECM), membrane
      components, and cytoskeleton (fibrils)
    explanation: >-
      Transcriptional consequence of mutant TWIST2 expression in zebrafish
      embryos, the only transcriptome available for a Barber-Say allele.
  downstream:
  - target: Dermal Extracellular Matrix Disorganization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Aberrant TWIST2 target expression is proposed to disturb the dermal
      extracellular matrix.
    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: >-
        TWIST2 mutations might alter the ECM by causing aberrant gene
        expression
      explanation: >-
        The authors' inference from zebrafish ECM gene down-regulation to the
        skin phenotype. INDIRECT because it is stated as a possibility, not
        shown in patient dermis.
  - target: Eyelid Anterior Lamella Underdevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disturbed TWIST2-directed mesenchymal development is proposed to underlie
      the facial and eyelid malformations; the steps in eyelid morphogenesis
      are not established.
    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: OTHER
      quote_role: BACKGROUND
      snippet: >-
        Disturbance of these processes due to dominant mutations in TWIST2
        could, therefore, cause the distinctive clinical features and facial
        patterning defects observed in AMS and BSS.
      explanation: >-
        Links disturbed mesenchymal and dermal development to the facial
        features. INDIRECT and BACKGROUND: it is the introduction's motivating
        hypothesis, not a result.
  - 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 and ears.
    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: OTHER
      quote_role: BACKGROUND
      snippet: >-
        Disturbance of these processes due to dominant mutations in TWIST2
        could, therefore, cause the distinctive clinical features and facial
        patterning defects observed in AMS and BSS.
      explanation: >-
        Links disturbed mesenchymal development to facial patterning. INDIRECT
        and BACKGROUND for the same reason as the eyelid edge.
    - 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: >-
        The injection of p.Glu75Lys and p.Glu75Gln hTWIST2 RNA, however, led to
        predominantly intermediate and severe developmental defects, including
        severe head hypoplasia, unclear midbrain-hindbrain boundary, dysmorphic
        body trunk, and pericardial edema.
      explanation: >-
        Mutant TWIST2 disturbs head development in zebrafish. INDIRECT because
        head hypoplasia in a fish embryo is not the human facial soft-tissue
        phenotype.
- name: Dermal Extracellular Matrix Disorganization
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Skin electron microscopy in BSS-3.1 showed thin, long elastic fibers, disordered collagen fibers of variable
    diameter, microfibrillar proliferation and amorphous deposits. A second individual, BSS-5.1, had reduced
    elastic fibers on biopsy. These are tissue observations; neither the rate of elastic-fiber assembly nor
    a direct causal link to each cutaneous feature was measured. The broader clinical review records normal
    biopsies in some other patients.
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    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: HUMAN_CLINICAL
    snippet: >-
      Electron microscopy of the skin biopsy of BSS-3.1 showed findings similar
      to those of AMS, i.e., thin and long elastic fibers, abnormally oriented
      collagen fibers, and areas of microfibrillar proliferation and amorphous
      deposits
    explanation: Ultrastructural dermal findings in a Barber-Say patient.
  - 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: >-
      clubfeet, reduced elastic fibers on skin biopsy
    explanation: >-
      Table 1 entry for a second Barber-Say individual (BSS-5.1) with reduced
      elastic fibres on biopsy.
  downstream:
  - target: Redundant Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disorganised dermal elastic and collagen fibres are the observed tissue
      correlate of lax, redundant skin; no study has tested the link directly.
  - target: Thin Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Thin dermis with disordered fibres is the tissue correlate of the thin
      skin.
  - target: Wrinkled Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of dermal fibre organisation is the tissue correlate of the
      excessive wrinkling and facial creases.
  - target: Atrophic Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Atrophic skin, one of the four features in the original descriptive
      name, is the clinical expression of the thin, disorganised dermis.
- name: Eyelid Anterior Lamella Underdevelopment
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Underdevelopment of the anterior lamella of the eyelid contributes to ectropion and incomplete lid closure.
    The degree of eyelid hypoplasia varies across Barber-Say and ablepharon-macrostomia syndromes. Clinical
    anatomy supports the local sequence from lamellar deficiency to corneal exposure; the molecular steps linking
    a specific TWIST2 allele to eyelid morphogenesis remain provisional.
  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: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: Critical review of published patients listing anterior lamellar underdevelopment.
  - 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: >-
      anterior lamella causes ectropion, causing in turn lagophtalmus
    explanation: >-
      The critical review connects anterior lamellar deficiency, ectropion and incomplete closure.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Ectropion
    causal_link_type: DIRECT
    description: >-
      A deficient anterior lamella everts 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
      snippet: >-
        anterior lamella causes ectropion, causing in turn lagophtalmus
      explanation: >-
        The critical review connects anterior lamellar deficiency, ectropion and incomplete closure.
      quote_role: REVIEW_SYNTHESIS
  - target: Eyelid Hypoplasia
    causal_link_type: DIRECT
    description: >-
      Reduced development of the anterior eyelid produces a smaller eyelid; the review describes minor size reduction
      in Barber-Say syndrome.
    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: The anterior parts of the eyelids vary in their under- development from being extremely small in AMS to minor reduc- tion in size in BSS
      explanation: The critical review explicitly connects anterior eyelid underdevelopment with reduced eyelid size in Barber-Say syndrome.
- name: Craniofacial Soft-Tissue Patterning Defect
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The facial gestalt - macrostomia, a broad bulbous nasal tip with thick
    alae, first-degree microtia with narrow ear canals, widely spaced eyes 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 Barber-Say syndrome.
  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
  downstream:
  - target: Macrostomia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Bulbous Nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Thick Nasal Alae
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: First-Degree Microtia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Narrow External Auditory Canals
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cheek Pads at the Oral Commissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low-Set Ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
mechanistic_hypotheses:
- hypothesis_group_id: twist2_glu75_dominant_negative
  hypothesis_label: Glu75 substitutions interfere with the wild-type TWIST2 pool
  status: EMERGING
  description: >-
    Under this model the mutant subunit still enters TWIST2 homodimers and
    bHLH heterodimers but those complexes fail to bind the normal E-box
    targets, so the wild-type protein is inactivated along with it. Support
    comes from the ChIP-seq loss of wild-type peaks, from the C. elegans hlh-8
    allelic series, which favours a predominantly dominant-negative mechanism
    for the TWIST1/TWIST2 residue substitutions, and from phenotypic overlap
    with Setleis syndrome, which is caused by biallelic loss of TWIST2
    function. Not mutually exclusive with the neomorphic 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: >-
      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 the TWIST2
      Glu75 alleles engineered at the equivalent hlh-8 residue.
  - 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: >-
      Supporting a contribution by the first mechanism is the phenotypic
      overlap with Setleis syndrome
    explanation: >-
      The primary paper's argument for the dominant-negative model from
      phenotypic overlap with the recessive loss-of-function allelic disorder.
  - 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: >-
      In examining egl-15::gfp expression in heterozygotes, the fs2728/+ animals resembled the WT population
    explanation: >-
      The frameshift-null heterozygous control helps distinguish the missense effect from simple loss of one
      functional copy.
- hypothesis_group_id: twist2_glu75_neomorphic_binding
  hypothesis_label: Glu75 substitutions give TWIST2 new genomic targets
  status: EMERGING
  description: >-
    Under this model the disease-relevant effect is the binding of mutant
    TWIST2 to sites the wild-type protein does not occupy, changing expression
    of genes TWIST2 does not normally regulate. The observation behind it is
    the large set of mutant-only ChIP-seq peaks. It would also offer an
    explanation for why lysine at the same residue (AMS) and glutamine or
    alanine (BSS) give different syndromes, but no study has tested that
    target-set difference in a relevant tissue.
  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: >-
      two possible mechanisms: a dominant-negative effect due to loss of
      binding to the normal contingent of TWIST2 DNA binding sites or a
      neomorphic mechanism due to binding of the mutant TWIST2 to extraneous
      promoter sites
    explanation: >-
      The primary functional study states the neomorphic mechanism as an
      alternative to the dominant-negative one.
  - 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: >-
      A significant number of binding peaks detected for the mutant TWIST2
      proteins were not detected for the wild-type protein
    explanation: The mutant-only binding peaks the neomorphic model rests on.
phenotypes:
- category: Integument
  name: Congenital Generalized Hypertrichosis
  frequency: VERY_FREQUENT
  description: >-
    Marked generalized hypertrichosis, most prominent over the back, forehead
    and limbs, present from birth. It is the feature that most clearly
    separates Barber-Say from ablepharon-macrostomia syndrome, in which scalp
    hair is sparse.
  phenotype_term:
    preferred_term: Congenital, generalized hypertrichosis
    term:
      id: HP:0004540
      label: Congenital, generalized hypertrichosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: ORPHA:1231
    reference_title: Barber-Say syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare congenital malformation syndrome with neonatal onset characterized
      by congenital generalized hypertrichosis, redundant skin and facial
      dysmorphism such as ectropion and macrostomia.
    explanation: Orphanet definition lists congenital generalized hypertrichosis first.
  - 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: Hypertrichosis as the BSS-specific feature relative to AMS.
  - 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: >-
      The BSS-affected individuals exhibited ectropion, macrostomia, bulbous
      noses, malformed ears in the spectrum of microtia first degree, thin,
      redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and
      development, together with other variable features
    explanation: Cohort-level summary of the molecularly confirmed BSS series.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records marked hypertrichosis in
    all 12 molecularly confirmed BSS individuals (VERY_FREQUENT rather than
    OBLIGATE, given the small series). The count is taken from the table rows;
    no single sentence states it.
- category: Ophthalmologic
  name: Ectropion
  frequency: VERY_FREQUENT
  description: >-
    Eversion of the eyelid margins, usually bilateral and present at birth,
    reflecting underdevelopment of the anterior lamella. It leaves the cornea
    exposed and drives the need for early lubrication, tarsorrhaphy and eyelid
    reconstruction.
  phenotype_term:
    preferred_term: Ectropion
    term:
      id: HP:0000656
      label: Ectropion
    onset:
      onset_category: CONGENITAL
  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: >-
      The BSS-affected individuals exhibited ectropion, macrostomia, bulbous
      noses, malformed ears in the spectrum of microtia first degree, thin,
      redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and
      development, together with other variable features
    explanation: Ectropion in the molecularly confirmed BSS series.
  - reference: PMID:30455119
    reference_title: 'Multidisciplinary eyelid reconstruction in Barber-Say syndrome: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The case is presented of a 2-day-old male child in whom ectropion,
      hypertelorism, hypertrichosis and other dysmorphic features led to the
      clinical diagnosis of Barber-Say syndrome, which was later confirmed with
      genetic tests.
    explanation: Ectropion recognised in the neonatal period.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records ectropion in 11 of 12 BSS
    individuals; the exception (BSS-4.1) is a mildly affected mosaic father.
    Counted from the table rows.
  sequelae:
  - target: Lagophthalmos
    causal_link_type: DIRECT
    description: Everted, deficient lids cannot close over the eye.
  - target: Exposure Keratitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Corneal exposure from the everted lids causes exposure keratitis.
    evidence:
    - reference: PMID:29329175
      reference_title: Clinical Description, Molecular Analysis of TWIST2 Gene, and Surgical Treatment in a Patient With Barber-Say Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The authors present the case of a pediatric patient with a clinical diagnosis of Barber-Say syndrome
        with ocular symptoms related to exposure keratitis.
      explanation: >-
        Corneal exposure and keratitis in a child with molecular analysis reported in the same case.
- category: Ophthalmologic
  name: Eyelid Hypoplasia
  frequency: OCCASIONAL
  description: >-
    Hypoplastic eyelids (microblepharon), with or without ectropion. Once taken
    as a feature of ablepharon-macrostomia syndrome only, it was first
    reported in Barber-Say syndrome in 2009 and is part of the shared TWIST2
    Glu75 eyelid spectrum.
  phenotype_term:
    preferred_term: Microblepharon
    term:
      id: HP:0430009
      label: Hypoplasia of eyelid
  evidence:
  - 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: >-
      This is the first report of microblepharon in BSS.
    explanation: Microblepharon in a patient with Barber-Say syndrome.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 7 months of age, patient had eye surgery with ophthalmology and
      plastic surgery to correct hypoplastic eyelids with skin grafting.
    explanation: Hypoplastic eyelids in a p.Glu75Gln-confirmed infant.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records hypoplastic eyelids or
    microblepharon in 3 of 12 BSS individuals (BSS-1.1, 6.1, 7.1). Counted from
    the table rows.
- category: Ophthalmologic
  name: Lagophthalmos
  description: >-
    Inability to close the eyes fully, from ectropion and eyelid hypoplasia;
    reported from the neonatal period and corrected by eyelid grafting in
    infancy.
  phenotype_term:
    preferred_term: Lagophthalmos
    term:
      id: HP:0030001
      label: Lagophthalmos
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recommended vigorous eye lubrication due to the hypoplastic eyelids and
      inability to close eyes
    explanation: Neonatal inability to close the eyes in a confirmed case.
  sequelae:
  - target: Exposure Keratitis
    causal_link_type: DIRECT
    description: Incomplete lid closure exposes the corneal surface.
- category: Ophthalmologic
  name: Exposure Keratitis
  description: >-
    Corneal exposure with dry-eye symptoms and keratitis, the main
    sight-threatening complication; it resolved after eyelid surgery in the
    reported cases.
  phenotype_term:
    preferred_term: Exposure keratitis
    term:
      id: HP:0000491
      label: Keratitis
  notes: >-
    Bound to the general Keratitis term because HPO has no exposure-keratitis
    or exposure-keratopathy term (runoak -i ols:hp search "Exposure
    keratopathy" and search "Corneal exposure" returned no hits on
    2026-09-23); the exposure mechanism is carried in preferred_term and the
    sequelae edges.
  evidence:
  - reference: PMID:29329175
    reference_title: Clinical Description, Molecular Analysis of TWIST2 Gene, and Surgical Treatment in a Patient With Barber-Say Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors present the case of a pediatric patient with a clinical
      diagnosis of Barber-Say syndrome with ocular symptoms related to exposure
      keratitis.
    explanation: Exposure keratitis in a child with Barber-Say syndrome.
- category: Craniofacial
  name: Macrostomia
  frequency: VERY_FREQUENT
  description: >-
    Congenital wide mouth with laterally extended oral commissures. Cheiloplasty has been reported as part
    of individualized facial reconstruction.
  phenotype_term:
    preferred_term: Macrostomia
    term:
      id: HP:0000154
      label: Wide mouth
    onset:
      onset_category: CONGENITAL
  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: >-
      The BSS-affected individuals exhibited ectropion, macrostomia, bulbous
      noses, malformed ears in the spectrum of microtia first degree, thin,
      redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and
      development, together with other variable features
    explanation: Macrostomia in the molecularly confirmed BSS series.
  - reference: PMID:8368246
    reference_title: 'Hypertrichosis, atrophic skin, ectropion, and macrostomia (Barber-Say syndrome): report of a new case.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with a multiple congenital anomalies (MCA) pattern consisting of
      severe hypertrichosis, macrostomia, ectropion, and atrophic skin
    explanation: The four features that gave the syndrome its descriptive name.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records macrostomia in all 12 BSS
    individuals. Counted from the table rows.
- category: Craniofacial
  name: Bulbous Nose
  frequency: VERY_FREQUENT
  description: >-
    Broad, bulbous nasal tip, often with broad nasal width and hypoplastic or
    thick alae. A columella extending onto the philtrum is described as a
    Barber-Say feature.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  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: >-
      The BSS-affected individuals exhibited ectropion, macrostomia, bulbous
      noses, malformed ears in the spectrum of microtia first degree, thin,
      redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and
      development, together with other variable features
    explanation: Bulbous nose in the molecularly confirmed BSS series.
  - 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 BSS a remarkable extension of the columella on the philtrum can be
      seen
    explanation: Columellar extension as a BSS-specific nasal feature.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records a bulbous nose in all 12
    BSS individuals. Counted from the table rows.
- category: Craniofacial
  name: Thick Nasal Alae
  description: Thick and flaring alae nasi, shared with ablepharon-macrostomia syndrome.
  phenotype_term:
    preferred_term: Thick nasal alae
    term:
      id: HP:0009928
      label: Thick nasal alae
  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: Lists thick and flaring alae nasi among the major facial characteristics.
- category: Craniofacial
  name: Cheek Pads at the Oral Commissures
  description: >-
    The medial cheeks bulge towards the corners of the mouth, a facial feature
    shared with ablepharon-macrostomia and Sweeney-Cox syndromes.
  phenotype_term:
    preferred_term: Cheek pads adjacent to the corners of the mouth
  notes: >-
    Left unbound, as in the Sweeney-Cox_Syndrome entry: HPO has no term for
    localised pads at the oral commissures, and HP:0000293 Full cheeks describes
    generalised fullness, a different finding.
  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.
- category: Craniofacial
  name: Hypertelorism
  frequency: FREQUENT
  description: Widely spaced eyes; telecanthus is reported separately in some patients.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  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: Hypertelorism among the major facial characteristics.
  - reference: PMID:30455119
    reference_title: 'Multidisciplinary eyelid reconstruction in Barber-Say syndrome: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The case is presented of a 2-day-old male child in whom ectropion,
      hypertelorism, hypertrichosis and other dysmorphic features led to the
      clinical diagnosis of Barber-Say syndrome, which was later confirmed with
      genetic tests.
    explanation: Hypertelorism in a neonate with confirmed BSS.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records hypertelorism in 4 of 12
    BSS individuals (BSS-3.1, 8.1, 9.1, 10.1), 33 percent. Counted from the
    table rows.
- category: Craniofacial
  name: Telecanthus
  frequency: OCCASIONAL
  description: Ocular telecanthus, reported in a father-daughter pair and in a family with a mosaic father.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: PMID:20799330
    reference_title: Barber-Say syndrome in a father and daughter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a rare, congenital disorder characterized by severe generalized
      hypertrichosis, macrostomia, ocular telecanthus, bulbous nose and
      atrophic skin
    explanation: Lists ocular telecanthus among the defining features.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records telecanthus in 3 of 12
    BSS individuals, all in one family (BSS-4.1, 4.2, 4.3). Counted from the
    table rows.
- category: Craniofacial
  name: First-Degree Microtia
  frequency: FREQUENT
  description: >-
    Small, malformed ears in the spectrum of first-degree microtia, sometimes
    cup-shaped or low-set.
  phenotype_term:
    preferred_term: Microtia, first degree
    term:
      id: HP:0011266
      label: Microtia, first degree
  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: >-
      The BSS-affected individuals exhibited ectropion, macrostomia, bulbous
      noses, malformed ears in the spectrum of microtia first degree, thin,
      redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and
      development, together with other variable features
    explanation: First-degree microtia in the molecularly confirmed BSS series.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records first-degree microtia in
    8 of 12 BSS individuals; most of the rest had other ear anomalies (small or
    low-set ears, narrow canals). Counted from the table rows.
- category: Ear
  name: Narrow External Auditory Canals
  frequency: FREQUENT
  description: Hypoplastic or narrow external auditory canals.
  phenotype_term:
    preferred_term: Hypoplastic external auditory canal
    term:
      id: HP:0000402
      label: Stenosis of the external auditory canal
  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: >-
      cup-shaped, hypoplastic external auditory canals, hearing loss
    explanation: Table 1 entry for BSS-1.1, with hypoplastic canals and hearing loss.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records hypoplastic, small or
    narrow external auditory canals in 6 of 12 BSS individuals (BSS-1.1, 2.1,
    3.1, 4.2, 8.1, 10.1). Counted from the table rows.
  sequelae:
  - target: Conductive Hearing Impairment
    causal_link_type: UNKNOWN
    description: >-
      Narrow canals are a plausible contributor to the conductive loss, but no
      source separates canal stenosis from middle-ear causes.
- category: Ear
  name: Conductive Hearing Impairment
  description: >-
    Mild conductive hearing loss, reported in several families. Newborn hearing
    screening was normal in at least one confirmed case.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:10440829
    reference_title: Autosomal dominant inheritance of Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mother also had cleft palate and mild conductive hearing loss.
    explanation: >-
      Conductive hearing loss in the mother retained as Barber-Say syndrome by the subsequent critical review;
      no inference is made from her incompletely documented son.
  - 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: >-
      She also demonstrated conductive hearing impairment and microblepharon.
    explanation: Conductive hearing impairment in a 7-year-old with BSS.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory tests, echocardiogram, head MRI, voiding cystourethrogram, and
      hearing screen were normal.
    explanation: >-
      A normal neonatal hearing screen in a molecularly confirmed case argues against hearing impairment being
      universal or necessarily present at birth.
- category: Integument
  name: Redundant Skin
  frequency: FREQUENT
  description: Lax, redundant skin, especially on the neck, trunk and limbs.
  phenotype_term:
    preferred_term: Redundant skin
    term:
      id: HP:0001582
      label: Redundant skin
  evidence:
  - reference: ORPHA:1231
    reference_title: Barber-Say syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare congenital malformation syndrome with neonatal onset characterized
      by congenital generalized hypertrichosis, redundant skin and facial
      dysmorphism such as ectropion and macrostomia.
    explanation: Redundant skin in the Orphanet definition.
  - reference: PMID:9674915
    reference_title: 'Barber-Say Syndrome: report of a new case.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a girl with lax, redundant skin, ectropion, bulbous nose,
      macrostomia, and absence of mammary glands.
    explanation: Lax, redundant skin in a reported patient.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 describes the skin as redundant
    or lax in 8 of 12 BSS individuals; the other four are described as thin or
    wrinkled. Counted from the table rows.
- category: Integument
  name: Thin Skin
  description: Thin, sometimes translucent skin with visible veins.
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  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: >-
      The BSS-affected individuals exhibited ectropion, macrostomia, bulbous
      noses, malformed ears in the spectrum of microtia first degree, thin,
      redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and
      development, together with other variable features
    explanation: Thin skin in the molecularly confirmed BSS series.
- category: Integument
  name: Wrinkled Skin
  description: >-
    Excessively wrinkled skin with facial creases, contributing to the aged
    facial appearance.
  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
  frequency: FREQUENT
  description: Dry skin, usually alongside redundant or wrinkled skin.
  phenotype_term:
    preferred_term: Dry skin
    term:
      id: HP:0000958
      label: Dry skin
  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: >-
      hearing loss | wrinkled, dry | marked hypertrichosis
    explanation: Table 1 row for BSS-1.1, recording wrinkled, dry skin.
  - 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: >-
      redundant, dry skin, lipodystrophy | marked hypertrichosis
    explanation: >-
      Table 1 skin entry shared by the sisters BSS-4.2 and BSS-4.3.
  - 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: >-
      generalized hypertrichosis especially at the back, dry lax skin,
      macrostomia, thin lips, cup-shaped ears, bulbous nose, hypoplastic
      nipples, and abnormal external genitalia
    explanation: >-
      Dry, lax skin in the 2009 Haensel case, subsequently included as BSS-1.1 in the discovery series; this
      is not an independent additional patient.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records dry skin in 4 of 12 BSS
    individuals (BSS-1.1, 4.1, 4.2, 4.3), 33 percent; three of the four are one
    family (a mosaic father and his two daughters). Counted from the table
    rows.
- category: Integument
  name: Lipodystrophy
  description: >-
    Lipodystrophy recorded in two sisters of one family in the discovery
    series.
  phenotype_term:
    preferred_term: Lipodystrophy
    term:
      id: HP:0009125
      label: Lipodystrophy
  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: >-
      redundant, dry skin, lipodystrophy | marked hypertrichosis
    explanation: >-
      Table 1 skin entry shared by the sisters BSS-4.2 and BSS-4.3.
  notes: >-
    Table 1 of PMID:26119818 records lipodystrophy in 2 of 12 BSS individuals,
    both daughters of one mosaic father (BSS-4.2, 4.3). No frequency band is
    assigned because the two observations are not independent, and the table
    does not say whether the lipodystrophy is generalized or partial, so the
    general term is bound.
- category: Integument
  name: Atrophic Skin
  description: >-
    Atrophic skin, one of the four features in the syndrome's original
    descriptive name.
  phenotype_term:
    preferred_term: Atrophic skin
    term:
      id: HP:0004334
      label: Dermal atrophy
  evidence:
  - reference: PMID:8368246
    reference_title: 'Hypertrichosis, atrophic skin, ectropion, and macrostomia (Barber-Say syndrome): report of a new case.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with a multiple congenital anomalies (MCA) pattern consisting of
      severe hypertrichosis, macrostomia, ectropion, and atrophic skin
    explanation: Atrophic skin as a core feature of an early case.
  - reference: PMID:20799330
    reference_title: Barber-Say syndrome in a father and daughter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a rare, congenital disorder characterized by severe generalized
      hypertrichosis, macrostomia, ocular telecanthus, bulbous nose and
      atrophic skin
    explanation: Atrophic skin in a father-daughter pair.
- category: Integument
  name: Hypoplastic Nipples
  frequency: FREQUENT
  description: >-
    Small, underdeveloped nipples. Inversion, nipple absence and absent or hypoplastic mammary tissue are distinct
    associated findings.
  phenotype_term:
    preferred_term: Hypoplastic nipples
    term:
      id: HP:0002557
      label: Hypoplastic nipples
  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: >-
      The BSS-affected individuals exhibited ectropion, macrostomia, bulbous
      noses, malformed ears in the spectrum of microtia first degree, thin,
      redundant skin, hypertrichosis, hypoplastic nipples, and normal hands and
      development, together with other variable features
    explanation: Hypoplastic nipples in the molecularly confirmed BSS series.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records hypoplastic nipples in 9
    of 12 BSS individuals, inverted nipples in 4 (three of them also
    hypoplastic) and absent nipples in 1. Counted from the table rows.
- category: Integument
  name: Low Anterior Hairline
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Low anterior hairline
    term:
      id: HP:0000294
      label: Low anterior hairline
  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: >-
      low anterior hairline, sparse eyebrows, hypertelorism, hypoplastic
      maxilla, gum hypertrophy, widely spaced teeth
    explanation: Table 1 entry for BSS-3.1.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records a low anterior hairline
    in 4 of 12 BSS individuals (BSS-3.1, 4.1, 4.2, 4.3). Counted from the table
    rows.
- category: Integument
  name: Sparse Eyebrows
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sparse eyebrow
    term:
      id: HP:0045075
      label: Sparse eyebrow
  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 eyebrows occur in BSS despite generalized hypertrichosis.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records sparse eyebrows in 2 of
    12 BSS individuals (BSS-3.1, 7.1). Counted from the table rows.
- category: Integument
  name: Sparse Eyelashes
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sparse eyelashes
    term:
      id: HP:0000653
      label: Sparse eyelashes
  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 eyelashes occur in BSS.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records sparse lashes in 2 of 12
    BSS individuals (BSS-5.1, 10.1). Counted from the table rows.
- 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.
- category: Craniofacial
  name: Micrognathia
  description: >-
    Small jaw, reported in two sisters in one family and in a confirmed infant
    with obstructive sleep apnea.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to feeding difficulties and intermittent stridor, ENT recommended a
      frenulectomy and a sleep study that showed abnormal sleep architecture,
      obstructive sleep apnea, and micrognathia.
    explanation: Micrognathia in a p.Glu75Gln-confirmed infant.
  notes: >-
    The two sisters are BSS-4.2 and BSS-4.3 in Table 1 of PMID:26119818
    ("macrostomia, mild micrognathia").
  sequelae:
  - target: Obstructive Sleep Apnea
    causal_link_type: UNKNOWN
    description: >-
      Reported together in the same infant; the source does not state that the
      micrognathia caused the apnoea.
- category: Craniofacial
  name: Low-Set Ears
  frequency: OCCASIONAL
  description: Low-set, sometimes posteriorly rotated or cup-shaped ears.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  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: >-
      low-set ears, microtia first degree, concha extra fold
    explanation: Table 1 ear entry for BSS-4.3.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      low set posteriorly rotated ears, redundant skin on the neck
    explanation: Low-set, posteriorly rotated ears in a p.Glu75Gln-confirmed boy.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records low-set ears in 3 of 12
    BSS individuals (BSS-4.2, 4.3, 7.1), 25 percent; two of the three are
    sisters. Counted from the table rows.
- category: Ophthalmologic
  name: Epiblepharon
  description: >-
    Epiblepharon, recorded together with ectropion and telecanthus in two
    sisters of one family in the discovery series.
  phenotype_term:
    preferred_term: Epiblepharon
    term:
      id: HP:0011225
      label: Epiblepharon
  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: >-
      ectropion, ocular telecanthus, epiblepharon | macrostomia, mild
      micrognathia
    explanation: Table 1 eyelid entry for BSS-4.3.
  - 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: >-
      ectropion, telecanthus, epiblepharon | macrostomia, mild micrognathia
    explanation: Table 1 eyelid entry for BSS-4.2, the sister of BSS-4.3.
  notes: >-
    Table 1 of PMID:26119818 records epiblepharon in 2 of 12 BSS individuals,
    both daughters of one mosaic father (BSS-4.2, 4.3). No frequency band is
    assigned because the two observations are not independent.
- category: Craniofacial
  name: High Palate
  description: High palate, recorded in one individual in the discovery series.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  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: >-
      high palate, lumbar flat angioma
    explanation: Table 1 "other" entry for BSS-6.1 (p.Glu75Ala, de novo).
- category: Craniofacial
  name: Velopharyngeal Insufficiency
  description: >-
    Velopharyngeal incompetence, recorded in the one individual with the
    p.Gln77_Arg78dup allele, who also had delayed language development.
  phenotype_term:
    preferred_term: Velopharyngeal incompetence
    term:
      id: HP:0000220
      label: Velopharyngeal insufficiency
  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: >-
      normal | velopharyngeal incompetence | delayed language development
    explanation: Table 1 row for BSS-1.1.
- category: Craniofacial
  name: Cleft Palate
  description: Cleft palate, including cleft of the soft palate, in a minority of reported patients.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:10440829
    reference_title: Autosomal dominant inheritance of Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mother also had cleft palate and mild conductive hearing loss.
    explanation: Cleft palate in an affected mother.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ENT evaluation showed a soft palate cleft.
    explanation: Soft palate cleft in a p.Glu75Gln-confirmed infant.
- category: Genitourinary
  name: Genital Anomalies
  frequency: FREQUENT
  description: >-
    Variable external genital anomalies include ambiguous genitalia, shawl scrotum and cryptorchidism in boys
    and hypoplastic labia in girls.
  phenotype_term:
    preferred_term: Abnormal external genitalia
    term:
      id: HP:0000811
      label: Abnormal external genitalia morphology
  evidence:
  - 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: >-
      generalized hypertrichosis especially at the back, dry lax skin,
      macrostomia, thin lips, cup-shaped ears, bulbous nose, hypoplastic
      nipples, and abnormal external genitalia
    explanation: Abnormal external genitalia in a girl with BSS.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records a genital anomaly in 6 of
    12 BSS individuals (ambiguous genitalia, shawl scrotum, bilateral
    cryptorchidism, hypoplastic or "snout-shaped" labia). Counted from the
    table rows. The individual anomalies with their own citations are curated
    below.
- category: Genitourinary
  name: Shawl Scrotum
  phenotype_term:
    preferred_term: Shawl scrotum
    term:
      id: HP:0000049
      label: Shawl scrotum
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient also had a shawl scrotum concealing an anatomically normal shaft
      and glans of the penis
    explanation: Shawl scrotum in a p.Glu75Gln-confirmed boy.
- category: Genitourinary
  name: Ambiguous Genitalia
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  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: >-
      marked hypertrichosis | normal | ambiguous | normal | parental
      consanguinity
    explanation: >-
      Table 1 row for BSS-2.1 (p.Glu75Gln, de novo), recording ambiguous
      genitalia in a molecularly confirmed individual.
- category: Oral
  name: Gingival Overgrowth
  description: >-
    Gingival fibromatosis or hypertrophy, with broad alveolar ridges, in
    childhood; treated by gingivoplasty.
  phenotype_term:
    preferred_term: Gingival fibromatosis
    term:
      id: HP:0000169
      label: Gingival fibromatosis
  evidence:
  - reference: PMID:20830793
    reference_title: Oral and dental abnormalities in Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral examination revealed macrostomia, broad alveolar ridges, gingival
      fibromatosis, taurodontism, delayed tooth eruption, and malocclusion.
    explanation: Gingival fibromatosis in a 7-year-old with BSS.
- category: Oral
  name: Delayed Eruption of Teeth
  phenotype_term:
    preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  evidence:
  - reference: PMID:20830793
    reference_title: Oral and dental abnormalities in Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral examination revealed macrostomia, broad alveolar ridges, gingival
      fibromatosis, taurodontism, delayed tooth eruption, and malocclusion.
    explanation: Delayed tooth eruption in a child with BSS.
- category: Oral
  name: Taurodontia
  description: Taurodontism, reported in one child.
  phenotype_term:
    preferred_term: Taurodontia
    term:
      id: HP:0000679
      label: Taurodontia
  evidence:
  - reference: PMID:20830793
    reference_title: Oral and dental abnormalities in Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral examination revealed macrostomia, broad alveolar ridges, gingival
      fibromatosis, taurodontism, delayed tooth eruption, and malocclusion.
    explanation: Taurodontism in a single reported child.
- category: Neurodevelopmental
  name: Delayed Speech and Language Development
  frequency: OCCASIONAL
  description: >-
    Language delay occurs in some reported individuals. Most patients have normal cognition and development;
    the phenotype is variable and its attribution may be complicated by hearing and palatal abnormalities.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  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: >-
      delayed language development, dyslalia, dysgrammatism
    explanation: Table 1 entry for BSS-1.1.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: At 1 year of age, patient was meeting all developmental milestones.
    explanation: >-
      Normal cognition or early milestones in this source argue against a universal developmental phenotype;
      they do not exclude language delay in other individuals.
  notes: >-
    Frequency basis: Table 1 of PMID:26119818 records language delay in 2 of 12
    BSS individuals (BSS-1.1, 10.1) and "mild delay" without further detail in
    one more (BSS-3.1). Counted from the table rows.
- category: Feeding
  name: Feeding Difficulties
  description: >-
    Feeding difficulty in infancy, reported with stridor and choking episodes
    in a confirmed infant.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to feeding difficulties and intermittent stridor, ENT recommended a
      frenulectomy and a sleep study that showed abnormal sleep architecture,
      obstructive sleep apnea, and micrognathia.
    explanation: Infant feeding difficulties in a p.Glu75Gln-confirmed case.
- category: Respiratory
  name: Obstructive Sleep Apnea
  description: Obstructive sleep apnea in one confirmed infant with micrognathia and a soft palate cleft.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to feeding difficulties and intermittent stridor, ENT recommended a
      frenulectomy and a sleep study that showed abnormal sleep architecture,
      obstructive sleep apnea, and micrognathia.
    explanation: Sleep-study-documented obstructive sleep apnea in an infant.
- category: Integument
  name: Rhabdomyomatous Mesenchymal Hamartomas
  description: >-
    Multiple rhabdomyomatous mesenchymal hamartomas of the nose and periocular
    skin in one 9-year-old boy with mosaic Barber-Say syndrome; the TWIST2
    variant was detected in blood and in the hamartoma tissue. A single report
    of a benign lesion.
  phenotype_term:
    preferred_term: Rhabdomyomatous mesenchymal hamartoma
    term:
      id: HP:0010566
      label: Hamartoma
  notes: >-
    Bound to the general Hamartoma term; rhabdomyomatous mesenchymal hamartoma
    has no HPO term (runoak -i ols:hp search "Hamartoma" on 2026-09-23 returned
    HP:0010566 and organ-specific hamartoma terms only). No malignancy is
    reported in any reference cited in this entry, but no study has looked for
    tumour risk, so absence of reports is not evidence of no risk.
  evidence:
  - reference: PMID:37817291
    reference_title: Multiple rhabdomyomatous mesenchymal hamartomas in a patient with mosaic Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a 9-year-old boy with congenital generalized hypertrichosis
      and multiple rhabdomyomatous mesenchymal hamartomas (RMHs) on his nose and
      periocular region.
    explanation: The single report of these hamartomas in BSS.
- name: Inverted Nipples
  category: Integument
  description: >-
    Inverted nipples in BSS-1.1 and the BSS-4 father and two daughters; inversion is distinct from hypoplasia.
  phenotype_term:
    preferred_term: Inverted Nipples
    term:
      id: HP:0003186
      label: Inverted nipples
  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: >-
      marked hypertrichosis | inverted, hypoplastic | normal | normal | low anterior hair line
    explanation: >-
      Table 1 records inversion and hypoplasia separately in BSS-4.1; the family clustering limits population-frequency
      inference.
- name: Absent Nipples
  category: Integument
  description: >-
    Nipple absence was recorded in BSS-7.1, distinct from small or inverted nipples.
  phenotype_term:
    preferred_term: Absent Nipples
    term:
      id: HP:0002561
      label: Absent nipple
  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: >-
      marked hypertrichosis, lanugo hair, sparse eyebrows | absent | normal | normal
    explanation: >-
      Table 1 nipple column for molecularly confirmed BSS-7.1.
- name: Breast Aplasia
  category: Integument
  description: >-
    Absence of mammary glands was reported in a girl with a clinical diagnosis of Barber-Say syndrome.
  phenotype_term:
    preferred_term: Breast Aplasia
    term:
      id: HP:0100783
      label: Breast aplasia
  evidence:
  - reference: PMID:9674915
    reference_title: 'Barber-Say Syndrome: report of a new case.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a girl with lax, redundant skin, ectropion, bulbous nose, macrostomia, and absence of mammary
      glands.
    explanation: >-
      A clinical report retained in the 2016 critical review; nipple size is a separate observation.
- name: Breast Hypoplasia
  category: Integument
  description: >-
    Mammary gland hypoplasia in a reported girl; breast development may become clinically relevant with age.
  phenotype_term:
    preferred_term: Breast Hypoplasia
    term:
      id: HP:0003187
      label: Breast hypoplasia
  evidence:
  - reference: PMID:20830793
    reference_title: Oral and dental abnormalities in Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 7-year-old female with multiple congenital anomalies such mammary gland hypoplasia, hypertrichosis,
      ectropion, and redundant skin
    explanation: >-
      Mammary hypoplasia was specifically described in this dental case report, rather than inferred from hypoplastic
      nipples.
- name: Bilateral Cryptorchidism
  category: Genitourinary
  description: >-
    Bilateral cryptorchidism in BSS-8.1.
  phenotype_term:
    preferred_term: Bilateral cryptorchidism
    term:
      id: HP:0008689
      label: Bilateral cryptorchidism
  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: >-
      hypoplastic | bilateral cryptorchidism | normal | hypertelorism | normal
    explanation: >-
      The genital column of Table 1 for BSS-8.1 records bilateral cryptorchidism.
- name: Hypoplastic Labia Majora
  category: Genitourinary
  description: >-
    Mild labia majora hypoplasia in BSS-6.1.
  phenotype_term:
    preferred_term: Hypoplastic Labia Majora
    term:
      id: HP:0000059
      label: Hypoplastic labia majora
    severity: MILD
  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: >-
      hypoplastic | mild hypoplasia of labia majora | brachydacytly and clinodactyly f5 prominent digit pads
    explanation: >-
      Table 1 genital findings in the p.Glu75Ala individual BSS-6.1.
- name: Hypoplastic Labia Minora
  category: Genitourinary
  description: >-
    Labia minora hypoplasia in BSS-10.1.
  phenotype_term:
    preferred_term: Hypoplastic Labia Minora
    term:
      id: HP:0000064
      label: Hypoplastic labia minora
  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: >-
      hypoplastic | hypoplastic labia minora | normal | hypertelorism, delayed eruption of teeth
    explanation: >-
      Table 1 genital findings in BSS-10.1.
- name: Clubfoot
  category: Musculoskeletal
  description: >-
    Clubfeet recorded in BSS-5.1; a case-level observation without an established frequency.
  phenotype_term:
    preferred_term: Clubfoot
    term:
      id: HP:0001762
      label: Talipes equinovarus
  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: >-
      shawl scrotum | normal | clubfeet, reduced elastic fibers on skin biopsy
    explanation: >-
      Table 1 records clubfeet in BSS-5.1.
- name: Brachydactyly
  category: Musculoskeletal
  description: >-
    Brachydactyly in BSS-6.1.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  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: >-
      brachydacytly and clinodactyly f5 prominent digit pads
    explanation: >-
      The source table uses the misspelling brachydacytly in its hand findings for BSS-6.1.
- name: Fifth-Finger Clinodactyly
  category: Musculoskeletal
  description: >-
    Fifth-finger clinodactyly in BSS-6.1.
  phenotype_term:
    preferred_term: Fifth-Finger Clinodactyly
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  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: >-
      brachydacytly and clinodactyly f5 prominent digit pads
    explanation: >-
      Table 1 specifies fifth-finger clinodactyly in BSS-6.1; direction is not stated.
- name: Prominent Digit Pads
  category: Musculoskeletal
  description: >-
    Prominent digit pads in BSS-6.1.
  phenotype_term:
    preferred_term: Prominent Digit Pads
    term:
      id: HP:0011298
      label: Prominent digit pad
  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: >-
      brachydacytly and clinodactyly f5 prominent digit pads
    explanation: >-
      Table 1 hand findings include prominent digit pads; no persistence from fetal life is inferred.
- name: Maxillary Hypoplasia
  category: Craniofacial
  description: >-
    Hypoplastic maxilla in BSS-3.1, illustrating variation from the more frequently described protruding premaxilla.
  phenotype_term:
    preferred_term: Maxillary Hypoplasia
    term:
      id: HP:0000327
      label: Hypoplasia of the maxilla
  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: >-
      low anterior hairline, sparse eyebrows, hypertelorism, hypoplastic maxilla, gum hypertrophy, widely spaced
      teeth
    explanation: >-
      The individual finding is documented in the primary table, not extrapolated from other craniofacial syndromes.
- name: Widely Spaced Teeth
  category: Oral
  description: >-
    Widely spaced teeth in BSS-3.1; the broader review also describes dental spacing.
  phenotype_term:
    preferred_term: Widely Spaced Teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  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: >-
      hypoplastic maxilla, gum hypertrophy, widely spaced teeth
    explanation: >-
      Table 1 oral findings in BSS-3.1.
- name: Hypodontia
  category: Oral
  description: >-
    Hypodontia recorded in BSS-7.1.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
  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: >-
      parental consanguinity, telengectasias, hypdontia malocculusion
    explanation: >-
      Table 1 lists hypdontia, a typographical form of hypodontia, in BSS-7.1.
- name: Dental Malocclusion
  category: Oral
  description: >-
    Dental malocclusion, described with gingival and tooth abnormalities and treated orthodontically in a child.
  phenotype_term:
    preferred_term: Dental Malocclusion
    term:
      id: HP:0000689
      label: Dental malocclusion
  evidence:
  - reference: PMID:20830793
    reference_title: Oral and dental abnormalities in Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed
      tooth eruption, and malocclusion.
    explanation: >-
      Direct oral examination in a 7-year-old girl.
- name: Telangiectasia
  category: Integument
  description: >-
    Telangiectasia recorded in BSS-7.1; no anatomical distribution is given.
  phenotype_term:
    preferred_term: Telangiectasia
    term:
      id: HP:0001009
      label: Telangiectasia
  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: >-
      parental consanguinity, telengectasias, hypdontia malocculusion
    explanation: >-
      Table 1 lists telengectasias among BSS-7.1 findings; the source spelling is retained in the quotation.
- name: Attached Earlobes
  category: Craniofacial
  description: >-
    Attached earlobes are among the facial findings documented by the critical clinical review.
  phenotype_term:
    preferred_term: Attached Earlobes
    term:
      id: HP:0009907
      label: Attached earlobe
  evidence:
  - reference: PMID:27196381
    reference_title: 'Barber-Say syndrome and Ablepharon-Macrostomia syndrome: An overview.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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: >-
      The review identifies attached lobes in the overlapping facial phenotype.
    quote_role: REVIEW_SYNTHESIS
- name: Bitemporal Narrowing
  category: Craniofacial
  description: >-
    Bitemporal narrowing occurs in Barber-Say and ablepharon-macrostomia syndromes.
  phenotype_term:
    preferred_term: Bitemporal Narrowing
    term:
      id: HP:0000341
      label: Narrow forehead
  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: >-
      Bitemporal narrowing and ﬂat malae are present in both syndromes
    explanation: >-
      The full clinical review documents narrowing between the temporal regions.
    quote_role: REVIEW_SYNTHESIS
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus was reported in three Barber-Say patients in the 2016 critical review.
  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
    explanation: >-
      The review identifies the three BSS reports separately from AMS reports. The small literature series
      is not a population prevalence estimate.
    quote_role: REVIEW_SYNTHESIS
- name: Lacrimal Duct Stenosis
  category: Ophthalmologic
  description: >-
    Lacrimal duct stenosis was reported in two Barber-Say patients in the critical review.
  phenotype_term:
    preferred_term: Lacrimal Duct Stenosis
    term:
      id: HP:0007678
      label: Lacrimal duct stenosis
  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: >-
      lacrimal duct stenosis in two BSS patients
    explanation: >-
      The review separates BSS lacrimal stenosis from AMS alacrimia.
    quote_role: REVIEW_SYNTHESIS
- name: Hydronephrosis
  category: Genitourinary
  description: >-
    Mild right hydronephrosis on abdominal ultrasound in the p.Glu75Gln infant; an isolated observation.
  phenotype_term:
    preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
    severity: MILD
    laterality: RIGHT
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrasound of the abdomen showed mild right hydronephrosis.
    explanation: >-
      Case-specific imaging finding with no syndrome-wide frequency inferred.
- name: Stridor
  category: Respiratory
  description: >-
    Intermittent stridor in the p.Glu75Gln infant with feeding difficulties.
  phenotype_term:
    preferred_term: Stridor
    term:
      id: HP:0010307
      label: Stridor
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to feeding difficulties and intermittent stridor, ENT recommended a frenulectomy and a sleep study
    explanation: >-
      Direct clinical observation in the confirmed infant; no specific laryngeal lesion was established.
- name: Diastasis Recti
  category: Gastrointestinal
  description: >-
    Diastasis recti noted at birth in the p.Glu75Gln infant.
  phenotype_term:
    preferred_term: Diastasis Recti
    term:
      id: HP:0001540
      label: Diastasis recti
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also observed were hypoplastic nipples, diastasis recti, and hypertrichosis on the back
    explanation: >-
      Direct neonatal examination in a molecularly confirmed case.
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  description: >-
    Reflux requiring gastroenterology follow-up in the p.Glu75Gln child.
  phenotype_term:
    preferred_term: Gastroesophageal Reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He continues to follow with ophthalmology, ENT for observation of cleft palate, gastroenterology for
      reflux, and pulmonology for obstructive sleep apnea.
    explanation: >-
      Follow-up describes reflux in this patient; not assumed universal.
- name: Absent Eyebrows
  category: Integument
  description: >-
    Absent eyebrows in a molecularly confirmed infant, distinct from sparse eyebrows.
  phenotype_term:
    preferred_term: Absent Eyebrows
    term:
      id: HP:0002223
      label: Absent eyebrow
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoplastic eyelids, ectropion, sparse eyelashes, absent eyebrows, low set posteriorly rotated ears
    explanation: >-
      The case explicitly distinguishes absent eyebrows from sparse eyelashes.
- name: Protruding Premaxilla
  category: Craniofacial
  description: >-
    Protrusion of the premaxilla, which may become more evident after infancy, is a characteristic finding
    in the critical review.
  phenotype_term:
    preferred_term: Protruding premaxilla
  notes: >-
    OLS HP searches for protruding premaxilla, maxillary protrusion and maxillary prognathism returned no exact
    match; Overjet describes a dental relationship and Hyperplasia of the maxilla asserts increased size rather
    than the reported position. The observed premaxillary protrusion is retained without either binding.
  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: >-
      protrusion of the maxilla (Fig. 5) occurs in three-quarters of all BSS patients, and becomes frequently
      more pronounced after infancy.
    explanation: >-
      The review describes the location and age-related prominence of the finding. Its selected literature
      cases should not be treated as a prospective population sample.
    quote_role: REVIEW_SYNTHESIS
genetic:
- name: TWIST2
  gene_term:
    preferred_term: TWIST2
    term:
      id: hgnc:20670
      label: TWIST2
  association: CAUSATIVE
  features: >-
    Heterozygous basic-domain variants include p.Glu75Gln (NM_057179.2:c.223G>C; nine individuals), p.Glu75Ala
    (c.224A>C; two individuals), and p.Gln77_Arg78dup (c.229_234dupCAGCGC; one individual) in the 12-person,
    10-family discovery series. De novo, inherited and mosaic presentations are documented. The father of the
    2017 p.Glu75Gln infant was not tested, so that patient's variant origin was unresolved. A later proband
    had tissue-dependent postzygotic mosaicism with the variant detected in blood and hamartoma tissue but
    not saliva.
  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: >-
      nine had a c.223G>C (p.Glu75Gln) mutation (GenBank: NM_057179.2) and two
      had c.224A>C (p.Glu75Ala) mutations
    explanation: Allele counts in the Glu75 BSS individuals of the discovery series.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'TWIST2 sequencing showed a pathogenic mutation: c.223G>C (p.Glu75Gln).'
    explanation: Independent confirmation of the recurrent allele in a later case.
  - reference: PMID:37817291
    reference_title: Multiple rhabdomyomatous mesenchymal hamartomas in a patient with mosaic Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Therefore, we consider this variant as de novo mosaicism.
    explanation: De novo mosaic TWIST2 variant in a proband.
  notes: >-
    PMID:27092433 is a further familial report. Repeat reference fetches during this review retrieved no quotable
    abstract or full text; it is retained as a lead, not affirmative evidence.
  variants:
  - name: NM_057179.2:c.223G>C (p.Glu75Gln)
    description: >-
      Recurrent missense variant, including de novo, inherited and mosaic individuals.
    gene:
      preferred_term: TWIST2
      term:
        id: hgnc:20670
        label: TWIST2
    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: >-
        nine had a c.223G>C (p.Glu75Gln) mutation
      explanation: >-
        Variant identified in the molecularly characterized discovery series.
  - name: NM_057179.2:c.224A>C (p.Glu75Ala)
    description: >-
      Missense variant found in two discovery-series individuals.
    gene:
      preferred_term: TWIST2
      term:
        id: hgnc:20670
        label: TWIST2
    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: >-
        two had c.224A>C (p.Glu75Ala) mutations
      explanation: >-
        Variant identified in the molecularly characterized discovery series.
  - name: NM_057179.2:c.229_234dupCAGCGC (p.Gln77_Arg78dup)
    description: >-
      In-frame basic-domain duplication, identified in BSS-1.1.
    gene:
      preferred_term: TWIST2
      term:
        id: hgnc:20670
        label: TWIST2
    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 12th individual with BSS, BSS-1.1, carried a heterozygous c.229_234dupCAGCGC (p.Gln77_Arg78dup) mutation
      explanation: >-
        Variant identified in the molecularly characterized discovery series.
diagnosis:
- name: TWIST2 Sequencing With Parental Testing
  description: >-
    The characteristic congenital phenotype prompts TWIST2 sequencing. Interpretation must distinguish disease-associated
    basic-domain alleles from variants of uncertain significance and from alleles associated with other TWIST2
    disorders. Testing both parents can establish inheritance or support de novo origin; testing a single tissue
    may miss mosaicism.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing is recommended in patients presenting with these
      phenotypic abnormalities, along with their parents, to establish de novo
      or inherited mutations.
    explanation: Recommends proband and parental TWIST2 testing.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paternal testing would have helped to clarify whether this finding is
      paternally inherited or de novo. Additionally, it would clarify recurrence
      risks for the patient's family.
    explanation: Parental testing informs recurrence risk.
- name: Assessment for Tissue-Dependent TWIST2 Mosaicism
  description: >-
    A negative result from one sampled tissue may not exclude mosaicism when the phenotype is suggestive. In
    one child, sequencing detected the variant in blood and rhabdomyomatous mesenchymal hamartoma tissue but
    not saliva or parental samples. This observation supports considering specimen choice and assay sensitivity
    in an individualized genetics assessment; it is not a validated universal testing algorithm.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:37817291
    reference_title: Multiple rhabdomyomatous mesenchymal hamartomas in a patient with mosaic Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Next-generation sequencing, performed in DNA from a blood sample, and RMH tissue, revealed a pathogenic
      variant in the TWIST2 gene, which was not detected in a salivary sample of the patient, nor in his parents.
    explanation: >-
      Direct evidence of tissue-dependent detection in one mosaic proband.
differential_diagnoses:
- name: Ablepharon-macrostomia syndrome
  description: >-
    Allelic TWIST2 disorder caused by p.Glu75Lys at the same residue. Shares macrostomia, eyelid underdevelopment,
    cheek pads, ear, nipple and genital anomalies; distinguished by absent or severely hypoplastic eyelids
    (ablepharon) and sparse scalp hair, whereas Barber-Say syndrome has generalized hypertrichosis and mostly
    ectropion. The known alleles and the clinical phenotype support the distinction; an uncharacterized TWIST2
    variant alone does not settle it.
  disease_term:
    preferred_term: ablepharon macrostomia syndrome
    term:
      id: MONDO:0008693
      label: ablepharon macrostomia 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: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: Setleis syndrome (focal facial dermal dysplasia type III)
  description: >-
    TWIST2-related Setleis syndrome is recessive and associated with biallelic loss-of-function alleles, bitemporal
    scar-like lesions and eyelash/eyebrow abnormalities. Temporal lesions can also occur in Barber-Say syndrome,
    so they are not an absolute discriminator. Genotype, inheritance and the full clinical pattern must be
    considered together; Setleis-like phenotypes are genetically heterogeneous.
  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: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 BSS.
treatments:
- name: Ocular Surface Protection
  description: >-
    Ophthalmic assessment and lubrication with artificial tears or ointment when eyelid closure is incomplete.
    Topical antibiotics were used in one clinically diagnosed neonate; that case does not establish routine
    prophylaxis for every patient. Severe exposure may require eyelid surgery.
  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:30984591
    reference_title: Barber Say Syndrome (A New Case Report).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eye care with artificial tear, eye lubricant and local antibiotics were
      started for the patient.
    explanation: Neonatal ocular surface protection in a one-day-old.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recommended vigorous eye lubrication due to the hypoplastic eyelids and
      inability to close eyes
    explanation: Lubrication recommended for lagophthalmos in a neonate.
  therapeutic_modality: OTHER
- name: Eyelid Reconstruction
  therapeutic_modality: SURGERY
  description: >-
    For clinically significant corneal exposure, reported approaches include tarsorrhaphy, eyelid reconstruction
    with skin grafts and autologous fat grafting. Donor sites in one confirmed case included forearm, retroauricular
    and supraclavicular skin. Surgery restored lid closure or relieved ocular symptoms in reported cases; timing
    and technique depend on the individual anatomy and exposure severity.
  treatment_term:
    preferred_term: eyelid reconstruction
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Ectropion
    term:
      id: HP:0000656
      label: Ectropion
  - preferred_term: Lagophthalmos
    term:
      id: HP:0030001
      label: Lagophthalmos
  evidence:
  - reference: PMID:30984591
    reference_title: Barber Say Syndrome (A New Case Report).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tarsoraphy was done on the second day of admission
    explanation: Neonatal tarsorrhaphy for severe ectropion.
  - reference: PMID:30455119
    reference_title: 'Multidisciplinary eyelid reconstruction in Barber-Say syndrome: A case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The approach in this case included a lateral tarsorrhaphy and skin grafts
      taken from the volar surface of the forearm, retroauricular area and
      supraclavicular fossa, as well as autologous lipografts from the inner
      side of both thighs for palpebral reconstruction.
    explanation: Staged eyelid reconstruction in an infant.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following this procedure, he was able to fully close the eyes.
    explanation: Restored lid closure after skin grafting at 7 months.
  - reference: PMID:29329175
    reference_title: Clinical Description, Molecular Analysis of TWIST2 Gene, and Surgical Treatment in a Patient With Barber-Say Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical treatment of the patient's eyelids resolved her signs and
      symptoms.
    explanation: Eyelid surgery resolved exposure keratitis in a child.
- name: Oral Commissure Repair for Macrostomia
  therapeutic_modality: SURGERY
  description: >-
    Cheiloplasty can form part of an individualized facial reconstruction plan. The patient-perspective study
    illustrates staged reconstruction in an adult woman with Barber-Say syndrome, including two cheiloplasties.
    Major elective craniofacial procedures are generally considered after growth, balancing function and the
    person's priorities.
  treatment_term:
    preferred_term: oral commissure repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Macrostomia
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cheiloplasty was performed twice to obtain a better vermilion exposure together with upper lip shortening,
      blepharoplasty, and correction of the eyelid position.
    explanation: >-
      Figure 2 describes cheiloplasty in an adult woman with Barber-Say syndrome.
- name: Dental and Gingival Management
  therapeutic_modality: SURGERY
  description: >-
    Gingivoplasty for gingival fibromatosis and orthodontic treatment for
    malocclusion and delayed eruption, reported in a 7-year-old.
  treatment_term:
    preferred_term: gingivoplasty and orthodontic treatment
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Gingival fibromatosis
    term:
      id: HP:0000169
      label: Gingival fibromatosis
  evidence:
  - reference: PMID:20830793
    reference_title: Oral and dental abnormalities in Barber-Say syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental treatment included gingivoplasty and orthodontic treatment.
    explanation: Reported dental management in a child with BSS.
- name: Multidisciplinary Care and Psychosocial Support
  description: >-
    Multidisciplinary care addresses ophthalmic, craniofacial, dental, genetic and developmental needs. The
    patient-perspective study emphasizes acceptance by family and peers, age-appropriate explanation of the
    condition and access to psychological support. Decisions about appearance-related procedures should reflect
    the person's preferences and functional needs. The study included both Barber-Say and ablepharon-macrostomia
    participants and did not establish a population-level quality-of-life effect.
  treatment_term:
    preferred_term: multidisciplinary supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20799330
    reference_title: Barber-Say syndrome in a father and daughter.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is challenging for both patients and doctors, requiring a
      multidisciplinary approach.
    explanation: Multidisciplinary management.
  - 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: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acceptance by family and peers is absolutely essential. Psychological support is useful at various ages.
    explanation: >-
      The mixed AMS/BSS patient-perspective study identifies family/peer acceptance and psychological support
      as priorities.
  therapeutic_modality: BEHAVIORAL
- name: Genetic Counseling
  description: >-
    Counseling incorporates proband and parental testing, variable expressivity and possible parental mosaicism.
    The patient-perspective review gives a likely 50% transmission risk for a non-mosaic affected parent, while
    noting uncertainty about live-born recurrence. Mosaicism requires individualized counseling rather than
    applying that figure automatically.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  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: >-
      Three disease-transmitting fathers with mild AMS or BSS and variable skin
      pigmentation were mosaic for a TWIST2 mutation
    explanation: Parental mosaicism is the counselling-relevant finding.
  - reference: PMID:28680619
    reference_title: 'Barber-say syndrome: a confirmed case of TWIST2 gene mutation.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic counseling was provided pre- and posttesting.
    explanation: Counselling given around TWIST2 testing in a confirmed case.
  - reference: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recurrence risk for a child of a non-mosaic affected person will likely be 50%
    explanation: >-
      The shared AMS/BSS counseling discussion gives an expected risk for non-mosaic parents, with uncertainty
      about live-born recurrence; it does not quantify risk from mosaic parents.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: BEHAVIORAL
  action_category: COUNSELING_INFORMATIONAL
- name: Laser Hair Removal
  therapeutic_modality: DEVICE
  description: >-
    Laser therapy has been used for hypertrichosis in Barber-Say syndrome, with favorable results reported especially
    for dark hair. Multiple sessions are required because of hair growth cycles. The review notes that treatment
    can be painful and children may require general anesthesia; this is a procedural consideration for an elective,
    preference-sensitive treatment.
  treatment_term:
    preferred_term: Laser Hair Removal
    term:
      id: NCIT:C15466
      label: Laser Therapy
  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: Hypertrichosis in BSS can be treated with laser therapy with good results, especially in patients with dark hair
    explanation: This passage concerns laser treatment specifically in Barber-Say syndrome.
  - 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: The disadvantages are that multiple sessions are needed due to the growth cycles of hairs and that general anesthesia is needed in children as laser therapy can be very painful.
    explanation: The review describes repeated sessions and general anesthesia in children as treatment burdens.
  target_phenotypes:
  - preferred_term: Congenital, generalized hypertrichosis
    term:
      id: HP:0004540
      label: Congenital, generalized hypertrichosis
    onset:
      onset_category: CONGENITAL
- name: Breast Reconstruction
  therapeutic_modality: SURGERY
  description: >-
    Reconstruction for absent or underdeveloped breasts is an elective option discussed after puberty. The
    mixed AMS/BSS literature and patient-perspective reports describe favorable experiences, without comparative
    outcome data or a requirement for surgery.
  treatment_term:
    preferred_term: Breast Reconstruction
    term:
      id: NCIT:C15354
      label: Mammoplasty
  evidence:
  - reference: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Can cosmetic surgery be done because of the small breasts? At what age? | This has been done several
      times with good success. It can be done at the end of puberty but also at any age thereafter.
    explanation: >-
      The source addresses optional breast surgery after puberty in its shared counseling table.
    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
    quote_role: REVIEW_SYNTHESIS
    snippet: Cosmetic mamma reconstructions using prostheses have been performed with good results
    explanation: The critical review reports favorable experience with prosthetic breast reconstruction, without comparative outcome data.
  target_phenotypes:
  - preferred_term: Breast aplasia
    term:
      id: HP:0100783
      label: Breast aplasia
  - preferred_term: Breast hypoplasia
    term:
      id: HP:0003187
      label: Breast hypoplasia
- name: Individualized Facial Reconstruction
  therapeutic_modality: SURGERY
  description: >-
    An adult woman with Barber-Say syndrome underwent staged maxillomandibular advancement, genioplasty, malar implants,
    rhinoplasty and soft-tissue procedures. The shared clinical review advises individualized planning, generally
    deferring major elective procedures until craniofacial growth is complete. This describes reported practice
    rather than a standardized surgical regimen. Botulinum toxin injections are also listed as an adjunct in the
    shared AMS/BSS review, without a Barber-Say-specific regimen or efficacy estimate.
  treatment_term:
    preferred_term: facial reconstruction
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      she underwent malar implants and rhinoplasty.
    explanation: >-
      Figure 2 records additional facial reconstruction in a woman with Barber-Say syndrome.
  - reference: PMID:28690482
    reference_title: "Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical procedures have included nasal reconstruction with rib cartilage grafts, orthognathic surgery,
      cheiloplasty, local skin flaps, and botox injections.
    explanation: >-
      The treatment is explicitly listed in the shared review-synthesis table; no efficacy estimate is assigned.
    quote_role: REVIEW_SYNTHESIS
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.Glu75Gln or p.Glu75Lys); stable Cre-inducible transgenic
    lines confirmed the phenotypes
  publication: PMID:26119818
  description: >-
    Overexpression model used to compare wild-type and mutant TWIST2 in vivo.
    Mutant protein caused more severe head hypoplasia and trunk defects than
    wild-type, and RNA-seq at shield stage showed down-regulation of
    extracellular matrix, membrane and cytoskeletal gene sets.
  modeled_mechanisms:
  - target: Dysregulated TWIST2-Dependent Mesenchymal Transcription
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Shows that the Barber-Say allele changes developmental transcription and
      head development more than wild-type TWIST2 does.
    limitations: >-
      Global overexpression of human mRNA from the one-cell stage, not a
      heterozygous allele expressed in mesenchyme; wild-type TWIST2
      overexpression alone produced a phenotype, so the comparison is between
      two gain-of-dose conditions. 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: 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: >-
        Simple overexpression of the wild-type protein in zebrafish caused a
        mild developmental phenotype.
      explanation: The overexpression caveat recorded in limitations.
- 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/Cas9 substitutions at endogenous hlh-8 Glu29 model the conserved human TWIST1/TWIST2 residue. BSS-equivalent
    Glu29Ala and Glu29Gln were examined as homozygotes and heterozygotes, with a frameshift-null control. Homozygotes
    had egg-laying and M-lineage defects, with residual tissue-specific reporter expression. Heterozygotes
    showed reduced vulval-muscle egl-15 reporter expression despite a wild-type allele; null heterozygotes
    resembled wild-type. Embryo retention was assessed in a sensitized multicopy reporter background.
  modeled_mechanisms:
  - target: Dysregulated TWIST2-Dependent Mesenchymal Transcription
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      BSS-equivalent substitutions impair target-gene reporter expression in endogenous heterozygous worms,
      contrasting with the recessive null control and supporting dominant-negative activity.
    limitations: >-
      The worm has a single Twist homolog and no mammalian eyelids or hair. Reporter transgenes contain multiple
      promoter copies; the embryo-retention assay uses a sensitized background. These assays address allele
      behavior rather than the specific human mesenchymal transcriptome, and do not map DNA-binding sites.
      Inferred sequestration into nonproductive dimers was not directly measured.
    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: >-
        Glu29Gln/+ and Glu29Ala/+ animals were also quite defective with 60% of the population barely expressing
        the GFP
      explanation: >-
        BSS-equivalent heterozygotes showed deficient egl-15 reporter expression in vulval muscles.
    - 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 examining egl-15::gfp expression in heterozygotes, the fs2728/+ animals resembled the WT population
      explanation: >-
        The frameshift-null heterozygous control helps distinguish the missense effect from simple loss of
        one functional copy.
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, 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 Barber-Say mutant
      proteins 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: bss_hypertrichosis_mechanism_gap
  prompt: >-
    How do the Glu75Gln and Glu75Ala substitutions produce generalized
    hypertrichosis, when Glu75Lys at the same residue gives sparse scalp hair?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Congenital Generalized Hypertrichosis
  - mechanistic_hypotheses#twist2_glu75_neomorphic_binding
  rationale: >-
    The opposing hair distributions in Barber-Say and ablepharon-macrostomia syndromes remain unexplained by
    the cited functional studies. Clinical skin biopsies have examined follicles, but the studies do not establish
    how these alleles alter the signaling that controls hair growth. HeLa binding differences suggest a testable
    hypothesis, not a demonstrated follicular mechanism.
  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: bss_model_fidelity_gap
  prompt: >-
    Would a heterozygous Twist2 Glu75Gln 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
  - pathophysiology#Altered TWIST2 Genomic DNA-Binding Pattern
  rationale: >-
    The cited Barber-Say functional studies use human TWIST2 overexpression in zebrafish or HeLa cells, or
    conserved-residue substitutions in C. elegans. The worm study does include endogenous heterozygotes with
    a wild-type allele, unlike the overexpression assays, but cannot reproduce mammalian skin, hair and eyelid
    anatomy. The cited studies do not include a Barber-Say knock-in mammalian model or identify the patient-tissue
    targets responsible for each manifestation.
  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: >-
      Simple overexpression of the wild-type protein in zebrafish caused a
      mild developmental phenotype.
    explanation: >-
      Shows that the zebrafish system responds to TWIST2 dose itself, limiting
      what it can say about the heterozygous allele.
histopathology:
- name: Abnormal Dermal Elastic and Collagen Fibers
  description: >-
    Electron microscopy in molecularly confirmed BSS-3.1 showed thin elongated elastic fibers, abnormal collagen
    orientation, microfibrillar proliferation and amorphous deposits. Reduced elastic fibers were recorded
    separately in BSS-5.1. Findings vary among patients and are not established as diagnostic.
  diagnostic: false
  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: >-
      Electron microscopy of the skin biopsy of BSS-3.1 showed findings similar
      to those of AMS, i.e., thin and long elastic fibers, abnormally oriented
      collagen fibers, and areas of microfibrillar proliferation and amorphous
      deposits
    explanation: Ultrastructural dermal findings in a Barber-Say patient.
  - 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: >-
      clubfeet, reduced elastic fibers on skin biopsy
    explanation: >-
      Table 1 entry for a second Barber-Say individual (BSS-5.1) with reduced
      elastic fibres on biopsy.
references:
- 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

2

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 (2)

Review Barber-Say evidence, inheritance, models and clinical completeness · 2026-09-27T23:22:29Z · View source

Reviewed the complete disorder and prior CREATE/EDIT histories, the matching deep-research scientific narrative and its validation metadata, every evidence-to-claim association, and cached references including available full text. The entry had no previous REVIEW event. It is a Mendelian TWIST2 disorder, within the campaign's scope excluding infectious and environmental diseases/poisonings. Sources: read the complete scientific text of PMID26119818 including its 12-person/10-family BSS table, microscopy, HeLa ChIP-seq and zebrafish methods/results; PMID28690482 including the patient-perspective tables and BSS adult surgical figure; PMID28680619 and PMID30984591 clinical reports; PMID20691403 Setleis functional study; and the full clinical/anesthesia reports PMID25614816 and PMID29497666. Read every other cited abstract and the ORPHA1231 structured record. The PMID28369379 cache remains abstract-only, but its complete accepted manuscript was already available in the Oxford URL cache: consumed results, heterozygous/null controls, methods and figure legends. The PMID27196381 landing-page cache only contains the abstract; consumed the full Amsterdam UMC publisher PDF, including its critical diagnostic reassessment and extracted Table IV. Image-only Tables I–III were not used for new row-level claims. Repeat fetches of PMID27092433 and PMID9415700 retrieved no quotable text. A PMC URL fetch returned a CAPTCHA and was not used. No cache text was hand-written. Corrected diagnostic provenance. The 2016 critical review excluded Suga2014 (PMID25614816) after negative TWIST2 testing and a divergent phenotype; the anesthesia report PMID29497666 identifies the same first Japanese child. Neither now establishes Barber-Say clinical/anesthetic risks. Ng/Rajguru2006 (PMID16714944) and the son in Dinulos/Pagon1999 (PMID10440829) were excluded as insufficiently documented. Removed their affirmative evidence, retaining the accepted mother's cleft-palate/hearing observations. Removed hypospadias supported only by the unconfirmed son. PMID34092176 concerns mosaic AMS and is no longer primary BSS eyelid evidence. The full-text exclusions and bibliographic correspondence are documented for future curators. Corrected inheritance, source scope and mechanism interpretation. The three mosaic transmitting parents belong to the combined AMS/BSS series, not three BSS fathers; BSS4.1 and his daughters are distinguished. Removed blanket DE_NOVO and SNV annotations from the mixed germline/mosaic and missense/duplication context. Added three structured variants with the source transcript and precise discovery-series counts. Clarified unresolved paternal origin in the 2017 infant and tissue-dependent postzygotic detection in the 2024 hamartoma case. Removed an unsupported numerical prevalence class from a case-count record. The HeLa study included all four mutant constructs, including E75Q. Removed the unmeasured claim that half of patient dimers are abnormal, the direct inference of reduced elastic-fiber assembly from microscopy, and the false assertion that no model expresses a mutant alongside an endogenous wild-type allele. The worm heterozygote reporter results and recessive null control now support the transcription model; multicopy reporters, sensitized embryo-retention background and species limits are explicit. No binding-site mapping was performed in worms. Human dermal histopathology is represented separately. Dominant-negative and neomorphic hypotheses remain alternatives with unresolved human-tissue contributions. Completeness assessment: 1. Phenotypes: adequate after expansion to 67. Separated nipple inversion/absence and breast aplasia/hypoplasia; added specific genital, dental, limb, craniofacial and ophthalmic findings from primary tables and the critical review, plus explicitly case-limited findings from a molecularly confirmed infant. Retained variation and family-cluster limitations; did not infer new population frequencies. Protruding premaxilla remains unbound rather than misbound to dental overjet or maxillary hyperplasia. 2. Subtypes: no established intradisease subtypes. AMS and Setleis remain allelic differentials; temporal lesions are not an absolute discriminator, and an uncharacterized TWIST2 variant alone is not diagnostic. 3. Mechanisms: adequate within evidence limits; six atomic nodes, two competing hypotheses, dermal histopathology, HeLa/fish/worm models with explicit experimental limitations. Hair-growth mechanism remains an honest knowledge gap. 4. Treatment/trials: ten care/intervention records, including ocular protection, tailored reconstruction, dental care, counseling, psychosocial support, laser hair removal and optional breast/facial procedures. Shared AMS/BSS recommendations are labeled as synthesis, not BSS-specific comparative efficacy. No disease-specific clinical trial was surfaced by the research or consumed references. 5. Genetics: three structured variants plus de novo/inherited/mosaic distinctions, uncertainty about individual origin, and non-mosaic versus mosaic counseling scope. No unsupported penetrance or modifier claims. 6. Diagnostics/biomarkers: two diagnostic approaches, including observed tissue-discordant mosaic detection; no established biochemical biomarker in the consumed sources. Online and offline GeneReviews check: NO_CHAPTER (Bookshelf snapshot2026-09-10). 7. References: full-text omissions addressed; exact quotes carry titles copied from cache. Off-entity and diagnostically doubtful reports are separated from affirmative evidence. 8. Overall: research themes assessed against primary and critical-review sources; rejected unsupported claims, incorrect ontology suggestions, uncertain historical diagnoses and model-to-human overgeneralization rather than importing them. OLS searches supplied canonical labels and definitions for new bindings, followed by term validation. Schema/term/reference batch validation passed 164 snippets and166 titles with no skipped/unavailable snippets. History and final content/cache gates are recorded in the PR validation summary. Cached institutional PDFs are reused from main; only relevant generated term-cache updates are included with the entry and this history.

Create: Barber-Say_Syndrome · 2026-09-23T19:21:50Z · View source

New Disease entry for Barber-Say syndrome (MONDO:0008853, TWIST2). Lump/split: kept as its own entry with ablepharon-macrostomia syndrome (MONDO:0008693, TWIST2 p.Glu75Lys) and Setleis syndrome (MONDO:0009203, biallelic TWIST2 truncation) as differential_diagnoses, following MONDO/OMIM/Orphanet and the residue-level genotype-phenotype split in PMID:26119818; the continuum view (PMID:19760652, PMID:27196381) is recorded in notes and evidence. The stub synonyms 'Brown Sequard Syndrome'/'Bss' were not carried over. Deep research: one run, falcon requested (HTTP 402, out of credits) with claude_code fallback, which produced research/Barber-Say_Syndrome-deep-research-claude_code.md (fell_back: true; no .citations.md sidecar produced). Report reference validation: 12/12 identifiers resolved, 1 quote attributed to PMID:26119818 not found verbatim (the closest source sentence was used instead), needs_review true. Term validation needs_review true: four report CURIEs name unrelated terms (UBERON:0004085, UBERON:0000151, UBERON:0000202 used for eyelid/nasal/mouth region; none bound) and two obsolete terms (HP:0007756, GO:0043433; not bound). preflight-dr PASS. All evidence was re-read against the primary abstracts or cached full text; phenotype frequency bands come from counting rows of Table 1 in PMID:26119818 (12 molecularly confirmed BSS individuals) and the count is stated in each phenotype's notes. functional_impact_category deliberately left unset: the primary paper frames dominant-negative and neomorphic mechanisms as alternatives, so both are curated as EMERGING mechanistic_hypotheses. Not cited: PMID:27092433 (mosaic father-to-child transmission; no abstract or full text available) and PMID:9415700 (milder form without ectropion; no abstract), both named by the report. The report's POSTN/Setleis fibroblast lead (PMID:33669496) was not used because it concerns loss-of-function Setleis cells. No GeneReviews chapter (check-genereviews --online NO_CHAPTER); no ClinGen gene-validity row for TWIST2. ORPHA:1231 cache built from the Orphadata snapshot. Validated with just validate, count-verified-snippets (121/121), validate-terms, and the offline gate set. After reading the automated research comment on the claim issue: added a notes paragraph on the Say-Barber-Biesecker-Young-Simpson (KAT6B) name collision, and added stubs/Ablepharon_Macrostomia_Syndrome.yaml so the allelic differential is in the curation queue. That comment named PMID:25620206 as the Marchegiani 2015 AJHG paper; PubMed resolves PMID:25620206 to an unrelated mtDNA-ancestry paper, and the correct PMID (26119818) was used. just validate-disorders passed (121/121 snippets).

Claude Code ▸

Barber-Say Syndrome (BBRSAY) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 2026-09-23T15:28:00.482229

Barber-Say Syndrome (BBRSAY) — Comprehensive Research Report

Important disambiguation up front

Barber-Say syndrome (BSS, this report) must not be confused with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), also called the SBBYS variant of Ohdo syndrome. Despite the overlapping eponym ("Say," "Barber"), SBBYSS is a distinct, unrelated disorder caused by KAT6B haploinsufficiency, featuring severe intellectual disability, blepharophimosis (narrow palpebral fissures — the opposite of BSS's macrostomia/ectropion pattern), and patellar anomalies. Several general search indices and even some clinical summaries conflate the two names. This report addresses only TWIST2-related Barber-Say syndrome. This is exactly the kind of named-entity confusion dismech's curation guidance warns about, and any future curation of this entry should not import KAT6B/SBBYSS content.

1. Disease Information

Barber-Say syndrome is an ultra-rare congenital malformation syndrome first delineated by Barber et al. in 1982 (Syndrome Identification VIII(1):6–9), describing a 3.5-year-old girl with "macrostomia, ectropion, atrophic skin, marked hypertrichosis, and growth retardation" (as summarized in later literature). It is now understood as an autosomal dominant disorder — virtually always arising de novo, occasionally transmitted by a mosaic parent — caused by recurrent heterozygous missense substitutions at a single codon (p.Glu75) in the basic DNA-binding domain of the bHLH transcription factor TWIST2 (Marchegiani et al. 2015, PMID:26119818).

Key identifiers: - OMIM: #209885 (phenotype), *607556 (TWIST2 gene) - Orphanet: ORPHA:1231 - MONDO: 0008853 - ICD-10: Q87.0 (congenital malformation syndromes predominantly affecting facial appearance) - SNOMED CT: 408537003 - Gene: TWIST2 / DERMO1, HGNC:20670, NCBI Gene 117581, chr2:238,848,032–238,910,534 (GRCh38), 2q37.3

Synonyms: none widely used beyond "Barber-Say syndrome" / "BBRSAY"; occasionally listed with the informal descriptive label "hypertrichosis-atrophic skin-ectropion-macrostomia syndrome."

Source basis: Information is derived almost entirely from aggregated individual case reports and small case series (fewer than 20–25 published probands as of the most recent literature identified in this search), plus one pivotal multi-family molecular genetics study (Marchegiani et al. 2015) that pooled 11 BSS-affected families with 7 ablepharon-macrostomia syndrome (AMS) families. There is no GeneReviews chapter for Barber-Say syndrome (none was found in this search), and no disease registry or EHR-aggregated cohort exists — this is a disease known only from the case-report literature, which should be reflected in any evidence_source: HUMAN_CLINICAL grading as individual-patient rather than population-level evidence.

2. Etiology

Disease causal factor: Purely genetic/molecular. BSS is caused by heterozygous, essentially always de novo, missense mutations in the basic domain of TWIST2, most recurrently p.Glu75Gln (E75Q) and less commonly p.Glu75Ala (E75A) (Marchegiani et al. 2015, PMID:26119818: "a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS," with 9 of 11 BSS families carrying p.Glu75Gln and 2 carrying p.Glu75Ala).

Genetic risk factors: - The causal locus is TWIST2 itself; there is no known population-level susceptibility variant — this is a fully penetrant, single-gene, single-codon dominant disorder, not a complex/multifactorial trait. - Germline/parental mosaicism is the specific recurrence-risk factor identified in the literature: Marchegiani et al. 2015 report "three disease-transmitting fathers with mild AMS or BSS and variable skin pigmentation were mosaic for a TWIST2 mutation," and Singh et al. 2016 (PMID:27092433) document transmission of the p.E75Q mutation from a somatically/gonadally mosaic, mildly affected father to a severely affected daughter in an Indian family — establishing that an apparently unaffected or minimally affected parent can still confer significant recurrence risk via germline mosaicism, relevant for genetic counseling. - No modifier genes have been reported.

Environmental risk factors: None identified or plausible for a single-gene bHLH transcription-factor disorder; no association with parental age, teratogen exposure, or periconceptional factors was found in this search.

Protective factors: None described; not applicable to this class of fully penetrant dominant missense disorder.

Gene-environment interactions: None reported; not applicable.

3. Phenotypes

BSS phenotypes cluster into craniofacial/ocular, integumentary (the dominant and defining system), and lesser genitourinary/dental/auditory findings. Onset is congenital in all cases (present at birth); there is no reported postnatal-onset phenotype, and the facial gestalt and skin findings are typically described as static/non-progressive rather than degenerative, though the aged, redundant-skin appearance can be mistaken for a progeroid process.

Phenotype	HPO term (suggested)	Frequency (qualitative, per case-series literature)	Onset	Notes
Generalized/congenital hypertrichosis (esp. back, forehead, limbs)	HP:0007497 (Generalized hypertrichosis) / HP:0000998 (Hypertrichosis)	Core/near-universal — defining feature distinguishing BSS from AMS	Congenital	Fine, long lanugo-like hair
Atrophic, thin, redundant/hyperlax skin ("cutis-laxa-like")	HP:0007756 (Atrophic skin) / HP:0000973 (Cutis laxa)	Core/near-universal	Congenital	Histologically thin dermis, decreased elastic fibers, hypocollagenosis (see §6)
Ectropion (bilateral, of both upper and lower eyelids)	HP:0000656	Core/near-universal (present in most, absent in some "milder" reported cases)	Congenital	Underdeveloped anterior lamella of eyelid; a documented milder BSS variant lacks ectropion (Pomili et al., PMID:9415700)
Macrostomia (wide mouth)	HP:0000154	Core/near-universal	Congenital
Absent/sparse eyebrows and eyelashes	HP:0045075 (Sparse eyebrow) / HP:0000653 (Sparse eyelashes)	Very common	Congenital
Telecanthus / hypertelorism	HP:0000506 / HP:0000316	Very common	Congenital
Broad, bulbous nasal tip with hypoplastic alae nasi	HP:0000414 / HP:0000430	Very common	Congenital
Low-set, misshapen/dysplastic ears	HP:0000369 / HP:0000377	Common	Congenital	Narrow ear canals reported
Low anterior hairline	HP:0000294	Common	Congenital
Nipple hypoplasia / absent or widely spaced nipples; hypo-/aplastic mammary glands	HP:0002557 (Hypoplastic nipples) / HP:0000006-adjacent	Common	Congenital
Genital anomalies (male: hypospadias, shawl scrotum, occasional cryptorchidism; female: prominent/enlarged labia majora)	HP:0000047 (Hypospadias) / HP:0000047-adjacent	Variable, minority	Congenital
Delayed dental eruption; small/malformed teeth; gingival overgrowth	HP:0000684 (Delayed eruption of teeth)	Common	Childhood
High-arched or cleft palate	HP:0002705 (High palate) / HP:0000175 (Cleft palate)	Occasional	Congenital
Conductive hearing loss	HP:0000405	Occasional/minority	Variable
Mild psychomotor/developmental delay	HP:0001263	Minority — most reports emphasize normal cognition	Infancy/childhood	Contrasts with the more severe developmental delay of KAT6B/SBBYSS — see disambiguation above
Corneal exposure keratopathy (secondary to ectropion/lagophthalmos)	HP:0025684-adjacent / exposure keratopathy	Complication, common where ectropion is severe	Any age	Drives ophthalmologic/surgical urgency
Growth retardation	HP:0001510	Reported in the original 1982 index case and others	Congenital/postnatal

Severity/progression: Facial and integumentary features are present at birth and are generally described as static rather than progressive; the main progression concern is secondary, acquired complications — corneal exposure and ulceration from chronic ectropion/lagophthalmos, which can worsen over time without surgical correction and represent the principal ophthalmologic threat to vision.

Quality-of-life impact: No formal EQ-5D/SF-36/QOL instrument data were found for this ultra-rare condition. Documented impacts described qualitatively in case reports and at least one patient-perspective publication (Küry et al./De Maria, "A Patient's View," PMID:28690482) include: disfigurement-related psychosocial burden, feeding difficulty related to macrostomia in infancy, need for repeated reconstructive surgeries (eyelid, oral commissure, craniofacial), and corneal/visual morbidity from exposure keratopathy. Cognitive/motor development is reported as normal in the majority of cases, a key point distinguishing BSS from many other multiple-congenital-anomaly syndromes and specifically from SBBYSS.

4. Genetic/Molecular Information

Causal gene: TWIST2 (OMIM *607556), HGNC:20670, chr2:238,848,032-238,910,534 (2q37.3).

Pathogenic variants (BSS-specific): - p.Glu75Gln (E75Q) — the recurrent, most common BSS allele (9/11 families in Marchegiani et al. 2015) - p.Glu75Ala (E75A) — the second recognized BSS allele (2/11 families) - Both fall within the basic domain of the bHLH protein — the DNA-contacting region — and were shown by ChIP-seq/EMSA-type analyses in the Marchegiani study to alter TWIST2's DNA-binding pattern: "All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells," with the mutant proteins sharing only a fraction of their genomic binding peaks with wild-type TWIST2 and gaining new, non-wild-type binding sites.

Variant classification: These recurrent missense substitutions are classified pathogenic under ACMG/AMP criteria in the primary literature (recurrent de novo occurrence across unrelated families, functional evidence of altered DNA binding, precise genotype-phenotype correlation). No formal ClinVar aggregate statistics were retrieved in this search; curators should independently confirm current ClinVar classification for p.Glu75Gln/p.Glu75Ala before citing a specific pathogenicity tier.

Allele frequency: Not present in population databases (gnomAD/1000 Genomes/TOPMed) at meaningful frequency — consistent with a fully penetrant, severe, essentially always-de-novo dominant disorder; no specific gnomAD constraint metrics (e.g., pLI, missense Z-score) for TWIST2 were retrieved in this search and should be pulled directly from gnomAD if needed for curation.

Somatic vs. germline origin: Germline (constitutional), with the specific and clinically important caveat of parental somatic/germline mosaicism as the recurrence mechanism in familial transmission (see §2 and §9).

Functional consequences — the central mechanistic ambiguity: The literature explicitly frames the E75Q/E75A (BSS) and E75K (AMS) substitutions as producing both dominant-negative and gain-of-function (neomorphic) effects simultaneously, rather than a clean loss- or gain-of-function classification:

"The mutations are located in the basic domain of the protein, and molecular analyses suggested that the mutations alter the DNA-binding activity of TWIST2, leading to both dominant-negative and gain-of-function effects" (Marchegiani et al. 2015, PMID:26119818, as reported in secondary summaries of the primary text).

Mechanistically this is attributed to (a) partial loss of binding to TWIST2's normal E-box target sites (dominant-negative component) combined with (b) acquisition of binding to abnormal, non-wild-type genomic sites (neomorphic/gain-of-function component) — "a dominant-negative effect due to loss of binding to the normal contingent of TWIST2 DNA binding sites or a neomorphic mechanism due to binding of the mutant TWIST2 to extraneous promoter sites." This dual mechanism is the key curatorial subtlety: a GeneticContext.functional_impact_category of a single enum value (e.g., DOMINANT_NEGATIVE) would understate what the primary literature actually claims; curators should consider whether the schema's controlled vocabulary can capture both components or whether free text is needed alongside the closest enum value.

Modifier genes: None established.

Epigenetic information: No disease-specific DNA methylation/histone data for BSS were found. Note, however, that TWIST2 itself functions partly through chromatin remodeling in dermal fibroblast maturation more broadly (Twist2-driven chromatin remodeling in postnatal dermal fibroblasts, ScienceDirect/iScience-type source found in search) — this is basic TWIST2 developmental biology, not BSS-specific pathological epigenetic data, and should not be conflated with disease-causing epigenetic changes.

Chromosomal abnormalities: Not applicable to BSS itself (a single-gene point-mutation disorder). Note for differential/related-locus awareness: TWIST2 sits within the region implicated in 2q37 deletion syndrome, and TWIST2 has been "proposed as a candidate gene for 2q37 deletion syndrome due to its localization in the smallest deleted chromosome region" — this is a distinct, contiguous-gene-deletion condition and should not be merged with BSS in curation.

5. Environmental Information

No environmental, lifestyle, or infectious contributing factors were identified in this search, consistent with BSS being a fully genetically determined, single-gene disorder with no reported gene-environment interaction. This section is not applicable beyond noting its inapplicability.

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flagged)

A de novo (or paternally/maternally transmitted-via-mosaicism) heterozygous missense substitution — most often p.Glu75Gln, less often p.Glu75Ala — arises in the basic DNA-binding domain of TWIST2, a basic helix-loop-helix (bHLH) transcription factor. (Demonstrated: recurrent mutation identification across 11 independent families, PMID:26119818.)
This alters the amino-acid sequence of the DNA-contacting basic domain, changing TWIST2's DNA-binding specificity: the mutant protein partially loses binding at wild-type TWIST2 target sites and gains binding at abnormal, non-wild-type genomic sites, as shown by comparative binding-peak analysis of mutant vs. wild-type TWIST2 in cell-based assays. (Demonstrated in vitro, PMID:26119818.)
This dual DNA-binding disruption leads downstream to a combined dominant-negative and neomorphic (gain-of-function) transcriptional effect on TWIST2's normal target gene network — rather than simple TWIST2 haploinsufficiency. (Inferred from binding data and genotype-phenotype correlation; direct downstream transcriptomic confirmation in human tissue is limited.)
TWIST2 is normally a heterodimeric partner (with E-box-binding partners such as the ubiquitous bHLH protein E12/TCF3) that, during embryogenesis, is highly expressed in craniofacial mesenchyme and chondrogenic/dermal precursor cells, where it inhibits terminal differentiation of mesenchymal lineages (myogenic, osteogenic) and directs dermal fibroblast and chondrogenic tissue development. (Established developmental biology of wild-type TWIST2; PMID:26119818 and general TWIST2 literature.)
Disrupted TWIST2 transcriptional output in these mesenchymal precursor populations leads to abnormal craniofacial mesenchymal and periocular (eyelid) tissue development, manifesting as underdevelopment of the eyelid anterior lamella (→ ectropion), abnormal maxillary/oral mesenchyme patterning (→ macrostomia), and abnormal nasal/auricular cartilage and soft-tissue development (→ bulbous nose, dysplastic ears). (Inferred from the tissue-expression pattern and the clinical phenotype; directly demonstrated in a zebrafish model, see below.)
In parallel, disrupted TWIST2 function in dermal fibroblast precursors impairs normal extracellular matrix (elastic fiber and collagen) deposition, producing the histologically documented thin epidermis, markedly reduced dermal elastic fibers, and hypocollagenosis. (Demonstrated histologically in patient skin biopsies; mechanistic link to TWIST2's fibroblast-differentiation role is inferred by analogy to TWIST2's known role in postnatal dermal fibroblast chromatin regulation, not directly shown in BSS patient fibroblast transcriptomics in the sources retrieved here.) This produces the clinical triad of atrophic, hyperlax, redundant ("cutis-laxa-like") skin.
Independently, disrupted TWIST2 function in hair-follicle-associated mesenchyme is associated with the striking congenital generalized hypertrichosis that clinically distinguishes BSS from its allelic neighbor AMS (which shares the eyelid/mouth phenotype but lacks prominent hypertrichosis). (Correlative/inferred — the precise mechanistic link between the E75Q/E75A substitution and follicular hair-cycle dysregulation, as opposed to the E75K/AMS substitution, has not been experimentally dissected in the sources found here; this is a genuine knowledge gap.)
Chronic ectropion/lagophthalmos secondary to the eyelid mesenchymal defect (step 5) leads, as a downstream secondary/acquired complication rather than a primary developmental defect, to chronic corneal exposure and exposure keratopathy, which is the principal driver of long-term ophthalmologic morbidity and surgical urgency. (Well-documented clinical complication, e.g., PMID:29329175, PMID:30455119.)

Supporting mechanistic detail by category

Molecular pathway / transcription factor biology: TWIST2 is a class II bHLH transcription factor that binds E-box motifs (5′-CANNTG-3′) as a heterodimer with widely expressed bHLH partners (e.g., E12); it classically inhibits transcriptional activation driven by myogenic (MYOD1, MYOG) and osteogenic/MEF2-family (MEF2A, MEF2C) factors, and represses pro-inflammatory cytokine gene expression via inhibition of NF-κB-mediated transactivation (general TWIST2 biology, GeneCards/NCBI Gene summary, and PMID:26119818 background). GO terms of interest: GO:0000981 (DNA-binding transcription factor activity, RNA polymerase II-specific), GO:0046983 (protein dimerization activity), GO:0043433 (negative regulation of DNA-binding transcription factor activity), GO:0045892 (negative regulation of DNA-templated transcription).
Cellular processes: Mesenchymal stem/progenitor cell differentiation is the central affected process — TWIST2 normally "mediates mesenchymal stem cell self-renewal by maintaining the immature phenotype and inhibiting osteogenesis and chondrogenesis" (search-derived synthesis of TWIST2 biology). Relevant GO biological process terms: GO:0030278 (regulation of ossification), GO:0045668 (negative regulation of osteoblast differentiation), GO:0060324 (face development), GO:0043010 (camera-type eye development)/eyelid-specific terms as available.
Protein dysfunction: Altered/gained DNA-binding specificity of a bHLH basic-domain mutant, rather than classical misfolding or aggregation — a sequence-specificity switch mechanism (PMID:26119818).
Tissue damage mechanisms: Skin — decreased elastic fiber content and hypocollagenosis (a developmental extracellular-matrix deficiency present from birth, not an acquired degenerative process) underlie the atrophic/redundant skin phenotype. Cornea — chronic mechanical exposure from ectropion/lagophthalmos (a biomechanical, not primary molecular, injury mechanism) underlies exposure keratopathy.
Molecular/target-gene profiling: In the allelic Setleis syndrome (TWIST2 loss-of-function; see below), expression profiling of patient fibroblasts identified dysregulation of periostin (POSTN), an extracellular-matrix protein gene, among TWIST2 target genes ("Nonsense mutations of the bHLH transcription factor TWIST2 found in Setleis Syndrome patients cause dysregulation of periostin" — title/summary level only; the primary text could not be directly retrieved in this session due to a bot-check wall, so this should be treated as a lead to verify against the primary source, not a confirmed quote). A zebrafish model expressing mutant TWIST2 showed "severe head hypoplasia" and downregulation of extracellular matrix, membrane, and cytoskeleton gene categories (PMID:26119818), directly supporting the craniofacial-mesenchyme mechanism above.
Single-cell / advanced omics: No single-cell, spatial transcriptomic, or multi-omic BSS-specific dataset was identified in this search — this is a clear gap consistent with the disease's extreme rarity.

Allelic mechanistic contrast (important for lump/split and mechanism curation)

The TWIST2 basic-domain locus at codon 75 shows a clean genotype-phenotype-mechanism correlation across three distinct disorders, useful for framing BSS's mechanism against its allelic neighbors:

Disorder	Variant(s)	Zygosity	Mechanism	Key discriminating phenotype
Ablepharon-macrostomia syndrome (AMS), OMIM #200110	p.Glu75Lys (E75K)	Heterozygous, de novo	Altered DNA binding (dominant-negative + gain-of-function)	Severe/absent eyelids (ablepharon), minimal hypertrichosis
Barber-Say syndrome (BSS), OMIM #209885	p.Glu75Gln (E75Q), p.Glu75Ala (E75A)	Heterozygous, de novo (or mosaic-transmitted)	Altered DNA binding (dominant-negative + gain-of-function)	Prominent generalized hypertrichosis, less severe eyelid findings, near-normal hands/genitalia
Setleis syndrome / focal facial dermal dysplasia 3 (FFDD3), OMIM #227260	Nonsense/frameshift (e.g., p.Gln65X, p.Gln119X, c.168delC)	Homozygous or compound heterozygous	Truncated, unstable protein — loss-of-function	Bitemporal "forceps-mark-like" atrophic scarring; autosomal recessive

This contrast is directly useful for the dismech mechanism module: it shows that the same gene, same protein domain produces a dominant gain-of-function/dominant-negative phenotype spectrum (AMS/BSS) when heterozygous missense, versus a recessive loss-of-function phenotype (Setleis) when biallelic null — a textbook illustration of the allelic-series concept, and a caution against treating "TWIST2-related disorder" as a single mechanism.

7. Anatomical Structures Affected

Organ level: - Primary: skin/integument (whole-body, most severe on back/trunk and forehead); periocular structures/eyelids; craniofacial skeleton and soft tissue (nose, mouth, ears); mammary tissue (hypoplasia); dentition. - Secondary/complication: cornea (exposure keratopathy secondary to eyelid dysfunction). - Body systems: integumentary system (primary), ophthalmologic/ocular adnexal system, craniofacial/musculoskeletal (mesenchymal patterning), reproductive/genitourinary (minority), auditory system (minority — conductive hearing loss), and, per some reports, mild central nervous system/developmental involvement in a minority of cases. - Suggested UBERON terms: UBERON:0002097 (skin of body), UBERON:0004085 (eyelid), UBERON:0000151 (nasal region), UBERON:0000202 (mouth region), UBERON:0001690 (ear), UBERON:0001911 (mammary gland).

Tissue and cell level: - Dermal fibroblasts and dermal connective tissue (atrophy, reduced elastic fiber and collagen content) — Cell Ontology CL:0000057 (fibroblast) / dermal fibroblast subtype if available. - Craniofacial mesenchyme / neural-crest-derived mesenchymal precursors — CL:0002092 (mesenchymal cell) or neural-crest-derived cell terms. - Hair follicle mesenchyme/dermal papilla (hypertrichosis) — CL:1001608-type dermal papilla terms if curating that level of detail. - Corneal epithelium (secondary exposure injury).

Subcellular level: Not a subcellular-pathology disease in the classical sense (no organelle-specific storage or trafficking defect reported); the core molecular lesion is nuclear — altered sequence-specific DNA binding of a transcription factor (GO Cellular Component: GO:0005634, nucleus; GO:0000785, chromatin).

Localization: - Skin findings are generalized/bilateral, with the back and forehead emphasized for hypertrichosis. - Facial/eyelid findings are essentially always bilateral and symmetric (bilateral ectropion, bilateral telecanthus) — no lateralization or asymmetry pattern was reported in this search.

8. Temporal Development

Onset: Congenital in essentially all reported features — the full facial gestalt, skin findings, hypertrichosis, and genital/nipple anomalies are present and recognizable at birth. No postnatal-onset primary features were identified.

Onset pattern: Not applicable in the acute/subacute/chronic sense used for acquired disease — this is a structural/developmental congenital malformation syndrome.

Progression: - The primary developmental phenotype (facial gestalt, skin texture, hypertrichosis) is generally stable/non-progressive after birth rather than degenerative, though the skin's aged/redundant appearance can create a superficial resemblance to a progressive progeroid process (see §6 differential). - The principal progressive element is secondary: chronic ectropion/lagophthalmos can lead to worsening corneal exposure, keratopathy, and potential visual compromise over time if uncorrected — this is the clearest example in BSS of a disease-stage trajectory (mild exposure → chronic keratopathy → risk of corneal scarring/vision loss), and the rationale for early and often repeated surgical intervention. - Growth retardation was noted in the original index case and some subsequent reports but is not universally emphasized as progressive.

Disease course pattern: Static congenital malformation with a superimposed chronic, potentially progressive ocular-surface complication; no remitting-relapsing pattern; lifelong condition (self-limited vs. chronic-lifelong: chronic lifelong, given permanence of the structural anomalies, though with normal life expectancy reported in most cases — no BSS-specific mortality data were found, and the disorder does not appear associated with reduced survival based on the case-report literature searched).

Critical periods: Neonatal/infant period is clinically critical for feeding support (macrostomia can complicate latch/feeding) and for early ophthalmologic assessment to prevent corneal complications; early childhood is the window for the major staged reconstructive surgical program (see §12).

9. Inheritance and Population

Epidemiology: Orphanet lists prevalence as <1/1,000,000, describing BSS as "a rare entity described in eleven patients to date" as of the Orphanet entry consulted; more recent case-report literature searched here suggests the total number of published probands has grown to roughly 15–25+ by the late 2010s (exact current total not independently re-tallied in this search — a precise current count should be obtained by a fresh literature search or GeneReviews-equivalent source at curation time rather than taken from this report as a fixed number). No incidence, national-registry, or GBD-level burden data exist for a disorder this rare.

Inheritance pattern: Autosomal dominant. Nearly all reported cases are simplex/de novo. Vertical (parent-to-child) transmission has been documented in at least two family reports and is explained mechanistically by parental mosaicism for the causative TWIST2 mutation rather than typical full heterozygosity in an overtly/typically-affected parent — i.e., recurrence in offspring of an apparently mildly affected or subtly affected parent reflects germline (and often somatic) mosaicism, not simple full penetrance with variable expressivity alone. (Note: some aggregator search snippets described BSS's inheritance as potentially "autosomal dominant or autosomal recessive" — this almost certainly reflects conflation with the separate, genuinely autosomal-recessive allelic disorder Setleis syndrome at the same locus, per §6, rather than a true AR form of BSS itself. Curators should not import an AR inheritance record for Barber-Say syndrome proper without independently verifying it against a primary source, as this looks like a database-level entity confusion rather than an established fact about BSS.)

Penetrance: Appears fully penetrant for the core facial/skin gestalt in every reported heterozygous carrier of a full (non-mosaic) E75Q/E75A mutation; formal penetrance estimates (e.g., from ClinGen) were not found in this search.

Expressivity: Variable — the mosaic-transmission family reports describe a mild-to-severe expressivity gradient tracking with mosaic vs. full germline mutation status (mosaic/mildly affected parent → severely affected, fully heterozygous child), and at least one report describes a distinctly milder BSS phenotype lacking ectropion (Pomili et al., PMID:9415700), indicating that even among fully heterozygous individuals there is a recognized phenotypic range.

Genetic anticipation: Not reported/not applicable (not a repeat-expansion disorder).

Germline mosaicism: Directly documented and clinically important (see §2, §9 above) — PMID:26119818 and PMID:27092433 are the primary sources.

Founder effects: None reported; the causal mutations (E75Q, E75A) are recurrent-de-novo across genetically diverse, geographically dispersed families (reports span European, Indian, Japanese, and other populations in the literature retrieved), consistent with a mutational hotspot rather than a population-specific founder allele.

Consanguinity: Not a relevant risk factor for BSS itself (dominant, de novo); consanguinity is relevant for the allelic recessive disorder Setleis syndrome, where homozygous/compound-heterozygous null alleles require biparental transmission of a rare variant, and consanguineous families (e.g., the Mexican-Nahua sibship reported) are overrepresented in the Setleis literature — this should be kept clearly on the Setleis side of any dismech entry, not attributed to BSS.

Carrier frequency: Not applicable/not meaningful for a fully penetrant, essentially always-de-novo dominant disorder with no population carrier reservoir.

Population demographics: No specific ethnic or geographic enrichment was identified for BSS; reported cases span multiple continents/ethnicities. No sex-ratio skew was identified in this search (both male and female probands reported, including father-to-daughter and father-to-child transmissions). Age distribution at recognition is uniformly neonatal/early infancy, since the defining features are present at birth.

10. Diagnostics

Clinical recognition: BSS is primarily a clinical/gestalt diagnosis made at birth from the combination of congenital generalized hypertrichosis, atrophic/redundant ("cutis laxa-like") skin, bilateral ectropion, and macrostomia, supported by the accessory facial features (telecanthus, bulbous nose, dysplastic ears, low anterior hairline) — molecular confirmation is then sought.

Laboratory/genetic tests: - Single-gene TWIST2 sequence analysis (targeted Sanger or NGS sequencing of TWIST2 coding exons) is the definitive confirmatory test, given the strong genotype-phenotype correlation at a single recurrent codon; an NCBI GTR-listed clinical test specifically targets "TWIST2 gene (Sequence Analysis-All Coding Exons)" for Barber-Say syndrome (postnatal testing), confirming this is an established, commercially available single-gene test rather than requiring exome-first strategies in a clinically classic case. - Whole-exome/whole-genome sequencing is appropriate when the clinical gestalt is atypical or overlaps with AMS/other differentials, or in the diagnostic-odyssey setting before the phenotype is recognized as TWIST2-related — this is in fact how the causal gene was originally identified (Marchegiani et al. 2015 used exome and candidate-gene sequencing). - Chromosomal microarray/karyotype may be used to exclude a 2q37 deletion or other structural chromosomal cause in atypical presentations, given TWIST2's location within the 2q37 deletion-syndrome critical region, though this is a differential-exclusion step rather than the primary diagnostic route for classic BSS. - Skin biopsy/histopathology is a supportive (not gene-confirmatory) diagnostic tool, showing atrophic epidermis with mild orthohyperkeratosis, a thin reticular dermis, markedly decreased elastic fibers, and hypocollagenosis — a distinctive but non-specific pattern that supports the clinical diagnosis and helps distinguish BSS from other cutis-laxa-spectrum conditions on biopsy. - Ophthalmologic examination (slit-lamp, corneal surface assessment) is an essential diagnostic/monitoring test given the risk of exposure keratopathy, not for syndrome diagnosis per se but for morbidity surveillance. - Audiology is indicated given the minority occurrence of conductive hearing loss. - No BSS-specific circulating biomarker, imaging signature, or electrophysiologic test was identified.

Differential diagnosis (key entities to exclude/distinguish, per this search): - Ablepharon-macrostomia syndrome (AMS), OMIM #200110 — the closest allelic differential; distinguished by more severe/absent eyelids and lack of prominent hypertrichosis (see §6 table). Some authors argue AMS and BSS (and Setleis) may represent "a continuum" rather than fully distinct entities (PMID:19760652, "Case report supporting that the Barber-Say and ablepharon macrostomia syndromes could represent one disorder") — a lump/split consideration directly relevant to dismech's granularity guidance, since the molecular data (distinct, non-overlapping codon-75 substitutions with a clean genotype-phenotype split) currently support keeping them as distinct but closely related allelic entries rather than a single lumped disorder, while flagging the continuum argument in notes. - Setleis syndrome (FFDD3) — distinguished by autosomal recessive inheritance, homozygous/compound-het loss-of-function TWIST2 alleles, and a localized bitemporal scarring phenotype rather than the generalized skin/hypertrichosis pattern of BSS. - Progeroid/cutis laxa spectrum disorders — Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), congenital cutis laxa syndromes (including the arterial tortuosity/emphysema-associated recessive form), De Barsy syndrome (distinguished by corneal clouding and pseudoathetoid movements), Costello syndrome, and Ehlers-Danlos syndrome are cited generically in the differential-diagnosis literature for the "prematurely aged appearance + cutis laxa" phenotype cluster that BSS superficially resembles; none of these share the TWIST2 molecular basis. - Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS/KAT6B) — critically, not a true differential in the biological sense but a name-collision risk (see disambiguation section at top); should be explicitly excluded by clinicians/curators on the basis of gene (KAT6B, not TWIST2) and phenotype (blepharophimosis + severe developmental delay, not macrostomia/ectropion + typically normal cognition).

Screening: No population or newborn screening program exists or would be applicable (private, ultra-rare, non-metabolic single-gene disorder); prenatal diagnosis by targeted TWIST2 sequencing is possible in families with a known mutation (including at-risk mosaic-parent families), and detailed prenatal ultrasound might in principle detect macrostomia/facial anomalies, though no specific prenatal-ultrasound detection report was retrieved in this search.

11. Outcome/Prognosis

Survival/mortality: No BSS-specific survival statistics, life-expectancy figures, or mortality-rate data were identified in this search. The case-report literature does not describe BSS as a life-limiting condition; growth retardation has been noted in some cases, but reports emphasize surgical/reconstructive and ophthalmologic management rather than mortality risk. This should be recorded as an absence of evidence rather than evidence of normal survival — no formal natural-history or registry-based survival study exists for a disorder this rare.

Morbidity/function: The dominant morbidity is related to (a) chronic ocular surface disease from ectropion-driven exposure, with risk of keratopathy, corneal scarring, and potential vision impairment if uncorrected, and (b) the disfigurement and functional (feeding, speech, dental) impact of macrostomia and craniofacial anomalies, generally managed with staged reconstructive surgery. Cognitive/motor function is reported as normal in the majority of documented cases; a minority describe mild developmental delay, but this is not a defining or universal feature (again in contrast to SBBYSS/KAT6B, which is essentially always associated with significant developmental disability — a further reason the two names must not be conflated when recording prognosis).

Complications: Exposure keratopathy (most significant, potentially sight-threatening); feeding difficulty in infancy from macrostomia; dental crowding/malocclusion from macrostomia and delayed eruption; psychosocial impact of facial disfigurement; hearing impairment in a minority.

Recovery potential: With surgical intervention (staged eyelid reconstruction, oral commissuroplasty, orthognathic/rhinoplasty/genioplasty procedures as needed — see §12), functional and cosmetic outcomes are reported as favorable in the case literature, though repeated procedures over childhood are typical and the underlying tissue laxity/atrophy (a developmental connective-tissue deficiency, not merely a positional deformity) can complicate surgical durability.

Prognostic factors: Severity of ectropion (driving ocular risk) and macrostomia/craniofacial involvement are the main clinically tracked severity axes; whether a patient has a full heterozygous mutation versus arose from a mosaic-parent transmission has been suggested (in the mosaicism case reports) to correlate with phenotypic severity, but this has not been formalized into a validated prognostic scoring system.

Prognostic biomarkers: None identified.

12. Treatment

There is no disease-modifying or gene-targeted therapy for Barber-Say syndrome; management is entirely supportive and reconstructive/surgical, aimed at correcting the anatomic anomalies and preventing/treating secondary complications (chiefly corneal exposure).

Surgical/interventional (the primary treatment modality): - Staged eyelid reconstruction for ectropion/lagophthalmos — techniques reported include lateral tarsorrhaphy, full-thickness skin grafting (donor sites reported: volar forearm, retroauricular area, supraclavicular fossa), and autologous fat (lipo)grafting for periorbital volume restoration (multidisciplinary case report, PMID:30455119, "Multidisciplinary eyelid reconstruction in Barber-Say syndrome"). Suggested NCIT term: NCIT:C15329 (Surgical Procedure), or a more specific oculoplastic reconstruction term if the KB's NCIT mapping supports it. - Mid-face lift and eyelid repositioning, sometimes combined with botulinum toxin adjunct treatment, reported for symptomatic corneal exposure management in an adult BSS patient, with resolution of signs/symptoms of exposure keratopathy. - Macrostomia correction (commissuroplasty/cheiloplasty) — lip/oral commissure reconstruction to narrow the mouth. NCIT: a specific cheiloplasty/reconstructive oral surgery term. - Orthognathic surgery for jaw correction, rhinoplasty for nasal reconstruction, genioplasty for chin correction, and malar (cheek) implants for facial contour — reported as part of the broader staged craniofacial reconstructive program in one comprehensive surgical case series retrieved in this search. - Anesthetic management considerations are themselves a documented topic in the literature — a case report specifically addresses "General anesthesia of a Japanese infant with Barber-Say syndrome," presumably reflecting airway/feeding-related considerations relevant to macrostomia and craniofacial anatomy (specific anesthetic findings were not independently extracted in this search and should be pulled directly from that source if curating perioperative-risk content).

Supportive/rehabilitative care: - Ophthalmologic surveillance and lubrication/ocular surface protection (artificial tears, ointments, protective measures against exposure) as first-line, non-surgical management of ectropion-related dryness, presumably standard-of-care though not separately quoted from a specific source in this search — this should be verified against a primary ophthalmology reference before being cited as an evidence-backed BSS-specific recommendation rather than general exposure-keratopathy management extrapolated to this condition. - Feeding support in infancy given macrostomia. - Dental/orthodontic management for delayed eruption, malocclusion, and gingival overgrowth. - Audiology follow-up and hearing support where conductive hearing loss is present. - Genetic counseling (NCIT:C15240) is clearly indicated given the demonstrated risk of parental germline mosaicism affecting recurrence-risk counseling, distinct from the low recurrence risk that would be quoted for a purely simplex de novo dominant disorder.

Pharmacotherapy: No BSS-specific pharmacologic treatment exists; botulinum toxin is used adjunctively for periocular/eyelid positioning in at least one reported case (see above) rather than as disease treatment per se.

Experimental/advanced therapeutics: None — no gene therapy, cell therapy, or targeted molecular therapy has been reported or is currently applicable given the transcription-factor, developmental-malformation nature of the disease; no active ClinicalTrials.gov or WHO ICTRP trial was identified for Barber-Say syndrome in this search (consistent with its extreme rarity and the absence of a modifiable downstream pathway analogous to, e.g., an enzyme-replacement target).

Treatment strategy: Management follows a staged, multidisciplinary reconstructive algorithm beginning in infancy (ophthalmologic protection, feeding support) and continuing through childhood/adolescence with sequential craniofacial and periocular surgeries, coordinated across ophthalmology/oculoplastics, craniofacial/plastic surgery, dentistry/orthodontics, audiology, and clinical genetics — rather than a single-specialty or drug-based algorithm.

13. Prevention

Primary prevention: Not applicable in the population sense — BSS arises from de novo or mosaic-transmitted dominant mutation and has no modifiable environmental risk factor to intervene on.

Secondary prevention: Early neonatal ophthalmologic assessment and initiation of ocular-surface protection is the key secondary-prevention measure, aimed at forestalling progression to corneal scarring/vision loss from chronic exposure keratopathy — this is the clearest tertiary/secondary-prevention opportunity documented in the literature reviewed.

Genetic counseling/reproductive prevention: For families with a previously affected child (especially where a parent shows even mild/subtle features suggestive of mosaicism), prenatal or preimplantation genetic testing using the known familial TWIST2 mutation is the applicable reproductive risk-reduction strategy, directly motivated by the documented germline mosaicism transmission cases (PMID:26119818, PMID:27092433). Recurrence risk counseling should explicitly account for the possibility of parental mosaicism rather than assuming a negligible recurrence risk purely because both parents appear clinically unaffected.

Screening: No population, newborn, or carrier screening program is applicable, as discussed in §10.

Public health/behavioral/immunization/prophylaxis: Not applicable to this disorder.

14. Other Species / Natural Disease

No naturally occurring TWIST2-related disease analogous to Barber-Say syndrome was identified in other species in this search (no OMIA entry, veterinary case series, or companion-animal report was found). This appears to be a human-specific clinical entity in the literature surveyed, though this absence should be read as "not found in this search" rather than a confirmed negative — a dedicated OMIA search was not exhaustively performed here.

Orthologous gene: Twist2 is highly conserved; the mouse ortholog is Twist2 (MGI:104685, "twist basic helix-loop-helix transcription factor 2"), and zebrafish possess a twist2/dermo1 ortholog used experimentally (see below and §6). No natural/spontaneous disease-causing Twist2 variant has been reported in these model species outside of engineered/knockout research models.

Comparative biology: TWIST2's role in inhibiting mesenchymal (myogenic/osteogenic) differentiation and in dermal fibroblast/scale development is evolutionarily conserved from fish to mammals — e.g., zebrafish twist2/dermo1 "regulates scale shape and scale organization during skin development and regeneration" (search-identified ScienceDirect source), a functional parallel to its role in mammalian dermal development, though scales are not a direct model for human skin pathology.

15. Model Organisms

Mouse (Mus musculus): - Twist2-null (knockout) mice are the best-characterized mammalian model of TWIST2 loss-of-function, though they model a phenotype closer to the biology relevant to the recessive Setleis end of the allelic spectrum (complete loss of function) rather than the dominant-negative/gain-of-function BSS mutations. Reported phenotype: "The Twist2-KO mouse presents relatively normal embryonic development and no notable bone abnormalities, but typically dies 2–3 days after birth due to cachexia, failure to thrive and high levels of pro-inflammatory cytokines," with the mechanism attributed to loss of TWIST2's normal repression of NF-κB-driven pro-inflammatory cytokine expression across multiple tissues, producing apoptosis, cachexia, and neonatal lethality, described as resembling TNFα-induced cachexia models. This is an important model-fidelity caveat for dismech curation: the null mouse's dominant, life-limiting phenotype (neonatal lethal systemic cytokine-driven cachexia) is not the human BSS phenotype (a viable, non-lethal craniofacial/dermal malformation syndrome) — consistent with the human disease being caused by a dominant dual dominant-negative/gain-of-function missense mechanism rather than simple biallelic loss of function, and any AnimalModel.modeled_mechanisms link from a Twist2-null mouse to a BSS pathophysiology node should likely be PARTIALLY_RECAPITULATES or FAILS_TO_RECAPITULATE at best, with explicit limitations describing this genotype mismatch (null vs. dominant-negative/gain-of-function missense) rather than RECAPITULATES. - No knock-in mouse model carrying the human BSS-specific p.Glu75Gln or p.Glu75Ala substitution was identified in this search — this appears to be a genuine gap in the literature (an E75K/E75Q/E75A knock-in mouse, which would far more faithfully model the dominant human mutation mechanism, does not appear to have been published as of the sources retrieved here). This is an explicit, actionable knowledge gap worth flagging in a HUMAN_MODEL_MISMATCH discussion if this entry is curated in dismech.

Zebrafish (Danio rerio): - Used directly in the pivotal Marchegiani et al. 2015 study to functionally test the human BSS/AMS mutant TWIST2 proteins: expression of mutant TWIST2 produced "severe head hypoplasia" and downregulation of extracellular-matrix, membrane, and cytoskeleton gene expression programs — this is the most disease-relevant model system identified for the dominant-negative/gain-of-function mechanism specifically, since it used the actual human disease-causing substitutions rather than a null allele, and directly supports the craniofacial-mesenchyme step of the causal chain in §6. - Separately, wild-type zebrafish twist2/dermo1 has been used as a normal-development model for dermal/scale formation, informing general TWIST2 developmental biology rather than disease modeling per se.

Cell-based/in vitro models: - HeLa cell transfection with Flag-tagged wild-type and mutant TWIST2 constructs, used for the ChIP-seq/DNA-binding-pattern comparison described in §6 (PMID:26119818) — an in vitro molecular model of the mechanistic lesion, not a tissue/organismal disease model. - Patient-derived fibroblasts have been used in the allelic Setleis syndrome literature for expression profiling of TWIST2 target genes (including the periostin/POSTN finding noted in §6) — no equivalent BSS (dominant-negative/gain-of-function allele) patient-fibroblast transcriptomic study was identified in this search, representing a further gap: the mechanistic downstream-target data that exists is largely from the loss-of-function (Setleis) side of the allelic series, not from BSS's own gain-of-function/dominant-negative alleles.

Model limitations, summarized: No model organism currently available (null mouse, zebrafish mutant-TWIST2 embryo, or in vitro assay) fully recapitulates the complete human BSS phenotype (combined hypertrichosis + cutis-laxa-like skin + ectropion + macrostomia + normal viability/typically normal cognition) in a single system; the null mouse models a different (lethal, cytokine-driven) end of the TWIST2 loss-of-function spectrum, and the zebrafish data — while using the correct disease-causing mutation — captures gross craniofacial hypoplasia and gene-expression changes rather than the specific eyelid/dermal/hair-follicle phenotypes that define the human clinical picture.

Summary of Key Citations

PMID/DOI	Citation	Relevance
PMID:26119818	Marchegiani S, et al. "Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes." Am J Hum Genet. 2015;97(1):99-110.	Primary molecular-genetics/mechanism paper; genotype-phenotype correlation; zebrafish and HeLa functional data; mosaicism
PMID:20691403	Kowalczyk C, et al. "Homozygous Nonsense Mutations in TWIST2 Cause Setleis Syndrome." Am J Hum Genet. 2010;87(2):289-96.	Allelic recessive/loss-of-function disorder; mechanistic contrast
PMID:27092433	Singh A, et al. "Transmission of Barber-Say syndrome from a mosaic father to his child in an Indian family." Clin Dysmorphol. 2016;25(4):181-185.	Germline mosaicism transmission, phenotype severity gradient
PMID:19760652	Case report supporting that the Barber-Say and ablepharon macrostomia syndromes could represent one disorder.	Lump/split argument for BSS/AMS continuum
PMID:29329175	"Clinical Description, Molecular Analysis of TWIST2 Gene, and Surgical Treatment in a Patient With Barber-Say Syndrome." Ophthalmic Plast Reconstr Surg.	Surgical/ophthalmologic management
PMID:30455119	"Multidisciplinary eyelid reconstruction in Barber-Say syndrome: A case report."	Detailed eyelid reconstructive technique
PMID:28680619 / PMC5494409	Yohannan et al. "Barber-say syndrome: a confirmed case of TWIST2 gene mutation." Clin Case Rep. 2017.	Molecular confirmation case report
PMID:8368246	"Hypertrichosis, atrophic skin, ectropion, and macrostomia (Barber-Say syndrome): report of a new case." 1993.	Early clinical case delineation
PMID:9415700	"Macrostomia, hypertelorism, atrophic skin, severe hypertrichosis without ectropion: milder form of Barber-Say Syndrome."	Phenotypic spectrum/expressivity
PMID:28690482	"Barber-Say Syndrome and Ablepharon-Macrostomia Syndrome: A Patient's View." Mol Syndromol. 2017.	Patient-perspective/QOL-adjacent content
ORPHA:1231	Orphanet entry, Barber-Say syndrome	Prevalence, synonym/definition source
OMIM #209885 / *607556	OMIM phenotype and gene entries	Clinical synopsis, nomenclature (note: full OMIM text could not be directly fetched in this session — HTTP 403 — so OMIM content above is drawn from indexed secondary summaries and should be re-verified against the live OMIM entry before formal curation)

Explicit gaps and caveats for curation

OMIM full-text access failed (HTTP 403) during this research session; the OMIM-attributed statements above come from search-engine-indexed excerpts of the OMIM entry/clinical synopsis, not a direct read of the primary source, and should be re-fetched and re-verified before being cited as OMIM content in a KB entry.
The periostin/POSTN target-gene finding is reported here at title/abstract-summary level only (PMC7922891 could not be fetched past a bot-check page); treat as an unverified lead, not a quotable finding, and it concerns Setleis syndrome (loss-of-function) fibroblasts, not BSS's dominant-negative/gain-of-function alleles specifically.
The apparent "autosomal recessive" inheritance tag for BSS surfaced in one aggregator search result and is very likely a database-level conflation with the genuinely recessive allelic disorder Setleis syndrome; do not curate BSS itself as having AR inheritance without independent primary-source verification.
No current, precise total case count was obtained (most specific figures found ranged from "11" (Orphanet, pre-2015) to "~15" (2017) to "<20" (2019); a fresh count was not independently performed here).
No GeneReviews chapter and no formal natural-history, registry, or QOL-instrument study exist for this condition — all clinical-course, prognosis, and QOL content in this report is aggregated from individual case reports, which should be reflected in evidence grading (individual human clinical case-report evidence, not cohort-level).
No knock-in mouse model of the human BSS mutation was found — an explicit, worth-flagging translational gap between the available Twist2-null mouse (a different, lethal loss-of-function phenotype) and the human dominant-negative/gain-of-function disease.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	0
Quoted claims not found in source	1
References weighed for topical relevance	12
On topic	10
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMID:26119818: "The mutations are located in the basic domain of the protein, and molecular analyses suggested that the mutations alter the DNA-binding activity of TWIST2, leading to both dominant-negative and gain-of-function effects"
closest text in source: "Molecular analyses suggest that these mutations alter the DNA-binding activity of TWIST2, leading to both dominant-negative and gain-of-function effects"

Term Validation

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

Outcome	Count
Terms checked	50
Resolved	45
Unresolved (possible confabulation)	0
Obsolete	2
Unverifiable	3
Terms whose name was checked	14
Terms named correctly	8
Terms named as a different term	4
Terms whose name is worth a second look	2

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:

HP:0000656 (1 mention) - the report calls it "Ectropion (bilateral, of both upper and lower eyelids)"; HP calls it Ectropion
UBERON:0004085 (1 mention) - the report calls it "eyelid"; UBERON calls it labium majora
UBERON:0000151 (1 mention) - the report calls it "nasal region"; UBERON calls it pectoral fin
UBERON:0000202 (1 mention) - the report calls it "mouth region"; UBERON calls it glial blood brain barrier

Obsolete terms

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

HP:0007756 (obsolete Slitlike anterior chamber angles in children) (1 mention) - replaced by HP:0000594
GO:0043433 (obsolete negative regulation of DNA-binding transcription factor activity) (1 mention)

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 (wide mouth)"; HP calls it Wide mouth
HP:0001263 (1 mention) - the report calls it "Mild psychomotor/developmental delay"; HP calls it Global developmental delay, and lists "Psychomotor developmental delay" 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, MGI.

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Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Barber-Say Syndrome (BBRSAY) — Comprehensive Research Report

Important disambiguation up front

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (ordered, with inference flagged)

Supporting mechanistic detail by category

Allelic mechanistic contrast (important for lump/split and mechanism curation)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Citations

Explicit gaps and caveats for curation

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Prefixes with no resolver