Beare-Stevenson Cutis Gyrata Syndrome

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant FGFR2-related disorder, with sporadic and molecularly confirmed de novo cases reported. Advanced paternal age has been observed, but individual case observations do not establish a specific germline selection mechanism. Parental testing and genetic counseling guide recurrence-risk assessment. For an affected heterozygous individual, each child has a 50% chance of inheriting the variant. When parental blood testing is negative, sibling recurrence risk remains slightly above the population background because of possible germline mosaicism.

Autosomal dominant inheritance

Show evidence (5 references)

PMID:8696350 SUPPORT Human Clinical

"Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death."

The defining molecular paper states the inheritance pattern and the core phenotype.

PMID:1519658 SUPPORT Human Clinical

"All cases observed to date have been sporadic. Increased paternal age suggests the possibility of an autosomal dominant mutation."

The premolecular 1992 series reported sporadic cases and proposed dominant inheritance; it did not establish de novo status by parental sequencing.

PMID:16531735 SUPPORT Human Clinical

"The paternal age at the time of conception was 62 years consistent with a paternal age effect."

A molecularly confirmed case had a 62-year-old father; this is a clinical observation consistent with, rather than proof of, a paternal-age mechanism.

+ 2 more references

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Discussions and Knowledge Gaps

3

What aspects of the p38-inhibitor response in Fgfr2+/Y394C mice could translate to human BSS?

HUMAN MODEL MISMATCH OPEN gap_bss_p38_inhibition_translation

Attached to

pathophysiology#p38 MAPK Activation pathophysiology#Epidermal Hyperplasia

Prenatal systemic SB203580 and early postnatal topical treatment improved epidermal hyperplasia in mice. Systemic treatment produced slight coronal-suture improvement in a minority of pups, but quantitative skull morphology did not significantly improve and survival was unchanged. This is preclinical evidence for pathway involvement, with unresolved developmental timing, efficacy and safety in humans. The mouse model does not reliably reproduce human tracheal sleeves, so an airway benefit cannot be inferred from skin rescue.

Proposed experiments

Timing and tissue specificity of p38 inhibition

exp_bss_p38_developmental_window

Compare developmental treatment windows and tissue-specific delivery with prespecified skin, suture, growth and survival outcomes; evaluate toxicity and pathways that remain active despite p38 inhibition.

Show evidence (3 references)

PMID:22585574 SUPPORT Model Organism

"Only a small portion of drug-treated mutant pups (20% of mutants from 2 litters) showed slight improvement and increased patency in coronal sutures."

The full paper reports limited suture benefit rather than skin-only efficacy.

PMID:22585574 SUPPORT Model Organism

"subsequent landmark-based quantification of skull morphology did not show significant differences between treated and untreated mutants"

Qualitative head-shape observations did not translate to significant quantitative morphology improvement.

PMID:22585574 SUPPORT Model Organism

"The SB203580 treatment did not improve the survival rate of Fgfr2+/Y394C mice"

The tested regimen did not improve survival.

Why does the newborn Fgfr2+/Y394C mouse incompletely reproduce the human tracheal cartilage phenotype?

HUMAN MODEL MISMATCH OPEN gap_bss_tracheal_sleeve_frequency_and_causation

Attached to

pathophysiology#Tracheal Cartilage Ring Fusion

Human p.Tyr375Cys cases have tracheal cartilaginous sleeves, but a systematic study found none among five newborn Fgfr2+/Y394C tracheas examined by whole-mount morphology. Sleeves occurred in Fgfr2C342Y mice. The small BSS sample, single time point and genetic-background differences limit inference. This is a demonstrated model limitation, not an experiment that has yet to be attempted. Human frequency and genotype-specific longitudinal airway risks remain uncertain.

Proposed experiments

Longitudinal tracheal morphology in larger BSS mouse cohorts

exp_bss_longitudinal_airway_model

Extend the existing newborn study to larger, age-stratified cohorts and controlled genetic backgrounds, and compare cartilage segmentation and airway dimensions with human serial imaging.

Show evidence (2 references)

PMID:32886384 SUPPORT Model Organism

"Though TCS has been seen in the human FGFR2Y375C variant, our results suggest that they are not present or are present at low frequency in the mouse model."

Directly states the human-model mismatch.

PMID:32886384 SUPPORT Model Organism

"There were substantially fewer Fgfr2+/Y394C, Fgfr2+/S252W and Fgfr2+/P253R specimens than Fgfr2C342Y/+. It is possible that more severely affected tracheas would have been present in other groups, had greater numbers of specimens been available."

The negative finding is limited by sample size.

Can Beare-Stevenson syndrome be distinguished from Crouzon syndrome prenatally, given that the two overlap in appearance but differ sharply in prognosis?

KNOWLEDGE GAP OPEN gap_bss_versus_crouzon_prenatal_discrimination

Attached to

pathophysiology#Premature Cranial Suture Fusion

Prenatal craniosynostosis syndromes overlap. In the 2015 report, cutis gyrata was recognized retrospectively on prenatal imaging after a postnatal BSS diagnosis. A 2026 case with hydrops and multiple anomalies used genome sequencing to identify p.Phe276Cys and inform delivery planning before craniosynostosis was confidently recognized. These cases support combined imaging and molecular evaluation; they do not establish diagnostic sensitivity or a survival benefit.

Proposed experiments

Diagnostic yield of FGFR2 testing in prenatally suspected Crouzon syndrome

exp_bss_prenatal_fgfr2_panel_yield

Apply FGFR2 sequencing to a consecutive series of fetuses with prenatally suspected syndromic craniosynostosis and report how often the result reassigns the diagnosis to BSS, which is the measurement the recommendation currently lacks.

Show evidence (3 references)

PMID:25706251 SUPPORT Human Clinical

"Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome."

A concrete instance of the prenatal misassignment this gap concerns.

PMID:25706251 SUPPORT Human Clinical

"Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth."

The skin finding was missed prospectively in this case; the observation does not establish that prospective detection is impossible.

PMID:25706251 SUPPORT Human Clinical

"Due to phenotypic overlap with Crouzon syndrome, but worse prognosis, we recommend consideration of prenatal 3D ultrasound and mutation testing for patients with suspected Crouzon to allow for prenatal diagnosis of BSS and to enable appropriate genetic counseling and postnatal care."

The proposed but untested solution.

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Pathophysiology

7

FGFR2 Activating Variant

Heterozygous FGFR2 variants cause the syndrome. The recurrent p.Tyr375Cys and p.Ser372Cys substitutions introduce cysteine residues in the juxtamembrane/transmembrane region. Functional studies demonstrate constitutive activation for human p.Tyr375Cys and the corresponding murine p.Tyr394Cys allele. A de novo p.Phe276Cys variant was classified as likely pathogenic in a 2026 prenatal case; its functional effect was not experimentally tested. A 63-nucleotide deletion has also been reported in a Beare-Stevenson-like presentation, so a cysteine-creating missense mechanism should not be imposed on every reported allele.

FGFR2 hgnc:3689 ⇑ GAIN OF FUNCTION

transmembrane receptor protein tyrosine kinase activity GO:0004714 ↑ INCREASED

Downstream

Ligand-Independent FGFR2 Activation The p.Tyr375Cys allele and its murine equivalent produce ligand-independent receptor activation in experimental systems.

Tracheal Cartilage Ring Fusion Human p.Tyr375Cys-associated BSS can include fusion of tracheal cartilage rings; the intervening developmental mechanism is unresolved and is not reproduced consistently in the corresponding mouse model.

Midface retrusion The corresponding Y394C knock-in allele produces midfacial hypoplasia in mice. The experiment does not isolate suture fusion as its mediator.

Show evidence (3 references)

PMID:8696350 SUPPORT Human Clinical

"In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin..."

The original identification of the two recurrent alleles and their domain positions. Quoted verbatim including the source's own typographical errors ("sporatic", "Ty375Cys", "Iglll"), which are in the published abstract and not introduced here.

PMID:8696350 SUPPORT Human Clinical

"In two patients, neither of these mutations were found suggesting further genetic heterogeneity."

Two clinically diagnosed patients lacked either recurrent variant in the original report; this does not by itself establish another causal locus.

PMID:41775672 SUPPORT Human Clinical

"GS resulted at 30 weeks 5 days and revealed a heterozygous, de novo, likely pathogenic FGFR2 variant (c.827 T > G, p.Phe276Cys) (Table 1B)."

The prenatal variant was classified as likely pathogenic; this case report does not experimentally establish disulfide bonding or gain of function.

Ligand-Independent FGFR2 Activation

Human FGFR2 p.Tyr375Cys increased receptor and FRS2 phosphorylation in transfected rat chondrosarcoma cells. Keratinocytes from Fgfr2+/Y394C mice also showed increased receptor phosphorylation without added FGF ligand. Intermolecular disulfide bonding is a proposed structural explanation for the cysteine substitutions. The 1998 biochemical study tested other FGFR2 variants and explicitly did not test p.Ser372Cys or p.Tyr375Cys.

transmembrane receptor protein tyrosine kinase activity GO:0004714 ↑ INCREASED

Experimental models

RCS chondrocytes expressing human FGFR2 Y375C CELL LINE Measures increased phosphorylation with the human disease allele.

Primary keratinocytes from Fgfr2 Y394C mice PRIMARY CELL CULTURE Measures receptor activation in cells bearing the knock-in allele.

Downstream

p38 MAPK Activation Constitutive receptor activation is accompanied by increased p38 phosphorylation in mutant mouse epidermis and calvaria.

Show evidence (3 references)

PMID:22585574 SUPPORT In Vitro

"Our results showed constitutive activation of FGFR2 receptor and FRS2, a major FGFR downstream mediator (52), in rat chondrosarcoma (RCS) chondrocytes transfected with human FGFR2 Y375C as compared with WT FGFR2 (Figure 4A)."

Direct receptor-signaling measurements in cells expressing the human disease allele.

PMID:22585574 SUPPORT In Vitro

"We confirmed this result in vivo by demonstrating increased phosphorylation of FGFR2 in epidermal keratinocytes derived from our Fgfr2+/Y394C mice without the addition of FGF ligand as compared with that of controls (Supplemental Figure 4), indicating that the Y394C mutation causes constitutive..."

Mouse-derived keratinocytes support ligand-independent activation.

PMID:9539778 SUPPORT In Vitro

"Although we have not examined these mutations in this work, we would predict that they also involve aberrant intermolecular disulfide bonding."

The authors explicitly identify disulfide bonding for the two BSS alleles as a prediction; their direct assays concerned other FGFR2 variants.

p38 MAPK Activation

Phosphorylated p38 is increased in epidermis and calvarial tissue of Fgfr2+/Y394C mice. ERK1/2 phosphorylation is additionally increased in mutant skull tissue, so the response is not exclusive to p38. Pharmacological p38 inhibition improves epidermal hyperplasia and produces limited suture effects without a significant overall skull-shape or survival benefit in the tested regimen.

p38MAPK cascade GO:0038066 ↑ INCREASED

Downstream

Cranial Suture Osteogenic Acceleration p38 contributes to the osteogenic phenotype, with increased ERK1/2 signaling also observed in skull tissue; p38 inhibition yields only limited suture improvement.

Epidermal Hyperplasia p38 inhibition reduces the mutant epidermal proliferation and differentiation abnormalities, supporting a functional contribution to epidermal hyperplasia.

Show evidence (3 references)

PMID:22585574 SUPPORT Model Organism

"We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues."

Establishes ligand-independent receptor activation and identifies p38 as the engaged downstream branch in the two affected tissues.

PMID:22585574 SUPPORT Model Organism

"We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities."

Names p38 MAPK as the mediating pathway for both the skin and skull phenotypes.

PMID:22585574 SUPPORT Model Organism

"None of the other pathways showed obvious changes of phosphorylation in both tissues; however, we noted phosphorylated ERK1/2 was increased in mutant skull tissues (Supplemental Figure 5)."

ERK1/2 activation in skull tissue qualifies an exclusively p38-based interpretation.

Cranial Suture Osteogenic Acceleration

Fgfr2+/Y394C mouse coronal sutures show decreased cell proliferation together with increased osteogenic differentiation. Expanded alkaline phosphatase and Runx2 expression and overlapping osteonectin-positive osteogenic fronts support premature bone formation at the suture.

Osteoblast CL:0000062

osteoblast differentiation GO:0001649 ↑ INCREASED

Animal models

Fgfr2 Y394C heterozygous knock-in mouse Mus musculus recapitulates Shows increased osteogenic differentiation at coronal sutures.

Downstream

Premature Cranial Suture Fusion

Show evidence (2 references)

PMID:22585574 SUPPORT Model Organism

"These data indicated increased osteogenic differentiation as well as abnormal bone growth at the coronal suture in Fgfr2+/Y394 mice."

ALP, Runx2 and osteonectin observations support increased differentiation; the source omits the final C in this genotype occurrence.

PMID:22585574 SUPPORT Model Organism

"Cell proliferation was analyzed by calculating the ratios of the number of BrdU-positive cells to total cells between and including the osteogenic fronts in mutants and littermate controls. At E17.5, the ratio was obviously decreased in mutants as compared with controls"

The osteogenic phenotype involves decreased proliferation, distinct from epidermal hyperproliferation.

Premature Cranial Suture Fusion

Premature fusion of multiple cranial sutures produces craniosynostosis and can yield a cloverleaf skull. In the six-case 1992 clinical series, four had craniosynostosis and three of those had cloverleaf skull. Associated hydrocephalus, Chiari malformation and midface abnormalities are clinically important but cannot all be attributed to restricted cranial volume alone.

cranial suture morphogenesis GO:0060363 ↓ DECREASED

Downstream

Craniosynostosis

Cloverleaf skull

Show evidence (3 references)

PMID:1519658 SUPPORT Human Clinical

"Craniosynostosis is present in four cases, with cloverleaf skull in three of these."

The original series' documentation of craniosynostosis and cloverleaf skull frequency.

PMID:1519658 SUPPORT Human Clinical

"Performance and life expectation appear to be related to the presence or absence of cloverleaf skull."

The small original clinical series suggested an association between cloverleaf skull and outcome; it does not establish an independently validated prognostic classifier.

PMID:12900900 SUPPORT Human Clinical

"The radiologic examination showed a cloverleaf-form craniosynostosis."

Independent radiological confirmation in molecularly confirmed p.Tyr375Cys patients.

Epidermal Hyperplasia

Fgfr2+/Y394C mouse epidermis shows keratinocyte hyperproliferation, acanthosis and papillomatosis with altered differentiation-marker expression. These findings model the cutaneous folds and acanthosis of human BSS. Human cutis gyrata has a variable distribution that includes scalp, forehead, face, neck, trunk, hands and feet.

Keratinocyte CL:0000312

keratinocyte proliferation GO:0043616 ↑ INCREASED

Animal models

Fgfr2 Y394C heterozygous knock-in mouse Mus musculus recapitulates Reproduces epidermal acanthosis, papillomatosis and hyperproliferation.

Downstream

Cutis gyrata of scalp

Palmoplantar cutis gyrata

Acanthosis nigricans

Show evidence (3 references)

PMID:22585574 SUPPORT Model Organism

"This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development."

Confirms in a model carrying the murine equivalent of the human allele that one variant produces both the skin and the skull phenotype.

PMID:1519658 SUPPORT Human Clinical

"Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet."

The human distribution of the skin phenotype.

PMID:22585574 SUPPORT Model Organism

"Histologically, the skin of E16.5, P0, and P5 Fgfr2+/Y394C mice displayed cutis gyrata, epidermal acanthosis, and papillomatosis (Figure 2, A–D)."

Mouse tissue histology supports the epidermal phenotype.

Tracheal Cartilage Ring Fusion

Vertical fusion of tracheal cartilage rings can produce a rigid sleeve along the trachea. Human BSS cases demonstrate this lesion, including progressive inward cartilage deformation in a child followed to age three. The resulting airway risks include impaired clearance and obstruction or tube malposition; tracheostomy does not remove the abnormal cartilage. No sleeve was found among the five newborn Fgfr2+/Y394C mice assessed by whole-mount morphology in a later study, limiting extrapolation from this model to the human airway phenotype.

Animal models

Fgfr2 Y394C heterozygous knock-in mouse Mus musculus fails to recapitulate No tracheal sleeves were detected in the newborn Y394C sample in the later comparative study.

Downstream

Tracheal cartilaginous sleeve

Show evidence (2 references)

PMID:41112086 SUPPORT Human Clinical

"The initial rigid bronchoscopy demonstrated tracheal cartilaginous sleeve, and tracheostomy was performed. At 3 years of age, rigid bronchoscopy revealed progressive tracheal cartilage deformity with inward protrusion."

Serial human imaging documents a sleeve and later deformation in one child.

PMID:32886384 SUPPORT Model Organism

"Though TCS has been seen in the human FGFR2Y375C variant, our results suggest that they are not present or are present at low frequency in the mouse model."

The negative newborn mouse result constrains the model; it does not refute the human association.

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Histopathology

2

Intestinal fibroblast proliferation and smooth-muscle thickening

In one p.Tyr375Cys autopsy case, jejunal tissue showed fibroblast proliferation from the submucosa into muscularis and thickened smooth muscle. A contribution to dysmotility was proposed, but recurrent infection, malnutrition and altered perfusion were potential secondary contributors.

Show evidence (1 reference)

PMID:41882888 SUPPORT Human Clinical

"Fibroblast proliferation was observed extending from the submucosal layer to the muscularis, accompanied by marked thick- ening of the smooth muscle."

The figure legend describes the tissue finding; causation and generalizability remain uncertain.

Reduced neuronal density and thin superficial myelin

The same autopsy case showed reduced neuronal density and a thin myelin sheath in the superficial brain layer. This isolated histologic observation does not establish a universal primary neurodevelopmental mechanism.

Show evidence (1 reference)

PMID:41882888 SUPPORT Human Clinical

"The brain exhibited hypertrophy, characterized by a reduced neural density and a thin myelin sheath in the superficial layer."

Direct autopsy observation in a single severely ill child.

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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

66

Breast 1

Accessory nipples Supernumerary nipple HP:0002558

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Widespread cutis gyrata and acanthosis nigricans are usually evident at birth; hirsutism, skin tags, prominent umbilicus with redundant tissue, and accessory nipples are also seen."

Accessory nipples are explicitly included in the BSS-specific clinical summary.

Cardiovascular 2

Facial hemangioma HP:0001028

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis,..."

The facial vascular lesion was recorded on clinical examination in this single patient.

Thymic enlargement Thymus hyperplasia HP:0010516

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low..."

The fetal imaging report describes an enlarged thymus; no specific immunologic consequence is inferred.

Digestive 5

Prominent umbilicus HP:0001544

Show evidence (1 reference)

PMID:12900900 SUPPORT Human Clinical

"Both female newborn patients presented at birth with craniofacial anomalies, variable cutis gyrata in forehead and preauricular regions, prominent umbilical stump and anogenital anomalies."

Prominent umbilical stump documented in two molecularly confirmed patients.

Pyloric stenosis HP:0002021

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus."

GeneReviews includes pyloric stenosis among additional BSS manifestations.

Anteriorly placed anus HP:0001545

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus."

The source calls the finding anterior anus, supporting the positional phenotype.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low..."

The prenatal imaging list includes liver enlargement, without proving its cause.

Ascites HP:0001541

Show evidence (1 reference)

PMID:41882888 SUPPORT Human Clinical

"abdominal distention due to ascites gradually wors- ened from 12 months of age. Tragically, the patient died of severe, uncontrollable ascites and respiratory failure at 2 years and 2 months of age (Fig. 3)."

The clinical course documents progressively worsening ascites before death in one patient.

Ear 4

Conductive hearing loss Conductive hearing impairment HP:0000405

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Moderate-to-severe midface retrusion, proptosis, abnormal ears, cleft palate, conductive hearing loss, natal teeth, and relative prognathism are seen."

The BSS-specific summary identifies a conductive hearing deficit, without giving a frequency.

Low-set ears HP:0000369

Show evidence (2 references)

PMID:41775672 SUPPORT Human Clinical

"Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low..."

Fetal ultrasound records elongated, low-set ears in the p.Phe276Cys case.

PMID:41882888 SUPPORT Human Clinical

"Additional findings in- cluded low-set ears, a prominent umbilical stump, and broad fingers and toes (Fig. 1)."

The autopsy report explicitly records low-set ears on examination, complementing the separate prenatal ultrasound observation.

External auditory canal atresia Atresia of the external auditory canal HP:0000413

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"complete atresia of the external ear canals"

The deletion-associated case explicitly records complete canal atresia.

Mixed hearing loss Mixed hearing impairment HP:0000410

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"Bilateral choanal stenosis and a mild to moderate mixed hearing loss requiring hearing aids were present."

The source distinguishes mixed hearing loss from purely conductive loss in the deletion-associated patient.

Eye 6

Proptosis HP:0000520

Show evidence (1 reference)

PMID:42495986 SUPPORT Human Clinical

"Clinical findings and imaging studies revealed severe proptosis, very severe midface hypoplasia, and reverse occlusion."

Direct documentation of severe proptosis.

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis,..."

The examination explicitly lists hypertelorism in the p.Phe276Cys patient.

Optic nerve hypoplasia HP:0000609

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"Ophthalmological examination detected mild optic nerve hypoplasia and high myopia with astigmatism requiring corrective lenses."

Ophthalmologic examination directly identifies mild optic nerve hypoplasia.

High myopia HP:0011003

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"Ophthalmological examination detected mild optic nerve hypoplasia and high myopia with astigmatism requiring corrective lenses."

The ophthalmologic examination records high myopia requiring corrective lenses.

Astigmatism HP:0000483

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"Ophthalmological examination detected mild optic nerve hypoplasia and high myopia with astigmatism requiring corrective lenses."

The same examination documents astigmatism in addition to high myopia.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"hypertelorism with a divergent strabismus"

The report specifies divergent strabismus in the deletion-associated patient.

Genitourinary 5

Bifid scrotum HP:0000048

Show evidence (1 reference)

PMID:16531735 SUPPORT Human Clinical

"We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage."

Documents bifid scrotum in a molecularly confirmed patient.

Perineal hypospadias HP:0000051

Show evidence (1 reference)

PMID:16531735 SUPPORT Human Clinical

"We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage."

Documents perineal hypospadias in a molecularly confirmed patient.

Micropenis HP:0000054

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis,..."

The postnatal examination confirms the genital finding suspected on prenatal imaging.

Pelvic kidney HP:0000125

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low..."

Ultrasound localizes the left kidney to the pelvis.

Hypoplastic labia minora HP:0000064

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"| Hypoplastic labia minora | 1/5 | 1/1 | NA |"

The genotype-stratified table records this finding in historical female cases; the male deletion patient is not applicable.

Head and Neck 17

Craniosynostosis HP:0001363

Show evidence (2 references)

PMID:8696350 SUPPORT Human Clinical

"Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death."

Craniosynostosis named among the defining features.

PMID:1519658 SUPPORT Human Clinical

"Craniosynostosis is present in four cases, with cloverleaf skull in three of these."

The report describes six total cases and does not establish universal craniosynostosis.

Cloverleaf skull HP:0002676

Show evidence (1 reference)

PMID:1519658 SUPPORT Human Clinical

"Craniosynostosis is present in four cases, with cloverleaf skull in three of these."

Documents cloverleaf skull in most craniosynostotic patients in the delineating series.

Cutis gyrata of scalp HP:0010541

Show evidence (4 references)

PMID:1519658 SUPPORT Human Clinical

"Beare-Stevenson cutis gyrata syndrome consists of skin furrows of corrugated appearance, acanthosis nigricans, craniofacial anomalies, particularly craniosynostosis and ear defects, anogenital anomalies, skin tags, and prominent umbilical stump."

The syndrome definition, leading with the corrugated skin furrows.

PMID:1519658 SUPPORT Human Clinical

"Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet."

Confirms scalp involvement within the characteristic distribution.

PMID:41112086 SUPPORT Human Clinical

"cutis gyrata, which had been unclear at birth but had gradually become apparent"

The finding was initially inconspicuous in this molecularly confirmed patient.

+ 1 more reference

Midface retrusion HP:0011800

Show evidence (1 reference)

PMID:42495986 SUPPORT Human Clinical

"Clinical findings and imaging studies revealed severe proptosis, very severe midface hypoplasia, and reverse occlusion."

Documents the severity of midface hypoplasia in a surgically managed patient.

Choanal stenosis HP:0000452

Show evidence (1 reference)

PMID:16531735 SUPPORT Human Clinical

"We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage."

Choanal stenosis documented in a molecularly confirmed p.Tyr375Cys patient.

Hypodontia HP:0000668

Show evidence (1 reference)

PMID:19860525 SUPPORT Human Clinical

"The patient had dental findings of natal teeth and hypodontia of the primary and permanent teeth."

Direct documentation of hypodontia in a BSS patient.

Natal tooth HP:0000695

Show evidence (1 reference)

PMID:19860525 SUPPORT Human Clinical

"The patient had dental findings of natal teeth and hypodontia of the primary and permanent teeth."

Direct documentation of natal teeth in a BSS patient.

Cleft palate HP:0000175

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Moderate-to-severe midface retrusion, proptosis, abnormal ears, cleft palate, conductive hearing loss, natal teeth, and relative prognathism are seen."

The BSS-specific GeneReviews paragraph includes cleft palate in its craniofacial spectrum.

Abnormal posterior cranial fossa morphology HP:0000932

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:21397175 SUPPORT Human Clinical

"The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging."

The MRI abstract names an abnormal posterior fossa without specifying its morphology.

Brachycephaly HP:0000248

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis,..."

The postnatal clinical genetics examination confirms brachycephaly in the prenatal case.

Macroglossia HP:0000158

Show evidence (2 references)

PMID:41775672 SUPPORT Human Clinical

"which was difficult due to significant macroglossia and micrognathia."

The neonatal intubation account identifies tongue enlargement as one contributor to airway difficulty.

PMID:41112086 SUPPORT Human Clinical

"Her characteristic craniofacial features included ocular proptosis, a narrow and protruding forehead, midface hypoplasia, macroglossia, and cutis gyrata, which had been unclear at birth but had gradually become apparent (Figure 3)."

The longitudinal airway case also documents macroglossia in a child with p.Tyr375Cys.

Micrognathia HP:0000347

Show evidence (2 references)

PMID:41775672 SUPPORT Human Clinical

"which was difficult due to significant macroglossia and micrognathia."

The same intubation account identifies a small mandible in addition to macroglossia.

PMID:38445861 SUPPORT Human Clinical

"This was because midfacial hypoplasia was so severe that it was hard to notice, but there was also micrognathia."

Coexisting micrognathia was described in the surgical case with persistent tracheostomy dependence.

Increased nuchal translucency HP:0010880

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"First trimester ultrasound identified an increased nuchal translucency (7 mm) (Table 1A)."

The first-trimester measurement directly supports increased nuchal translucency.

Cleft soft palate HP:0000185

Show evidence (1 reference)

PMID:41112086 SUPPORT Human Clinical

"she presented with a cloverleaf‐like skull, bulging anterior fontanelle, proptosis, maxillary hypoplasia, cleft soft palate, perineal skin defects, and broad toes (Figure 1)."

The neonatal examination specifies the soft palate as the site of the cleft.

Gingival overgrowth HP:0000212

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"There were multiple neonatal teeth, gingival hyperplasia and a high-arched, narrow palate with a bifid uvula."

The source uses gingival hyperplasia for the observed gum enlargement.

High narrow palate HP:0002705

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"There were multiple neonatal teeth, gingival hyperplasia and a high-arched, narrow palate with a bifid uvula."

Both height and narrowing of the palate are explicitly described.

Bifid uvula HP:0000193

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"There were multiple neonatal teeth, gingival hyperplasia and a high-arched, narrow palate with a bifid uvula."

The oral examination separately identifies a bifid uvula.

Integument 5

Palmoplantar cutis gyrata HP:0007469

Show evidence (1 reference)

PMID:12900900 SUPPORT Human Clinical

"Furrowed palms and soles were also observed."

Direct observation in two molecularly confirmed patients.

Acanthosis nigricans HP:0000956

Show evidence (2 references)

PMID:8696350 SUPPORT Human Clinical

"Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death."

Acanthosis nigricans named among the defining features.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Widespread cutis gyrata and acanthosis nigricans are usually evident at birth"

BSS-specific neonatal clinical description.

Skin tags HP:0010609

Show evidence (1 reference)

PMID:1519658 SUPPORT Human Clinical

"Beare-Stevenson cutis gyrata syndrome consists of skin furrows of corrugated appearance, acanthosis nigricans, craniofacial anomalies, particularly craniosynostosis and ear defects, anogenital anomalies, skin tags, and prominent umbilical stump."

Skin tags listed in the syndrome definition.

Hirsutism HP:0001007

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Widespread cutis gyrata and acanthosis nigricans are usually evident at birth; hirsutism, skin tags, prominent umbilicus with redundant tissue, and accessory nipples are also seen."

GeneReviews lists excess hair growth alongside the characteristic cutaneous findings.

Small nails HP:0001792

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"| Nail hypoplasia | 1/9 | 2/2 | + |"

Table I records nail hypoplasia in the historical p.Tyr375Cys/p.Ser372Cys groups and the propositus; no population frequency is inferred.

Limbs 5

2-3 toe syndactyly HP:0004691

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis,..."

The lower-extremity second-to-third digit fusion is explicitly listed on examination.

Broad toes HP:0001837

Show evidence (1 reference)

PMID:41112086 SUPPORT Human Clinical

"she presented with a cloverleaf‐like skull, bulging anterior fontanelle, proptosis, maxillary hypoplasia, cleft soft palate, perineal skin defects, and broad toes (Figure 1)."

The neonatal examination includes broad toes, without establishing a population frequency.

Broad thumbs HP:0011304

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"Examination of the hands and feet showed redundant palmar and plantar skin, slightly broad thumbs and halluces and mild skin syndactyly of the second and third toes with overlapping fourth toes."

The hand-and-foot examination explicitly describes the thumbs as slightly broad.

Broad halluces Broad hallux HP:0010055

Show evidence (1 reference)

PMID:19610084 SUPPORT Human Clinical

"Examination of the hands and feet showed redundant palmar and plantar skin, slightly broad thumbs and halluces and mild skin syndactyly of the second and third toes with overlapping fourth toes."

The same examination separately identifies slightly broad great toes.

Broad fingers HP:0001500

Show evidence (1 reference)

PMID:41882888 SUPPORT Human Clinical

"Additional findings in- cluded low-set ears, a prominent umbilical stump, and broad fingers and toes (Fig. 1)."

The autopsy case examination explicitly identifies broad fingers.

Metabolism 1

Hydrops fetalis HP:0001789

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"patient referred for hydrops fetalis (skin edema around the fetal cranium and face extending down to the abdomen, mild ascites, thickened nuchal fold measuring up to 18 mm) and multiple congenital anomalies."

The referral description documents edema and ascites constituting the fetal hydrops presentation.

Musculoskeletal 2

Pectus excavatum HP:0000767

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low..."

Fetal ultrasound explicitly identifies the chest-wall depression.

Caudal appendage HP:0002825

Show evidence (1 reference)

PMID:16531735 SUPPORT Human Clinical

"We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage."

The clinical case abstract explicitly includes a caudal appendage in its observed phenotype.

Nervous System 6

Hydrocephalus HP:0000238

Show evidence (2 references)

PMID:42495986 SUPPORT Human Clinical

"At 2 months of age, she underwent a ventriculoperitoneal shunt placement, followed by occipital cranial expansion at 1 year and fronto-orbital distraction at 2 years of age."

Shunt placement in infancy evidences clinically significant hydrocephalus in a documented BSS patient.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hydrocephalus and Chiari I malformations are common."

This statement occurs in the BSS-specific neurologic section.

Chiari malformation HP:0002308

Show evidence (2 references)

PMID:42495986 SUPPORT Human Clinical

"It is characterized by craniosynostosis, midface hypoplasia, Chiari malformations, and other extensive congenital abnormalities."

Chiari malformation named as a characteristic feature of the syndrome.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hydrocephalus and Chiari I malformations are common."

The BSS-specific clinical section identifies Chiari I malformation.

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:25706251 SUPPORT Human Clinical

"BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy."

States the developmental outcome among survivors.

PMID:19610084 REFUTE Human Clinical

"He has had initial mild motor delays, but the propositus’ neurodevelopmental progress was normal."

A child with a Beare-Stevenson-like presentation and FGFR2 deletion had normal later progress; this qualifies universality, not the association in classical BSS.

Intellectual disability HP:0001249

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Intellectual disability is present in all affected individuals who have survived (neonatal mortality is common)."

This summary supports intellectual disability in the classic surviving cases; the separately cited deletion-associated case limits its universal wording.

PMID:19610084 REFUTE Human Clinical

"He has had initial mild motor delays, but the propositus’ neurodevelopmental progress was normal."

The deletion-associated Beare-Stevenson-like case limits claims of universal intellectual disability across the broader clinical spectrum.

Simplified gyral pattern HP:0009879

Show evidence (1 reference)

PMID:21397175 SUPPORT Human Clinical

"The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging."

Cranial MRI in the reported patients directly showed simplified gyration.

Abnormal hippocampal morphology Abnormal hippocampus morphology HP:0025100

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:21397175 SUPPORT Human Clinical

"The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging."

The abstract names a hippocampal abnormality without sufficient detail for a narrower binding.

Respiratory 2

Tracheal cartilaginous sleeve HP:0005347

Show evidence (1 reference)

PMID:25706251 SUPPORT Human Clinical

"One of our patients was noted to have a tracheal cartilaginous sleeve, which if present could explain sudden death."

The index report of this finding in BSS.

Tracheomalacia HP:0002779

Show evidence (1 reference)

PMID:41112086 SUPPORT Human Clinical

"Due to respiratory distress secondary to upper airway obstruction and tracheomalacia, the patient was admitted to the neonatal intensive care unit and she received high-flow nasal support."

The admission account names tracheomalacia separately from upper-airway obstruction.

Growth 1

Failure to thrive HP:0001508

Show evidence (3 references)

PMID:41882888 SUPPORT Human Clinical

"We herein present an autopsy case of BSS characterized by a disproportionate organ size and severe failure to thrive."

Documents severe failure to thrive in an autopsied BSS patient.

PMID:41882888 SUPPORT Human Clinical

"Notably, the small intestine was much shorter in our patient than in infants with a similar body size, which could explain the poor weight gain."

Offers a structural explanation for the failure to thrive, phrased by the authors as a possibility and based on one autopsy.

PMID:41882888 SUPPORT Human Clinical

"We could not determine the cause of insufficient body weight"

The full report explicitly retains uncertainty about the cause of growth failure.

Other 4

Relative prognathism

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Moderate-to-severe midface retrusion, proptosis, abnormal ears, cleft palate, conductive hearing loss, natal teeth, and relative prognathism are seen."

The source specifies relative prognathism; it does not establish elongation of the mandible.

Prominent labial raphe

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus."

The named genital finding is recorded without inferring a more specific malformation.

Rugated labia majora

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus."

The source describes labial rugation rather than labial enlargement or fusion.

Short small intestine

Show evidence (1 reference)

PMID:41882888 SUPPORT Human Clinical

"The lengths of the total intestinal tract, small intestine, and colon were 120, 75, and 45 cm, respec- tively (Table 1B)."

The autopsy measurement supports a short small intestine but does not establish congenital origin.

🧬

Genetic Associations

1

FGFR2-associated allelic spectrum (Causative)

Gene: FGFR2 hgnc:3689 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:8696350 SUPPORT Human Clinical

"We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome."

The original assignment of the syndrome to FGFR2.

PMID:25706251 SUPPORT Human Clinical

"Here we report on two additional patients with molecularly confirmed BSS, one each with p.Ser372Tyr and p.Tyr375Cys mutations in FGFR2."

The abstract reports p.Ser372Tyr; a later case table reports p.Ser372Cys. This unresolved nomenclature discrepancy is retained explicitly rather than interpreted as established non-cysteine disease biology.

Variants (4)

c.1124A>G (p.Tyr375Cys)

Recurrent p.Tyr375Cys substitution near the membrane. The c.1124A>G notation is documented on NM_000141.5 in the 2026 autopsy report; mouse p.Tyr394Cys is the corresponding experimental allele.

Show evidence (2 references)

PMID:12900900 SUPPORT Human Clinical

"The molecular analysis of these patients identified the mutation Tyr375Cys in the FGFR2 gene."

Molecular confirmation of the recurrent transmembrane allele.

PMID:41882888 SUPPORT Human Clinical

"Trio-based whole-exome sequencing and a filtering analy- sis subsequently identified a c.1124A>G pathogenic variant in FGFR2 (NM_000141.5), resulting in a p.Tyr375Cys sub- stitution."

The report identifies c.1124A>G on NM_000141.5 and its p.Tyr375Cys consequence; the source line-break hyphens are retained.

p.Ser372Cys

The second recurrent allele, at the carboxyl-terminal end of the Ig-III to transmembrane linker.

Show evidence (1 reference)

PMID:18247426 SUPPORT Human Clinical

"Reported causes are an FGFR2 Tyr375Cys mutation in nine cases and an FGFR2 Ser372Cys mutation in one case. Here, we report on a second patient with the FGFR2 Ser372Cys mutation."

A second independent report of the p.Ser372Cys allele, establishing it as recurrent rather than private, and quantifying the relative frequency of the two recurrent alleles at the time: nine p.Tyr375Cys to two p.Ser372Cys.

c.827T>G (p.Phe276Cys)

Heterozygous de novo variant classified as likely pathogenic in one fetus with a postnatally concordant BSS phenotype; no functional assay was reported.

Show evidence (1 reference)

PMID:41775672 SUPPORT Human Clinical

"GS resulted at 30 weeks 5 days and revealed a heterozygous, de novo, likely pathogenic FGFR2 variant (c.827 T > G, p.Phe276Cys) (Table 1B)."

The prenatal variant was classified as likely pathogenic; this case report does not experimentally establish disulfide bonding or gain of function.

c.859del63 (reported nomenclature)

De novo 63-nucleotide intragenic deletion predicting loss of 21 amino acids, reported in a child with Beare-Stevenson-like syndrome. The proposed altered-splicing mechanism remains unproven.

Show evidence (2 references)

PMID:19610084 SUPPORT Human Clinical

"a de novo, intragenic deletion of 63 nucleotides starting in exon 8 of the gene, c.859del63, was detected (Fig. 2). This deletion predicts the loss of 21 amino acids from the FGFR2 protein."

Direct molecular identification in the Beare-Stevenson-like case; preserve the authors’ nomenclature without inventing a normalized HGVS interval.

PMID:19610084 SUPPORT Human Clinical

"A similar activating mechanism, although unproven, could be present in this child."

The splicing-based gain-of-function interpretation was proposed by analogy, not established by a functional assay.

💊

Medical Actions

16

Tracheostomy for clinically significant airway obstruction

Category: Therapeutic Action: Tracheostomy Ontology label: Tracheotomy NCIT:C15341

Platform: Surgery

Airway support may require tracheostomy, with ventilation when indicated by the level and severity of obstruction. A tracheal cartilaginous sleeve remains present after tracheostomy; progressive deformation, tube malposition and granulation require continued specialist surveillance.

Show evidence (2 references)

PMID:25706251 SUPPORT Human Clinical

"This association and our experience suggests that BSS patients be evaluated for tracheal cartilaginous sleeve to prevent airway compromise."

The authors' explicit surveillance recommendation.

PMID:41112086 SUPPORT Human Clinical

"Importantly, sudden and life-threatening airway obstruction can occur despite the presence of a tracheostomy tube due to severe deformity of the tracheal cartilage."

Tracheostomy does not remove the structural lesion or eliminate airway risk.

Cranial vault expansion

Category: Therapeutic Action: Cranial vault expansion Ontology label: Craniotomy NCIT:C15214

Platform: Surgery

Cranial expansion addresses craniosynostosis and inadequate intracranial volume. GeneReviews recommends repair of multisuture synostosis generally within the first year, with timing and technique guided by anatomy, intracranial pressure and respiratory status. The sequence is individualized rather than fixed by one published surgical case.

Target Phenotypes: Craniosynostosis HP:0001363

Show evidence (2 references)

PMID:42495986 SUPPORT Human Clinical

"At 2 months of age, she underwent a ventriculoperitoneal shunt placement, followed by occipital cranial expansion at 1 year and fronto-orbital distraction at 2 years of age."

Documents the staged sequence and its timing in a BSS patient.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"In general, multisuture craniosynostosis should be surgically repaired in 1st yr of life."

The FGFR overview provides general timing, qualified by the individual anatomy and clinical status.

Midface advancement (Le Fort III distraction)

Category: Therapeutic Action: Midface advancement Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Halo-type external distraction osteogenesis to advance the severely hypoplastic midface, correcting proptosis and occlusion. The first successful Le Fort III distraction in BSS was reported in 2026 in a 5-year-old, achieving roughly 25 mm of distraction without major complications and sustained improvement at two years. Reported experience with the alternative monobloc advancement is more cautionary: in one BSS patient the temporal fossa was too narrow for the procedure to work well, and unrecognized micrognathia meant decannulation remained impossible despite the advancement. Prior shunt tubing and skull defects constrain the operative approach.

Target Phenotypes: Midface retrusion HP:0011800 Proptosis HP:0000520

Show evidence (2 references)

PMID:42495986 SUPPORT Human Clinical

"Two uneventful years after surgery, the patient showed significant improvements in proptosis, occlusion, and facial profile, with an excellent clinical course."

Medium-term outcome of the procedure.

PMID:38445861 SUPPORT Human Clinical

"In addition, even though midface advancement, it was difficult to remove tracheostomy. This was because midfacial hypoplasia was so severe that it was hard to notice, but there was also micrognathia."

The counter-case: midface advancement did not achieve decannulation, because coexisting micrognathia was masked by the severity of the midface hypoplasia.

Cerebrospinal fluid diversion for hydrocephalus

Action: Ventriculoperitoneal shunt placement Ontology label: Ventriculoperitoneal Shunt Placement NCIT:C168483

Platform: Surgery

Ventriculoperitoneal shunting has been used for progressive hydrocephalus in reported patients. Indication and timing require neurosurgical assessment.

Target Phenotypes: Hydrocephalus HP:0000238

Show evidence (1 reference)

PMID:41112086 SUPPORT Human Clinical

"a ventriculoperitoneal shunt was placed at 6 months of age to treat hydrocephalus."

Case-level use of CSF diversion in molecularly confirmed BSS.

Airway assessment and tracheostomy surveillance

Assess multilevel obstruction with otolaryngology. The FGFR overview advises operative airway evaluation at the first anesthetic, or during infancy if no procedure is planned, because a sleeve may otherwise be missed. Continued evaluation after tracheostomy should account for progressive cartilage deformation, tube position and granulation. The optimal repeat-endoscopy schedule is individualized.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"eval should occur in infancy because of risk of sudden death if tracheal cartilaginous sleeve is present."

GeneReviews Table 6 supports infant airway evaluation; it does not prescribe a fixed repeat-bronchoscopy interval.

PMID:41112086 SUPPORT Human Clinical

"This case underscores the importance of thorough preoperative airway assessment and meticulous attention to tube placement in patients with BSS and TCS."

Direct BSS case evidence for continued airway precautions.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"At the time of 1st anesthesia, performed by otolaryngologist. Craniofacial otolaryngologist should direct timing of operative airway eval if no sedation is planned, but eval should occur in infancy because of risk of sudden death if tracheal cartilaginous sleeve is present."

GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.

Sleep-disordered breathing surveillance

Platform: Other

Evaluate sleep-apnea symptoms at least every three months during infancy and annually thereafter under the FGFR overview, with polysomnography when indicated. Central apnea can prompt evaluation for Chiari I malformation. The choice of respiratory support is individualized; prolonged mask pressure from CPAP or BiPAP can worsen midface retrusion.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Avoid use of CPAP/BiPAP for long-term treatment of sleep apnea when possible, as pressure on midface exacerbates midface retrusion."

This is an FGFR craniosynostosis precaution, not a prohibition on necessary ventilation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Clinical eval for symptoms of sleep apnea At least every 3 mos in 1st year & annually thereafter"

GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.

Ocular protection and ophthalmic follow-up

Assess corneal exposure, globe protection, eye alignment and optic nerves. GeneReviews recommends at least annual ophthalmic review, with urgent assessment for concerns. Inadequate lid closure can require lubrication, and severe exposure or globe subluxation may require tarsorrhaphy. Protective eyewear may be appropriate for activities posing an eye-injury risk.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Early initiation of topical eye lubrication if inadequate lid closure"

The FGFR management table supports ocular-surface protection in patients with proptosis.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Ophthalmologic exam of optic nerves; eval for sclerocornea, orbital protection, strabismus &/or amblyopia At least annually, & urgently if any concern arises"

GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Individuals with exophthalmos may require protective eyewear during activities with risk of eye injury (e.g., ball sports)."

The precaution applies when proptosis increases eye-injury risk.

Audiologic surveillance and hearing support

Platform: Other

Evaluate hearing at diagnosis and at least annually. Conductive hearing loss is part of the BSS phenotype; hearing aids, bone-conduction devices or middle-ear procedures are selected according to the lesion and degree of loss. Optimizing hearing supports language development.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Optimization of hearing facilitates language & communication development."

The FGFR treatment table provides the rationale for hearing support.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Hearing loss Audiology eval At least annually"

GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.

Developmental and speech support

Arrange early-intervention and developmental assessment, with continued speech-language evaluation and individualized therapies. GeneReviews recommends developmental evaluation at least every three months in the first year and annually thereafter; speech assessment begins around 18 months and continues annually, with additional assessment around midface surgery.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Referral for early intervention services. Consider referral to a neurodevelopmental specialist."

The initial-evaluation table supports developmental referral rather than assuming a fixed developmental outcome.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Neurodevelopment Early intervention &/or neurodevelopmental pediatrics eval At least every 3 mos in 1st yr & annually thereafter"

GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Speech issues Speech pathology eval • At age ~18 mos, then annually • Additional speech assessments before & after midface surgeries"

Table 6 specifies speech surveillance beginning around 18 months and around midface surgery.

Feeding assessment and nutritional support

Action: Feeding assessment and nutritional support Ontology label: Nutritional Support NCIT:C15433

Assess swallowing safety and growth, and provide feeding therapy and enteral support when needed. Reassess swallowing after craniofacial surgery. Persistent poor growth requires evaluation of multiple possible contributors; the short-intestine autopsy observation does not establish a universal mechanism.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Feeding therapy is helpful to assess swallowing safety & support eating by mouth."

The FGFR management table supports feeding evaluation and therapy.

Dental and orthodontic care

Coordinate pediatric dentistry and craniofacial orthodontics for hypodontia, natal teeth, occlusion and eruption problems. Timing of orthodontic and surgical interventions depends on anatomy and growth.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Pediatric dental care & eval by craniofacial orthodontist as part of coordinated craniofacial team care"

Shared FGFR craniosynostosis management is relevant to the documented BSS dental phenotype.

Cervical spine assessment and positioning precautions

Assess cervical fusion and instability, particularly before surgery. If cervical anomalies are present, positioning, intubation technique and activity restrictions should minimize spinal cord injury risk.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Individuals with cervical spine anomalies may be at risk for spinal cord injury with hyperextension and may require fiberoptic intubation and/or sports restrictions for activities that pose a risk for head/neck injury."

GeneReviews qualifies these precautions by the presence of cervical spine anomalies.

Intracranial pressure surveillance

Monitor head growth and symptoms of raised intracranial pressure. The FGFR overview advises clinical assessment at least every three months during the first year and ophthalmic assessment for papilledema at least annually or with concerning symptoms. Imaging and neurosurgical reassessment are guided by concern for hydrocephalus or Chiari malformation.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Eval for signs of ↑ intracranial pressure (e.g., headaches, vomiting)"

The surveillance table supports symptom-directed reassessment in addition to head-growth monitoring.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Clinical eval at least every 3 mos in 1st year of life; can be done in conjunction w/team visits to assess for craniosynostosis Ophthalmologic exam for papilledema At least annually, & w/any concerning symptoms"

GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.

Genetic counseling and reproductive testing

Action: Genetic counseling and reproductive testing Ontology label: Genetic Counseling NCIT:C15240

Offer counseling with parental testing, residual mosaic recurrence risk and the 50% variant-transmission risk for an affected heterozygous individual. Once a familial pathogenic variant is identified, prenatal and preimplantation testing are possible; genotype alone cannot reliably predict individual clinical severity.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Once the FGFR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews supports reproductive testing after variant identification.

Delivery planning for an affected fetus

Coordinate delivery at a center with pediatric airway, craniofacial and neurosurgical expertise. A clinician skilled in neonatal intubation and resuscitation should be present because airway obstruction can require immediate intervention.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"a health care provider skilled in endotracheal intubation and resuscitation should be present at the delivery."

GeneReviews recommends specialist preparedness for FGFR craniosynostosis pregnancies.

Psychosocial and family support

Action: Psychosocial and family support Ontology label: Supportive Care NCIT:C15747

Provide ongoing psychosocial assessment, educational support and attention to the family’s practical needs and the child’s social experience. Care goals and elective reconstruction should be individualized.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Psychosocial assessments & mental health support throughout childhood"

The shared FGFR management table supports longitudinal psychosocial care.

🔬

Diagnosis

2

Clinical assessment and molecular confirmation

Assess cranial sutures, characteristic skin folds, umbilical and anogenital findings, and airway involvement. Because craniosynostosis syndromes overlap and no formal clinical criteria exist, confirm the suspected diagnosis with FGFR2 testing. A craniosynostosis multigene panel or genomic testing can be appropriate when the phenotype is atypical or initial testing is unrevealing. Hotspot-only testing will miss rarer alleles.

Show evidence (4 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing."

The FGFR overview recommends molecular confirmation in the overlapping syndromic spectrum.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Approaches include gene-targeted testing (targeted analysis, single-gene testing, multigene panel) or comprehensive genomic testing (exome sequencing, exome array, genome sequencing)."

Provides the diagnostic options; selection depends on phenotype and prior results.

PMID:19610084 SUPPORT Human Clinical

"was performed on DNA extracted from peripheral blood lymphocytes from the propositus, and was negative."

A deletion-associated BSS-like case illustrates the limitation of testing only the two recurrent substitutions.

+ 1 more reference

Prenatal imaging with molecular evaluation

Prenatal ultrasound may identify cloverleaf skull, abnormal skin folding or additional anomalies, but suggestive craniosynostosis can emerge late and imaging findings overlap other syndromes. In one 2026 case, amniocyte genome sequencing identified de novo p.Phe276Cys and informed delivery planning. Molecular results require interpretation with detailed fetal and postnatal phenotyping.

Show evidence (2 references)

PMID:41775672 SUPPORT Human Clinical

"This case expands the genotype–phenotype correlation of BSS and demonstrates the clinical utility of prenatal SNV analysis available via modalities such as GS, given that the genetic diagnosis had direct implications for delivery planning."

A single prenatal case supports clinical utility without establishing diagnostic sensitivity.

PMID:25706251 SUPPORT Human Clinical

"Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth."

The skin finding was missed prospectively in this case; the observation does not establish that prospective detection is impossible.

📈

Progression

2

Infancy

Age: Birth through the first year

Published case literature records respiratory distress and deaths in early infancy. A 2024 surgical case report summarizes historical first-year mortality as about half, but this selected literature is not a contemporary survival cohort. Multilevel airway obstruction, tracheal cartilage abnormalities and neurologic complications require individual assessment.

Show evidence (3 references)

PMID:25706251 SUPPORT Human Clinical

"Beare-Stevenson syndrome (BSS) is a rare FGFR2-associated craniosynostosis syndrome with a higher rate of sudden unexplained death than related conditions such as Apert, Pfeiffer, and Crouzon syndromes."

States the excess mortality relative to the other members of the FGFR2 craniosynostosis group, which is the entry's central clinical claim.

PMID:38445861 SUPPORT Human Clinical

"Half of patients with BSS died within the first year of life due to cardiorespiratory arrest or unexpected sudden death."

A historical summary in a surgical case report, not a prospective BSS survival estimate.

PMID:12900900 SUPPORT Human Clinical

"They were born with respiratory distress and were connected to mechanical ventilation for ventilatory support. Both of them died in 50 days after birth due to secondary complications."

A concrete instance of the early respiratory course in two confirmed patients.

Childhood

Age: Beyond infancy, in survivors

Surviving children may require staged airway, cranial and midface procedures and developmental support. An eight-year-old survivor is described in the 2024 surgical report. Airway cartilage deformation and Chiari-related tonsillar herniation can progress during childhood, as observed in a three-year-old with p.Tyr375Cys.

Show evidence (3 references)

PMID:25706251 SUPPORT Human Clinical

"BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy."

The developmental outcome that characterizes the surviving group.

PMID:38445861 SUPPORT Human Clinical

"We currently have an 8-year-old patient who is being followed up. She underwent tracheostomy, cranioplasty, and shunting."

Documents survival beyond infancy and the staged surgical burden.

PMID:41112086 SUPPORT Human Clinical

"At 3 years of age, rigid bronchoscopy revealed progressive tracheal cartilage deformity with inward protrusion."

Serial imaging demonstrates progression in one child; it does not define the course of all BSS sleeves.

📊

Prevalence

1

Worldwide, published-case literature

Cases In Literature

Published-case counts are not population prevalence estimates. The 2015 report described 21 previously reported patients and the 2024 report fewer than 30. These dated literature counts are affected by ascertainment and do not establish incidence or current total case numbers.

Show evidence (2 references)

PMID:25706251 SUPPORT Human Clinical

"There have only been 21 reported patients with BSS, which limits prognostication for clinicians and likely does not capture the full extent of the phenotype."

The 2015 published-case count, with the authors' own caveat about what it supports.

PMID:38445861 SUPPORT Human Clinical

"In addition, there have only been fewer than 30 cases, which limits prognostication for clinicians."

An updated 2024 count, consistent with the 2015 figure.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Beare-Stevenson Cutis Gyrata Syndrome:

Crouzon syndrome MONDO:0007405

Overlapping Features Craniosynostosis, proptosis and midface retrusion overlap with BSS, including prenatal cloverleaf presentations.

Distinguishing Features

BSS characteristically combines cutis gyrata with umbilical and anogenital findings; skin redundancy can also occur in some Crouzon genotypes, so it is not an absolute discriminator.
Detailed phenotyping and molecular testing are needed because the craniofacial appearances overlap.

Show evidence (2 references)

PMID:25706251 SUPPORT Human Clinical

"Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome."

A concrete instance of the prenatal misassignment this gap concerns.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Linear skin rugations, deep creases, and redundant scalp skin (similar to those seen in Beare-Stevenson cutis gyrata syndrome) were reported"

The Crouzon section documents skin overlap, limiting claims that skin folds alone establish BSS.

Pfeiffer syndrome MONDO:0007043

Overlapping Features Severe craniosynostosis, midface hypoplasia, airway abnormalities and broad digits can resemble BSS.

Distinguishing Features

Cutis gyrata may be inconspicuous in infancy; a p.Tyr375Cys child initially suspected to have Pfeiffer syndrome was reassigned to BSS after genetic testing.

Show evidence (1 reference)

PMID:41112086 SUPPORT Human Clinical

"This patient was initially suspected to have Pfeiffer syndrome from her clinical features because cutis gyrata (which is indicative of BSS) was not apparent in infancy."

A molecularly confirmed case demonstrates the clinical diagnostic overlap.

🧫

Experimental Models

2

RCS chondrocytes expressing human FGFR2 Y375C CELL_LINE

Rat chondrosarcoma cells transfected with wild-type or mutant human FGFR2; receptor and FRS2 phosphorylation were measured.

Publication

PMID:22585574

Pathograph links

Ligand-Independent FGFR2 Activation measures observes: molecular Measures increased phosphorylation with the human disease allele.

Limitations: Heterologous overexpression in a tumor-derived rat cell line does not reproduce endogenous expression in human skin or cranial sutures.

Show evidence (1 reference)

PMID:22585574 SUPPORT In Vitro

"Our results showed constitutive activation of FGFR2 receptor and FRS2, a major FGFR downstream mediator (52), in rat chondrosarcoma (RCS) chondrocytes transfected with human FGFR2 Y375C as compared with WT FGFR2 (Figure 4A)."

Direct receptor-signaling measurements in cells expressing the human disease allele.

Show evidence (1 reference)

PMID:22585574 SUPPORT In Vitro

"Our results showed constitutive activation of FGFR2 receptor and FRS2, a major FGFR downstream mediator (52), in rat chondrosarcoma (RCS) chondrocytes transfected with human FGFR2 Y375C as compared with WT FGFR2 (Figure 4A)."

Direct receptor-signaling measurements in cells expressing the human disease allele.

Primary keratinocytes from Fgfr2 Y394C mice PRIMARY_CELL_CULTURE

Mouse-derived epidermal keratinocytes used to assess FGFR2 phosphorylation without added FGF ligand.

Publication

PMID:22585574

Pathograph links

Ligand-Independent FGFR2 Activation measures observes: molecular Measures receptor activation in cells bearing the knock-in allele.

Limitations: Mouse-derived culture is informative about ligand-independent signaling, not human clinical efficacy.

Show evidence (1 reference)

PMID:22585574 SUPPORT In Vitro

"We confirmed this result in vivo by demonstrating increased phosphorylation of FGFR2 in epidermal keratinocytes derived from our Fgfr2+/Y394C mice without the addition of FGF ligand as compared with that of controls (Supplemental Figure 4), indicating that the Y394C mutation causes constitutive..."

Mouse-derived keratinocytes support ligand-independent activation.

Show evidence (1 reference)

PMID:22585574 SUPPORT In Vitro

"We confirmed this result in vivo by demonstrating increased phosphorylation of FGFR2 in epidermal keratinocytes derived from our Fgfr2+/Y394C mice without the addition of FGF ligand as compared with that of controls (Supplemental Figure 4), indicating that the Y394C mutation causes constitutive..."

Mouse-derived keratinocytes support ligand-independent activation.

🐁

Animal Models

1

Fgfr2 Y394C heterozygous knock-in mouse

Knock-in of the murine allele corresponding to human p.Tyr375Cys. The model develops epidermal hyperplasia, premature suture fusion, midface hypoplasia, reduced growth and early mortality. p38 inhibition improves skin histology, with limited suture benefit and no survival improvement under the reported regimen.

Species

Mus musculus

Genotype

Fgfr2+/Y394C

Background

C57BL/6J

Publication

PMID:22585574

Pathograph links

Epidermal Hyperplasia recapitulates observes: tissue Reproduces epidermal acanthosis, papillomatosis and hyperproliferation.

Limitations: Pigmentation was not increased; this is not a complete reproduction of human acanthosis nigricans.

Show evidence (1 reference)

PMID:22585574 SUPPORT Model Organism

"Histologically, the skin of E16.5, P0, and P5 Fgfr2+/Y394C mice displayed cutis gyrata, epidermal acanthosis, and papillomatosis (Figure 2, A–D)."

Mouse tissue histology supports the epidermal phenotype.

Cranial Suture Osteogenic Acceleration recapitulates observes: tissue Shows increased osteogenic differentiation at coronal sutures.

Limitations: The model carries one recurrent allele and does not establish equivalent effects for every reported FGFR2 variant.

Show evidence (1 reference)

PMID:22585574 SUPPORT Model Organism

"These data indicated increased osteogenic differentiation as well as abnormal bone growth at the coronal suture in Fgfr2+/Y394 mice."

ALP, Runx2 and osteonectin observations support increased differentiation; the source omits the final C in this genotype occurrence.

Tracheal Cartilage Ring Fusion fails to recapitulate observes: tissue No tracheal sleeves were detected in the newborn Y394C sample in the later comparative study.

Limitations: Whole-mount morphology included five newborn Y394C mice; low-frequency or later abnormalities cannot be excluded.

Show evidence (1 reference)

PMID:32886384 SUPPORT Model Organism

"Though TCS has been seen in the human FGFR2Y375C variant, our results suggest that they are not present or are present at low frequency in the mouse model."

Directly states the human-model mismatch.

Show evidence (2 references)

PMID:22585574 SUPPORT Model Organism

"with age the mutants showed reduced growth and early death, usually within 2 weeks"

The initial model study records growth and survival limitations.

PMID:22585574 SUPPORT Model Organism

"The SB203580 treatment did not improve the survival rate of Fgfr2+/Y394C mice"

The tested regimen did not improve survival.

{ }

Source YAML

click to show

name: Beare-Stevenson Cutis Gyrata Syndrome
synonyms:
- BSS
- Beare-Stevenson syndrome
- cutis gyrata-acanthosis nigricans-craniosynostosis syndrome
- BSTVS
creation_date: '2026-08-20T00:00:00Z'
category: Mendelian
description: >-
  Beare-Stevenson cutis gyrata syndrome is an FGFR2-related craniosynostosis disorder
  characterized by
  cutis gyrata, acanthosis nigricans, craniofacial abnormalities, a prominent umbilical
  stump and anogenital
  anomalies. Recurrent p.Tyr375Cys and p.Ser372Cys substitutions introduce cysteine
  residues near the
  transmembrane domain; additional alleles and a Beare-Stevenson-like presentation
  with an intragenic
  deletion have been reported. Severe multisuture craniosynostosis, hydrocephalus,
  Chiari malformation
  and multilevel airway obstruction can require early multidisciplinary intervention.
  Tracheal cartilaginous
  sleeves are an important airway complication. Published case series report substantial
  early mortality,
  but provide limited guidance for individual prognosis.
disease_term:
  preferred_term: Beare-Stevenson cutis gyrata syndrome
  term:
    id: MONDO:0007412
    label: Beare-Stevenson cutis gyrata syndrome
parents:
- FGFR2-related craniosynostosis
- Craniosynostosis syndrome
classifications:
  isds_skeletal_category:
  - classification_value: craniosynostosis_syndromes
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019 revision
      (Mortier et al., PMID:31633310),
      Table 1 group 33 "Craniosynostosis syndromes"; listed as "Beare-Stevenson syndrome".
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant FGFR2-related disorder, with sporadic and molecularly confirmed
    de novo cases reported.
    Advanced paternal age has been observed, but individual case observations do not
    establish a specific
    germline selection mechanism. Parental testing and genetic counseling guide recurrence-risk
    assessment.
    For an affected heterozygous individual, each child has a 50% chance of inheriting
    the variant. When
    parental blood testing is negative, sibling recurrence risk remains slightly above
    the population
    background because of possible germline mosaicism.
  evidence:
  - reference: PMID:8696350
    reference_title: Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death.
    explanation: The defining molecular paper states the inheritance pattern and the core phenotype.
  - reference: PMID:1519658
    reference_title: Beare-Stevenson cutis gyrata syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All cases observed to date have been sporadic. Increased paternal age suggests the possibility of an autosomal dominant mutation.
    explanation: >-
      The premolecular 1992 series reported sporadic cases and proposed dominant inheritance;
      it did not
      establish de novo status by parental sequencing.
  - reference: PMID:16531735
    reference_title: A case of Beare-Stevenson syndrome with a broad spectrum of features and a review of the FGFR2 Y375C mutation phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The paternal age at the time of conception was 62 years consistent with a paternal age effect.
    explanation: A molecularly confirmed case had a 62-year-old father; this is a clinical observation consistent with, rather than proof of, a paternal-age mechanism.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Each child of an individual with an FGFR craniosynostosis syndrome has a 50% chance of inheriting the FGFR pathogenic variant.
    explanation: General autosomal dominant FGFR counseling applies to variant transmission; clinical severity is not fixed by this probability.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
    explanation: GeneReviews retains residual recurrence risk after negative parental leukocyte testing.
    quote_role: REVIEW_SYNTHESIS
prevalence:
- population: Worldwide, published-case literature
  measure_type: CASES_IN_LITERATURE
  notes: >-
    Published-case counts are not population prevalence estimates. The 2015 report
    described 21 previously
    reported patients and the 2024 report fewer than 30. These dated literature counts
    are affected by
    ascertainment and do not establish incidence or current total case numbers.
  evidence:
  - reference: PMID:25706251
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There have only been 21 reported patients with BSS, which limits prognostication for clinicians and likely does not capture the full extent of the phenotype.
    explanation: The 2015 published-case count, with the authors' own caveat about what it supports.
  - reference: PMID:38445861
    reference_title: Pitfall of Monobloc Advancement in Beare-Stevenson Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, there have only been fewer than 30 cases, which limits prognostication for clinicians.
    explanation: An updated 2024 count, consistent with the 2015 figure.
pathophysiology:
- name: FGFR2 Activating Variant
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: fgfr_gain_of_function_skeletal_dysplasia#Constitutive FGFR Activation
  description: >-
    Heterozygous FGFR2 variants cause the syndrome. The recurrent p.Tyr375Cys and
    p.Ser372Cys substitutions
    introduce cysteine residues in the juxtamembrane/transmembrane region. Functional
    studies demonstrate
    constitutive activation for human p.Tyr375Cys and the corresponding murine p.Tyr394Cys
    allele. A de
    novo p.Phe276Cys variant was classified as likely pathogenic in a 2026 prenatal
    case; its functional
    effect was not experimentally tested. A 63-nucleotide deletion has also been reported
    in a Beare-Stevenson-like
    presentation, so a cysteine-creating missense mechanism should not be imposed
    on every reported allele.
  gene:
    preferred_term: FGFR2
    description: >-
      FGFR2 activation demonstrated for p.Tyr375Cys; functional consequences of rarer
      reported alleles
      require allele-specific interpretation.
    modifier: GAIN_OF_FUNCTION
    term:
      id: hgnc:3689
      label: FGFR2
  molecular_functions:
  - preferred_term: transmembrane receptor protein tyrosine kinase activity
    term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:8696350
    reference_title: Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains." # codespell:ignore-line
    explanation: "The original identification of the two recurrent alleles and their domain positions. Quoted verbatim including the source's own typographical errors (\"sporatic\", \"Ty375Cys\", \"Iglll\"), which are in the published abstract and not introduced here." # codespell:ignore-line
  - reference: PMID:8696350
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In two patients, neither of these mutations were found suggesting further genetic heterogeneity.
    explanation: >-
      Two clinically diagnosed patients lacked either recurrent variant in the original
      report; this does
      not by itself establish another causal locus.
    reference_title: Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GS resulted at 30 weeks 5 days and revealed a heterozygous, de novo, likely pathogenic FGFR2 variant (c.827 T > G, p.Phe276Cys) (Table 1B).
    explanation: The prenatal variant was classified as likely pathogenic; this case report does not experimentally establish disulfide bonding or gain of function.
  downstream:
  - target: Ligand-Independent FGFR2 Activation
    description: >-
      The p.Tyr375Cys allele and its murine equivalent produce ligand-independent
      receptor activation
      in experimental systems.
    causal_link_type: DIRECT

  - causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Human p.Tyr375Cys-associated BSS can include fusion of tracheal cartilage rings; the intervening developmental mechanism is unresolved and is not reproduced consistently in the corresponding mouse model.
    evidence:
    - evidence_source: HUMAN_CLINICAL
      explanation: Identifies the human disease allele in the same patient whose fused tracheal cartilage was imaged.
      reference: PMID:41112086
      reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
      snippet: However, genetic testing conducted at the previous hospital revealed the Y375C variant of FGFR2, and the patient was diagnosed with BSS.
      supports: SUPPORT
    - evidence_source: HUMAN_CLINICAL
      explanation: The genotype-defined human case establishes the structural airway phenotype; it does not resolve the intervening signaling mechanism.
      reference: PMID:41112086
      reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
      snippet: The upper to mid‐trachea exhibits a tracheoesophageal membrane, yet it maintains a cylindrical shape, with the fused tracheal cartilaginous rings.
      supports: SUPPORT
    target: Tracheal Cartilage Ring Fusion
  - causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The corresponding Y394C knock-in allele produces midfacial hypoplasia in mice. The experiment does not isolate suture fusion as its mediator.
    evidence:
    - evidence_source: MODEL_ORGANISM
      explanation: Mutant-versus-littermate imaging supports an allele-to-midface effect, without identifying which cranial abnormality mediates it.
      reference: PMID:22585574
      reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
      snippet: High-resolution micro-CT scans of Fgfr2+/Y394C mice revealed midfacial hypoplasia, brachycephalic-shaped skull, and premature fusion of coronal and other sutures (Figure 1, E–H, and Supplemental Figure 2).
      supports: SUPPORT
    target: Midface retrusion
- name: Ligand-Independent FGFR2 Activation
  biological_scale: MOLECULAR
  description: >-
    Human FGFR2 p.Tyr375Cys increased receptor and FRS2 phosphorylation in transfected
    rat chondrosarcoma
    cells. Keratinocytes from Fgfr2+/Y394C mice also showed increased receptor phosphorylation
    without
    added FGF ligand. Intermolecular disulfide bonding is a proposed structural explanation
    for the cysteine
    substitutions. The 1998 biochemical study tested other FGFR2 variants and explicitly
    did not test
    p.Ser372Cys or p.Tyr375Cys.
  molecular_functions:
  - preferred_term: transmembrane receptor protein tyrosine kinase activity
    term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our results showed constitutive activation of FGFR2 receptor and FRS2, a major FGFR downstream mediator (52), in rat chondrosarcoma (RCS) chondrocytes transfected with human FGFR2 Y375C as compared with WT FGFR2 (Figure 4A).
    explanation: Direct receptor-signaling measurements in cells expressing the human disease allele.
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We confirmed this result in vivo by demonstrating increased phosphorylation of FGFR2 in epidermal keratinocytes derived from our Fgfr2+/Y394C mice without the addition of FGF ligand as compared with that of controls (Supplemental Figure 4), indicating that the Y394C mutation causes constitutive or ligand-independent activation of the receptor.
    explanation: Mouse-derived keratinocytes support ligand-independent activation.
  - reference: PMID:9539778
    reference_title: Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Although we have not examined these mutations in this work, we would predict that they also involve aberrant intermolecular disulfide bonding.
    explanation: The authors explicitly identify disulfide bonding for the two BSS alleles as a prediction; their direct assays concerned other FGFR2 variants.
  downstream:
  - target: p38 MAPK Activation
    description: >-
      Constitutive receptor activation is accompanied by increased p38 phosphorylation
      in mutant mouse
      epidermis and calvaria.
    causal_link_type: DIRECT

- name: p38 MAPK Activation
  biological_scale: CELLULAR
  conforms_to: fgfr_gain_of_function_skeletal_dysplasia#Sustained MAPK/STAT Signaling
  description: >-
    Phosphorylated p38 is increased in epidermis and calvarial tissue of Fgfr2+/Y394C
    mice. ERK1/2 phosphorylation
    is additionally increased in mutant skull tissue, so the response is not exclusive
    to p38. Pharmacological
    p38 inhibition improves epidermal hyperplasia and produces limited suture effects
    without a significant
    overall skull-shape or survival benefit in the tested regimen.
  biological_processes:
  - preferred_term: p38MAPK cascade
    term:
      id: GO:0038066
      label: p38MAPK cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found ligand-independent phosphorylation of FGFR2 and activation of p38 signaling in mutant skin and calvarial tissues.
    explanation: >-
      Establishes ligand-independent receptor activation and identifies p38 as the
      engaged downstream
      branch in the two affected tissues.
  - reference: PMID:22585574
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We developed a mouse model of BSS harboring a FGFR2 Y394C mutation and identified p38 MAPK as an important signaling pathway mediating these abnormalities.
    explanation: Names p38 MAPK as the mediating pathway for both the skin and skull phenotypes.
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: None of the other pathways showed obvious changes of phosphorylation in both tissues; however, we noted phosphorylated ERK1/2 was increased in mutant skull tissues (Supplemental Figure 5).
    explanation: ERK1/2 activation in skull tissue qualifies an exclusively p38-based interpretation.
  downstream:
  - target: Cranial Suture Osteogenic Acceleration
    description: >-
      p38 contributes to the osteogenic phenotype, with increased ERK1/2 signaling
      also observed in skull
      tissue; p38 inhibition yields only limited suture improvement.
    causal_link_type: DIRECT
  - target: Epidermal Hyperplasia
    description: >-
      p38 inhibition reduces the mutant epidermal proliferation and differentiation
      abnormalities, supporting
      a functional contribution to epidermal hyperplasia.
    causal_link_type: DIRECT

- name: Cranial Suture Osteogenic Acceleration
  biological_scale: TISSUE
  conforms_to: fgfr_gain_of_function_skeletal_dysplasia#Cranial Suture Osteogenic Acceleration
  description: >-
    Fgfr2+/Y394C mouse coronal sutures show decreased cell proliferation together
    with increased osteogenic
    differentiation. Expanded alkaline phosphatase and Runx2 expression and overlapping
    osteonectin-positive
    osteogenic fronts support premature bone formation at the suture.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: These data indicated increased osteogenic differentiation as well as abnormal bone growth at the coronal suture in Fgfr2+/Y394 mice.
    explanation: ALP, Runx2 and osteonectin observations support increased differentiation; the source omits the final C in this genotype occurrence.
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Cell proliferation was analyzed by calculating the ratios of the number of BrdU-positive cells to total cells between and including the osteogenic fronts in mutants and littermate controls. At E17.5, the ratio was obviously decreased in mutants as compared with controls
    explanation: The osteogenic phenotype involves decreased proliferation, distinct from epidermal hyperproliferation.
  downstream:
  - target: Premature Cranial Suture Fusion
    causal_link_type: DIRECT

- name: Premature Cranial Suture Fusion
  biological_scale: TISSUE
  conforms_to: fgfr_gain_of_function_skeletal_dysplasia#Premature Suture Fusion and Craniosynostosis
  description: >-
    Premature fusion of multiple cranial sutures produces craniosynostosis and can
    yield a cloverleaf
    skull. In the six-case 1992 clinical series, four had craniosynostosis and three
    of those had cloverleaf
    skull. Associated hydrocephalus, Chiari malformation and midface abnormalities
    are clinically important
    but cannot all be attributed to restricted cranial volume alone.
  biological_processes:
  - preferred_term: cranial suture morphogenesis
    term:
      id: GO:0060363
      label: cranial suture morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:1519658
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Craniosynostosis is present in four cases, with cloverleaf skull in three of these.
    explanation: The original series' documentation of craniosynostosis and cloverleaf skull frequency.
    reference_title: Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:1519658
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Performance and life expectation appear to be related to the presence or absence of cloverleaf skull.
    explanation: >-
      The small original clinical series suggested an association between cloverleaf
      skull and outcome;
      it does not establish an independently validated prognostic classifier.
    reference_title: Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:12900900
    reference_title: 'Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The radiologic examination showed a cloverleaf-form craniosynostosis.
    explanation: Independent radiological confirmation in molecularly confirmed p.Tyr375Cys patients.
  downstream:
  - target: Craniosynostosis
  - target: Cloverleaf skull
- name: Epidermal Hyperplasia
  biological_scale: TISSUE
  description: >-
    Fgfr2+/Y394C mouse epidermis shows keratinocyte hyperproliferation, acanthosis
    and papillomatosis
    with altered differentiation-marker expression. These findings model the cutaneous
    folds and acanthosis
    of human BSS. Human cutis gyrata has a variable distribution that includes scalp,
    forehead, face,
    neck, trunk, hands and feet.
  cell_types:
  - preferred_term: Keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  biological_processes:
  - preferred_term: keratinocyte proliferation
    term:
      id: GO:0043616
      label: keratinocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:22585574
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: This study reveals the pleiotropic effects of the FGFR2 Y394C mutation evidenced by cutis gyrata, acanthosis nigricans, and craniosynostosis and provides a useful model for investigating the molecular mechanisms of skin and skull development.
    explanation: >-
      Confirms in a model carrying the murine equivalent of the human allele that
      one variant produces
      both the skin and the skull phenotype.
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
  - reference: PMID:1519658
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet.
    explanation: The human distribution of the skin phenotype.
    reference_title: Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Histologically, the skin of E16.5, P0, and P5 Fgfr2+/Y394C mice displayed cutis gyrata, epidermal acanthosis, and papillomatosis (Figure 2, A–D).
    explanation: Mouse tissue histology supports the epidermal phenotype.
  downstream:
  - target: Cutis gyrata of scalp
  - target: Palmoplantar cutis gyrata
  - target: Acanthosis nigricans
- name: Tracheal Cartilage Ring Fusion
  biological_scale: TISSUE
  description: >-
    Vertical fusion of tracheal cartilage rings can produce a rigid sleeve along the
    trachea. Human BSS
    cases demonstrate this lesion, including progressive inward cartilage deformation
    in a child followed
    to age three. The resulting airway risks include impaired clearance and obstruction
    or tube malposition;
    tracheostomy does not remove the abnormal cartilage. No sleeve was found among
    the five newborn Fgfr2+/Y394C
    mice assessed by whole-mount morphology in a later study, limiting extrapolation
    from this model to
    the human airway phenotype.
  evidence:
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The initial rigid bronchoscopy demonstrated tracheal cartilaginous sleeve, and tracheostomy was performed. At 3 years of age, rigid bronchoscopy revealed progressive tracheal cartilage deformity with inward protrusion.
    explanation: Serial human imaging documents a sleeve and later deformation in one child.
  - reference: PMID:32886384
    reference_title: Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Though TCS has been seen in the human FGFR2Y375C variant, our results suggest that they are not present or are present at low frequency in the mouse model.
    explanation: The negative newborn mouse result constrains the model; it does not refute the human association.
  downstream:
  - target: Tracheal cartilaginous sleeve
phenotypes:
- category: Craniofacial
  name: Craniosynostosis
  description: >-
    Premature fusion of cranial sutures, often multisutural. It is a central feature
    but was present in
    four of six patients in the original clinical series, so it should not be described
    as universal.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:8696350
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death.
    explanation: Craniosynostosis named among the defining features.
    reference_title: Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:1519658
    reference_title: Beare-Stevenson cutis gyrata syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Craniosynostosis is present in four cases, with cloverleaf skull in three of these.
    explanation: The report describes six total cases and does not establish universal craniosynostosis.
- category: Craniofacial
  name: Cloverleaf skull
  description: >-
    Trilobar skull configuration associated with severe multisuture craniosynostosis;
    present in three
    of the four craniosynostotic patients in the original six-case series.
  phenotype_term:
    preferred_term: Cloverleaf skull
    term:
      id: HP:0002676
      label: Cloverleaf skull
  evidence:
  - reference: PMID:1519658
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Craniosynostosis is present in four cases, with cloverleaf skull in three of these.
    explanation: Documents cloverleaf skull in most craniosynostotic patients in the delineating series.
    reference_title: Beare-Stevenson cutis gyrata syndrome.
- category: Dermatologic
  name: Cutis gyrata of scalp
  description: >-
    Convoluted, cerebriform folds and furrows of scalp skin. A characteristic finding
    that may be subtle
    in infancy and become more apparent with age.
  phenotype_term:
    preferred_term: Cutis gyrata of scalp
    term:
      id: HP:0010541
      label: Cutis gyrata of scalp
  evidence:
  - reference: PMID:1519658
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Beare-Stevenson cutis gyrata syndrome consists of skin furrows of corrugated appearance, acanthosis nigricans, craniofacial anomalies, particularly craniosynostosis and ear defects, anogenital anomalies, skin tags, and prominent umbilical stump.
    explanation: The syndrome definition, leading with the corrugated skin furrows.
    reference_title: Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:1519658
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cutis gyrata variably affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet.
    explanation: Confirms scalp involvement within the characteristic distribution.
    reference_title: Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: cutis gyrata, which had been unclear at birth but had gradually become apparent
    explanation: The finding was initially inconspicuous in this molecularly confirmed patient.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Widespread cutis gyrata and acanthosis nigricans are usually evident at birth
    explanation: The Beare-Stevenson clinical section describes usual neonatal onset, with individual exceptions documented elsewhere.
    quote_role: REVIEW_SYNTHESIS
- category: Dermatologic
  name: Palmoplantar cutis gyrata
  description: >
    Furrowed, corrugated skin of the palms and soles, part of the wide distribution
    of the cutis gyrata
    phenotype.
  phenotype_term:
    preferred_term: Palmoplantar cutis gyrata
    term:
      id: HP:0007469
      label: Palmoplantar cutis gyrata
  evidence:
  - reference: PMID:12900900
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Furrowed palms and soles were also observed.
    explanation: Direct observation in two molecularly confirmed patients.
    reference_title: 'Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis.'
- category: Dermatologic
  name: Acanthosis nigricans
  description: >
    Velvety hyperpigmented plaques in flexural skin. Shared with Crouzon syndrome
    with acanthosis nigricans,
    where the causal allele is instead FGFR3 p.Ala391Glu — the same cutaneous readout
    reached through
    a different receptor.
  phenotype_term:
    preferred_term: Acanthosis nigricans
    term:
      id: HP:0000956
      label: Acanthosis nigricans
  evidence:
  - reference: PMID:8696350
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death.
    explanation: Acanthosis nigricans named among the defining features.
    reference_title: Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Widespread cutis gyrata and acanthosis nigricans are usually evident at birth
    explanation: BSS-specific neonatal clinical description.
    quote_role: REVIEW_SYNTHESIS
- category: Dermatologic
  name: Skin tags
  description: Cutaneous skin tags, part of the characteristic dermatological picture.
  phenotype_term:
    preferred_term: Skin tags
    term:
      id: HP:0010609
      label: Skin tags
  evidence:
  - reference: PMID:1519658
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Beare-Stevenson cutis gyrata syndrome consists of skin furrows of corrugated appearance, acanthosis nigricans, craniofacial anomalies, particularly craniosynostosis and ear defects, anogenital anomalies, skin tags, and prominent umbilical stump.
    explanation: Skin tags listed in the syndrome definition.
    reference_title: Beare-Stevenson cutis gyrata syndrome.
- category: Gastrointestinal
  name: Prominent umbilicus
  description: >-
    A prominent umbilical stump with redundant tissue is a characteristic finding described in the original
    clinical series and molecularly confirmed cases.
  phenotype_term:
    preferred_term: Prominent umbilicus
    term:
      id: HP:0001544
      label: Prominent umbilicus
  evidence:
  - reference: PMID:12900900
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both female newborn patients presented at birth with craniofacial anomalies, variable cutis gyrata in forehead and preauricular regions, prominent umbilical stump and anogenital anomalies.
    explanation: Prominent umbilical stump documented in two molecularly confirmed patients.
    reference_title: 'Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis.'
- category: Craniofacial
  name: Midface retrusion
  description: >-
    Midface hypoplasia can be severe. Persistent tracheostomy dependence after midface advancement may
    reflect additional airway contributors, including micrognathia.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:42495986
    reference_title: First Successful Le Fort III Distraction in a Patient With Beare-Stevenson Cutis Gyrata Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical findings and imaging studies revealed severe proptosis, very severe midface hypoplasia, and reverse occlusion.
    explanation: Documents the severity of midface hypoplasia in a surgically managed patient.
- category: Ophthalmologic
  name: Proptosis
  description: >-
    Marked globe protrusion can accompany severe midface hypoplasia. The cited clinical report documents
    their co-occurrence without separating the contribution of orbital anatomy from other craniofacial
    abnormalities.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:42495986
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical findings and imaging studies revealed severe proptosis, very severe midface hypoplasia, and reverse occlusion.
    explanation: Direct documentation of severe proptosis.
    reference_title: First Successful Le Fort III Distraction in a Patient With Beare-Stevenson Cutis Gyrata Syndrome.
- category: Respiratory
  name: Choanal stenosis
  description: >
    Narrowing of the posterior nasal apertures, contributing with midface hypoplasia
    to the neonatal airway
    compromise that characterizes the syndrome.
  phenotype_term:
    preferred_term: Choanal stenosis
    term:
      id: HP:0000452
      label: Choanal stenosis
  evidence:
  - reference: PMID:16531735
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage.
    explanation: Choanal stenosis documented in a molecularly confirmed p.Tyr375Cys patient.
    reference_title: A case of Beare-Stevenson syndrome with a broad spectrum of features and a review of the FGFR2 Y375C mutation phenotype.
- category: Respiratory
  name: Tracheal cartilaginous sleeve
  description: >-
    Fusion of normal segmented tracheal cartilage into a sleeve. Its frequency in
    BSS is unknown. A historical
    90% untreated mortality estimate cited across syndromic craniosynostosis is not
    a BSS-specific prospective
    risk estimate.
  phenotype_term:
    preferred_term: Tracheal cartilaginous sleeve
    term:
      id: HP:0005347
      label: Tracheal cartilaginous sleeve
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One of our patients was noted to have a tracheal cartilaginous sleeve, which if present could explain sudden death.
    explanation: The index report of this finding in BSS.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
- category: Neurologic
  name: Hydrocephalus
  description: >-
    Hydrocephalus can progress in infancy and require cerebrospinal fluid diversion.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:42495986
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 2 months of age, she underwent a ventriculoperitoneal shunt placement, followed by occipital cranial expansion at 1 year and fronto-orbital distraction at 2 years of age.
    explanation: >-
      Shunt placement in infancy evidences clinically significant hydrocephalus in
      a documented BSS patient.
    reference_title: First Successful Le Fort III Distraction in a Patient With Beare-Stevenson Cutis Gyrata Syndrome.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hydrocephalus and Chiari I malformations are common.
    explanation: This statement occurs in the BSS-specific neurologic section.
    quote_role: REVIEW_SYNTHESIS
- category: Neurologic
  name: Chiari malformation
  description: >
    Hindbrain herniation, reported repeatedly in BSS and compounding the posterior
    fossa consequences
    of multisuture fusion.
  phenotype_term:
    preferred_term: Chiari malformation
    term:
      id: HP:0002308
      label: Chiari malformation
  evidence:
  - reference: PMID:42495986
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is characterized by craniosynostosis, midface hypoplasia, Chiari malformations, and other extensive congenital abnormalities.
    explanation: Chiari malformation named as a characteristic feature of the syndrome.
    reference_title: First Successful Le Fort III Distraction in a Patient With Beare-Stevenson Cutis Gyrata Syndrome.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hydrocephalus and Chiari I malformations are common.
    explanation: The BSS-specific clinical section identifies Chiari I malformation.
    quote_role: REVIEW_SYNTHESIS
- category: Neurologic
  name: Global developmental delay
  description: >-
    Significant developmental delay is reported among survivors of classical BSS.
    Developmental outcome
    is not uniform across the broader Beare-Stevenson-like spectrum.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy.
    explanation: States the developmental outcome among survivors.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: He has had initial mild motor delays, but the propositus’ neurodevelopmental progress was normal.
    explanation: A child with a Beare-Stevenson-like presentation and FGFR2 deletion had normal later progress; this qualifies universality, not the association in classical BSS.
- category: Dental
  name: Hypodontia
  description: >
    Reduced tooth number affecting primary and permanent dentition, reported with
    natal teeth in the same
    patients. Dental anomalies recur across the FGFR-related craniosynostosis syndromes.
  phenotype_term:
    preferred_term: Hypodontia
    term:
      id: HP:0000668
      label: Hypodontia
  evidence:
  - reference: PMID:19860525
    reference_title: 'Hypodontia in Beare-Stevenson syndrome: an example of dental anomalies in FGFR-related craniosynostosis syndromes.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had dental findings of natal teeth and hypodontia of the primary and permanent teeth.
    explanation: Direct documentation of hypodontia in a BSS patient.
- category: Dental
  name: Natal tooth
  description: Teeth present at birth, reported alongside hypodontia in BSS.
  phenotype_term:
    preferred_term: Natal tooth
    term:
      id: HP:0000695
      label: Natal tooth
  evidence:
  - reference: PMID:19860525
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient had dental findings of natal teeth and hypodontia of the primary and permanent teeth.
    explanation: Direct documentation of natal teeth in a BSS patient.
    reference_title: 'Hypodontia in Beare-Stevenson syndrome: an example of dental anomalies in FGFR-related craniosynostosis syndromes.'
- category: Genitourinary
  name: Bifid scrotum
  description: >-
    Bifid scrotum with perineal hypospadias was documented in a molecularly confirmed p.Tyr375Cys patient.
  phenotype_term:
    preferred_term: Bifid scrotum
    term:
      id: HP:0000048
      label: Bifid scrotum
  evidence:
  - reference: PMID:16531735
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage.
    explanation: Documents bifid scrotum in a molecularly confirmed patient.
    reference_title: A case of Beare-Stevenson syndrome with a broad spectrum of features and a review of the FGFR2 Y375C mutation phenotype.
- category: Genitourinary
  name: Perineal hypospadias
  description: Severe proximal hypospadias, reported with bifid scrotum.
  phenotype_term:
    preferred_term: Perineal hypospadias
    term:
      id: HP:0000051
      label: Perineal hypospadias
  evidence:
  - reference: PMID:16531735
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage.
    explanation: Documents perineal hypospadias in a molecularly confirmed patient.
    reference_title: A case of Beare-Stevenson syndrome with a broad spectrum of features and a review of the FGFR2 Y375C mutation phenotype.
- category: Growth
  name: Failure to thrive
  description: >-
    Severe poor weight gain has been reported. In one p.Tyr375Cys autopsy case, a
    markedly short small
    intestine was a possible contributor, but poor growth persisted despite parenteral
    nutrition and its
    cause remained uncertain.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We herein present an autopsy case of BSS characterized by a disproportionate organ size and severe failure to thrive.
    explanation: Documents severe failure to thrive in an autopsied BSS patient.
  - reference: PMID:41882888
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, the small intestine was much shorter in our patient than in infants with a similar body size, which could explain the poor weight gain.
    explanation: >-
      Offers a structural explanation for the failure to thrive, phrased by the authors
      as a possibility
      and based on one autopsy.
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
  - reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We could not determine the cause of insufficient body weight
    explanation: The full report explicitly retains uncertainty about the cause of growth failure.
- name: Cleft palate
  category: Craniofacial
  description: Cleft palate is included in the BSS-specific GeneReviews clinical description.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Moderate-to-severe midface retrusion, proptosis, abnormal ears, cleft palate, conductive hearing loss, natal teeth, and relative prognathism are seen.
    explanation: The BSS-specific GeneReviews paragraph includes cleft palate in its craniofacial spectrum.
    quote_role: REVIEW_SYNTHESIS
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
- name: Conductive hearing loss
  category: Audiologic
  description: Conductive hearing loss is a recognized component of BSS. Other hearing-loss patterns have been reported in Beare-Stevenson-like cases.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Moderate-to-severe midface retrusion, proptosis, abnormal ears, cleft palate, conductive hearing loss, natal teeth, and relative prognathism are seen.
    explanation: The BSS-specific summary identifies a conductive hearing deficit, without giving a frequency.
    quote_role: REVIEW_SYNTHESIS
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
- name: Relative prognathism
  category: Craniofacial
  description: Relative jaw prominence is described in the BSS-specific GeneReviews section. The source does not establish increased mandibular length.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Moderate-to-severe midface retrusion, proptosis, abnormal ears, cleft palate, conductive hearing loss, natal teeth, and relative prognathism are seen.
    explanation: The source specifies relative prognathism; it does not establish elongation of the mandible.
    quote_role: REVIEW_SYNTHESIS
- name: Hirsutism
  category: Dermatologic
  description: Hirsutism is reported in the BSS-specific GeneReviews clinical description.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Widespread cutis gyrata and acanthosis nigricans are usually evident at birth; hirsutism, skin tags, prominent umbilicus with redundant tissue, and accessory nipples are also seen.
    explanation: GeneReviews lists excess hair growth alongside the characteristic cutaneous findings.
    quote_role: REVIEW_SYNTHESIS
  phenotype_term:
    preferred_term: Hirsutism
    term:
      id: HP:0001007
      label: Hirsutism
- name: Accessory nipples
  category: Breast
  description: Accessory nipples are reported in the BSS-specific GeneReviews clinical description.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Widespread cutis gyrata and acanthosis nigricans are usually evident at birth; hirsutism, skin tags, prominent umbilicus with redundant tissue, and accessory nipples are also seen.
    explanation: Accessory nipples are explicitly included in the BSS-specific clinical summary.
    quote_role: REVIEW_SYNTHESIS
  phenotype_term:
    preferred_term: Supernumerary nipple
    term:
      id: HP:0002558
      label: Supernumerary nipple
- name: Pyloric stenosis
  category: Gastrointestinal
  description: Pyloric stenosis is included among the reported BSS-associated findings.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus.
    explanation: GeneReviews includes pyloric stenosis among additional BSS manifestations.
    quote_role: REVIEW_SYNTHESIS
  phenotype_term:
    preferred_term: Pyloric stenosis
    term:
      id: HP:0002021
      label: Pyloric stenosis
- name: Anteriorly placed anus
  category: Gastrointestinal
  description: Anterior anal position is described among BSS-associated findings.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus.
    explanation: The source calls the finding anterior anus, supporting the positional phenotype.
    quote_role: REVIEW_SYNTHESIS
  phenotype_term:
    preferred_term: Anteriorly placed anus
    term:
      id: HP:0001545
      label: Anteriorly placed anus
- name: Prominent labial raphe
  category: Genitourinary
  description: GeneReviews describes a prominent labial raphe among genitourinary findings.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus.
    explanation: The named genital finding is recorded without inferring a more specific malformation.
    quote_role: REVIEW_SYNTHESIS
- name: Rugated labia majora
  category: Genitourinary
  description: Rugation of the labia majora is included in the BSS-specific clinical description.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other findings include genitourinary anomalies (e.g., bifid scrotum, prominent labial raphe, rugated labia majora), pyloric stenosis, and anterior anus.
    explanation: The source describes labial rugation rather than labial enlargement or fusion.
    quote_role: REVIEW_SYNTHESIS
- name: Intellectual disability
  category: Neurodevelopmental
  description: Intellectual disability is described in survivors of classical BSS. The GeneReviews statement of universality should not be generalized to every Beare-Stevenson-like presentation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Intellectual disability is present in all affected individuals who have survived (neonatal mortality is common).
    explanation: >-
      This summary supports intellectual disability in the classic surviving cases; the separately cited
      deletion-associated case limits its universal wording.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: He has had initial mild motor delays, but the propositus’ neurodevelopmental progress was normal.
    explanation: The deletion-associated Beare-Stevenson-like case limits claims of universal intellectual disability across the broader clinical spectrum.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
- name: Simplified gyral pattern
  category: Neurologic
  description: Reported on MRI in two p.Tyr375Cys patients.
  evidence:
  - reference: PMID:21397175
    reference_title: 'Beare-Stevenson syndrome: two Dutch patients with cerebral abnormalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging.
    explanation: Cranial MRI in the reported patients directly showed simplified gyration.
  phenotype_term:
    preferred_term: Simplified gyral pattern
    term:
      id: HP:0009879
      label: Simplified gyral pattern
- name: Abnormal posterior cranial fossa morphology
  category: Neurologic
  description: Posterior fossa abnormality was reported in two patients; the available abstract does not specify its morphology.
  evidence:
  - reference: PMID:21397175
    reference_title: 'Beare-Stevenson syndrome: two Dutch patients with cerebral abnormalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging.
    explanation: The MRI abstract names an abnormal posterior fossa without specifying its morphology.
  phenotype_term:
    preferred_term: Abnormal posterior cranial fossa morphology
    term:
      id: HP:0000932
      label: Abnormal posterior cranial fossa morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
- name: Abnormal hippocampal morphology
  category: Neurologic
  description: Hippocampal abnormality was reported in two patients; no specific form is defined in the available abstract.
  evidence:
  - reference: PMID:21397175
    reference_title: 'Beare-Stevenson syndrome: two Dutch patients with cerebral abnormalities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging.
    explanation: The abstract names a hippocampal abnormality without sufficient detail for a narrower binding.
  phenotype_term:
    preferred_term: Abnormal hippocampus morphology
    term:
      id: HP:0025100
      label: Abnormal hippocampus morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
- name: Brachycephaly
  category: Craniofacial
  description: Brachycephaly was observed after birth in the p.Phe276Cys case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis, hypospadias, large umbilical stump, facial hemangioma, and limited movement (Table 1A).
    explanation: The postnatal clinical genetics examination confirms brachycephaly in the prenatal case.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
- name: Hypertelorism
  category: Craniofacial
  description: Hypertelorism was documented in the p.Phe276Cys case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis, hypospadias, large umbilical stump, facial hemangioma, and limited movement (Table 1A).
    explanation: The examination explicitly lists hypertelorism in the p.Phe276Cys patient.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
- name: Micropenis
  category: Genitourinary
  description: Micropenis was observed postnatally in the p.Phe276Cys case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis, hypospadias, large umbilical stump, facial hemangioma, and limited movement (Table 1A).
    explanation: The postnatal examination confirms the genital finding suspected on prenatal imaging.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
- name: 2-3 toe syndactyly
  category: Limbs
  description: Lower-extremity 2-3 syndactyly was observed in the p.Phe276Cys case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis, hypospadias, large umbilical stump, facial hemangioma, and limited movement (Table 1A).
    explanation: The lower-extremity second-to-third digit fusion is explicitly listed on examination.
  phenotype_term:
    preferred_term: 2-3 toe syndactyly
    term:
      id: HP:0004691
      label: 2-3 toe syndactyly
- name: Facial hemangioma
  category: Dermatologic
  description: A facial hemangioma was reported in the p.Phe276Cys case; its histologic subtype was not specified.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical genetics evaluation noted brachycephaly, skin redundancy, proptosis, hypertelorism, natal teeth, cutis gyrata, edematous ears with linear divets, large/contracted left thumb, possible contractures of the digits, lower extremity 2‐3 syndactyly, right nipple skin tag, micropenis, hypospadias, large umbilical stump, facial hemangioma, and limited movement (Table 1A).
    explanation: The facial vascular lesion was recorded on clinical examination in this single patient.
  phenotype_term:
    preferred_term: Hemangioma
    term:
      id: HP:0001028
      label: Hemangioma
- name: Macroglossia
  category: Craniofacial
  description: Macroglossia contributed to difficult neonatal intubation in the p.Phe276Cys case and was also observed in a p.Tyr375Cys child.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which was difficult due to significant macroglossia and micrognathia.
    explanation: >-
      The neonatal intubation account identifies tongue enlargement as one contributor to airway difficulty.
  - evidence_source: HUMAN_CLINICAL
    explanation: The longitudinal airway case also documents macroglossia in a child with p.Tyr375Cys.
    reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    snippet: Her characteristic craniofacial features included ocular proptosis, a narrow and protruding forehead, midface hypoplasia, macroglossia, and cutis gyrata, which had been unclear at birth but had gradually become apparent (Figure 3).
    supports: SUPPORT
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
- name: Micrognathia
  category: Craniofacial
  description: Micrognathia can contribute to airway difficulty; it was reported in the p.Phe276Cys infant and in a later surgical case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which was difficult due to significant macroglossia and micrognathia.
    explanation: The same intubation account identifies a small mandible in addition to macroglossia.
  - reference: PMID:38445861
    reference_title: Pitfall of Monobloc Advancement in Beare-Stevenson Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This was because midfacial hypoplasia was so severe that it was hard to notice, but there was also micrognathia.
    explanation: Coexisting micrognathia was described in the surgical case with persistent tracheostomy dependence.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
- name: Low-set ears
  category: Craniofacial
  description: Low-set ears were described on fetal imaging in the p.Phe276Cys case and on examination in the autopsy case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low set ears), skeletal (thoracolumbar segmentation anomalies, pectus excavatum), gastrointestinal (hepatomegaly, possible esophageal atresia/tracheoesophageal fistula), genitourinary (left pelvic kidney, flattened left adrenal gland, non‐visualized perineum/anal region, hypospadias, microphallus), and enlarged thymus.
    explanation: Fetal ultrasound records elongated, low-set ears in the p.Phe276Cys case.
  - evidence_source: HUMAN_CLINICAL
    explanation: The autopsy report explicitly records low-set ears on examination, complementing the separate prenatal ultrasound observation.
    reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    snippet: Additional findings in- cluded low-set ears, a prominent umbilical stump, and broad fingers and toes (Fig. 1).
    supports: SUPPORT
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
- name: Pectus excavatum
  category: Thoracic
  description: Pectus excavatum was identified on prenatal ultrasound in the p.Phe276Cys case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low set ears), skeletal (thoracolumbar segmentation anomalies, pectus excavatum), gastrointestinal (hepatomegaly, possible esophageal atresia/tracheoesophageal fistula), genitourinary (left pelvic kidney, flattened left adrenal gland, non‐visualized perineum/anal region, hypospadias, microphallus), and enlarged thymus.
    explanation: Fetal ultrasound explicitly identifies the chest-wall depression.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
- name: Hepatomegaly
  category: Gastrointestinal
  description: Hepatomegaly was identified on prenatal ultrasound in the p.Phe276Cys case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low set ears), skeletal (thoracolumbar segmentation anomalies, pectus excavatum), gastrointestinal (hepatomegaly, possible esophageal atresia/tracheoesophageal fistula), genitourinary (left pelvic kidney, flattened left adrenal gland, non‐visualized perineum/anal region, hypospadias, microphallus), and enlarged thymus.
    explanation: The prenatal imaging list includes liver enlargement, without proving its cause.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
- name: Pelvic kidney
  category: Genitourinary
  description: A left pelvic kidney was identified on prenatal ultrasound in the p.Phe276Cys case.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low set ears), skeletal (thoracolumbar segmentation anomalies, pectus excavatum), gastrointestinal (hepatomegaly, possible esophageal atresia/tracheoesophageal fistula), genitourinary (left pelvic kidney, flattened left adrenal gland, non‐visualized perineum/anal region, hypospadias, microphallus), and enlarged thymus.
    explanation: Ultrasound localizes the left kidney to the pelvis.
  phenotype_term:
    preferred_term: Pelvic kidney
    term:
      id: HP:0000125
      label: Pelvic kidney
- name: Thymic enlargement
  category: Immunologic
  description: An enlarged thymus was described on fetal imaging and coded as thymus hyperplasia by the prenatal report; histology was not reported.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ultrasound at our center at 25 weeks 2 days gestation revealed multiple anomalies including craniofacial (brachycephaly, focal regions of abnormal/absent calvarial ossification, midface hypoplasia, depressed nasal bridge, macroglossia, hypertelorism, proptosis, unopposed eyelids, elongated/low set ears), skeletal (thoracolumbar segmentation anomalies, pectus excavatum), gastrointestinal (hepatomegaly, possible esophageal atresia/tracheoesophageal fistula), genitourinary (left pelvic kidney, flattened left adrenal gland, non‐visualized perineum/anal region, hypospadias, microphallus), and enlarged thymus.
    explanation: >-
      The fetal imaging report describes an enlarged thymus; no specific immunologic consequence is inferred.
  phenotype_term:
    preferred_term: Thymus hyperplasia
    term:
      id: HP:0010516
      label: Thymus hyperplasia
- name: Hydrops fetalis
  category: Prenatal
  description: Hydrops with skin edema, mild ascites and a thickened nuchal fold prompted referral in the p.Phe276Cys pregnancy.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: patient referred for hydrops fetalis (skin edema around the fetal cranium and face extending down to the abdomen, mild ascites, thickened nuchal fold measuring up to 18 mm) and multiple congenital anomalies.
    explanation: The referral description documents edema and ascites constituting the fetal hydrops presentation.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
- name: Increased nuchal translucency
  category: Prenatal
  description: First-trimester nuchal translucency measured 7 mm in the p.Phe276Cys pregnancy.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: First trimester ultrasound identified an increased nuchal translucency (7 mm) (Table 1A).
    explanation: The first-trimester measurement directly supports increased nuchal translucency.
  phenotype_term:
    preferred_term: Increased nuchal translucency
    term:
      id: HP:0010880
      label: Increased nuchal translucency
- name: Cleft soft palate
  category: Craniofacial
  description: Cleft soft palate was observed in the p.Tyr375Cys child followed with serial airway imaging.
  evidence:
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she presented with a cloverleaf‐like skull, bulging anterior fontanelle, proptosis, maxillary hypoplasia, cleft soft palate, perineal skin defects, and broad toes (Figure 1).
    explanation: The neonatal examination specifies the soft palate as the site of the cleft.
  phenotype_term:
    preferred_term: Cleft soft palate
    term:
      id: HP:0000185
      label: Cleft soft palate
- name: Tracheomalacia
  category: Respiratory
  description: Tracheomalacia contributed to neonatal respiratory distress in the p.Tyr375Cys airway case.
  evidence:
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Due to respiratory distress secondary to upper airway obstruction and tracheomalacia, the patient was admitted to the neonatal intensive care unit and she received high-flow nasal support.
    explanation: The admission account names tracheomalacia separately from upper-airway obstruction.
  phenotype_term:
    preferred_term: Tracheomalacia
    term:
      id: HP:0002779
      label: Tracheomalacia
- name: Broad toes
  category: Limbs
  description: Broad toes were observed in the p.Tyr375Cys airway case.
  evidence:
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she presented with a cloverleaf‐like skull, bulging anterior fontanelle, proptosis, maxillary hypoplasia, cleft soft palate, perineal skin defects, and broad toes (Figure 1).
    explanation: The neonatal examination includes broad toes, without establishing a population frequency.
  phenotype_term:
    preferred_term: Broad toe
    term:
      id: HP:0001837
      label: Broad toe
- name: External auditory canal atresia
  category: Audiologic
  description: Bilateral external auditory canal atresia in the child with a de novo FGFR2 deletion and Beare-Stevenson-like syndrome.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: complete atresia of the external ear canals
    explanation: The deletion-associated case explicitly records complete canal atresia.
  phenotype_term:
    preferred_term: Atresia of the external auditory canal
    term:
      id: HP:0000413
      label: Atresia of the external auditory canal
- name: Mixed hearing loss
  category: Audiologic
  description: Mild-to-moderate mixed hearing loss requiring hearing aids in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bilateral choanal stenosis and a mild to moderate mixed hearing loss requiring hearing aids were present.
    explanation: >-
      The source distinguishes mixed hearing loss from purely conductive loss in the deletion-associated
      patient.
  phenotype_term:
    preferred_term: Mixed hearing impairment
    term:
      id: HP:0000410
      label: Mixed hearing impairment
- name: Optic nerve hypoplasia
  category: Ophthalmologic
  description: Mild optic nerve hypoplasia in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmological examination detected mild optic nerve hypoplasia and high myopia with astigmatism requiring corrective lenses.
    explanation: Ophthalmologic examination directly identifies mild optic nerve hypoplasia.
  phenotype_term:
    preferred_term: Optic nerve hypoplasia
    term:
      id: HP:0000609
      label: Optic nerve hypoplasia
- name: High myopia
  category: Ophthalmologic
  description: High myopia requiring corrective lenses in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmological examination detected mild optic nerve hypoplasia and high myopia with astigmatism requiring corrective lenses.
    explanation: The ophthalmologic examination records high myopia requiring corrective lenses.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
- name: Astigmatism
  category: Ophthalmologic
  description: Astigmatism requiring corrective lenses in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmological examination detected mild optic nerve hypoplasia and high myopia with astigmatism requiring corrective lenses.
    explanation: The same examination documents astigmatism in addition to high myopia.
  phenotype_term:
    preferred_term: Astigmatism
    term:
      id: HP:0000483
      label: Astigmatism
- name: Gingival overgrowth
  category: Dental
  description: Gingival hyperplasia in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There were multiple neonatal teeth, gingival hyperplasia and a high-arched, narrow palate with a bifid uvula.
    explanation: The source uses gingival hyperplasia for the observed gum enlargement.
  phenotype_term:
    preferred_term: Gingival overgrowth
    term:
      id: HP:0000212
      label: Gingival overgrowth
- name: High narrow palate
  category: Craniofacial
  description: A high narrow palate in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There were multiple neonatal teeth, gingival hyperplasia and a high-arched, narrow palate with a bifid uvula.
    explanation: Both height and narrowing of the palate are explicitly described.
  phenotype_term:
    preferred_term: High, narrow palate
    term:
      id: HP:0002705
      label: High, narrow palate
- name: Bifid uvula
  category: Craniofacial
  description: Bifid uvula in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There were multiple neonatal teeth, gingival hyperplasia and a high-arched, narrow palate with a bifid uvula.
    explanation: The oral examination separately identifies a bifid uvula.
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
- name: Broad thumbs
  category: Limbs
  description: Slightly broad thumbs in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Examination of the hands and feet showed redundant palmar and plantar skin, slightly broad thumbs and halluces and mild skin syndactyly of the second and third toes with overlapping fourth toes.
    explanation: The hand-and-foot examination explicitly describes the thumbs as slightly broad.
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
- name: Broad halluces
  category: Limbs
  description: Slightly broad halluces in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Examination of the hands and feet showed redundant palmar and plantar skin, slightly broad thumbs and halluces and mild skin syndactyly of the second and third toes with overlapping fourth toes.
    explanation: The same examination separately identifies slightly broad great toes.
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
- name: Strabismus
  category: Ophthalmologic
  description: Divergent strabismus in the deletion-associated Beare-Stevenson-like case.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypertelorism with a divergent strabismus
    explanation: The report specifies divergent strabismus in the deletion-associated patient.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
- name: Caudal appendage
  category: Skeletal
  description: A caudal appendage was reported in a molecularly confirmed p.Tyr375Cys patient.
  evidence:
  - reference: PMID:16531735
    reference_title: A case of Beare-Stevenson syndrome with a broad spectrum of features and a review of the FGFR2 Y375C mutation phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We present a case of Beare-Stevenson syndrome with a broad range of phenotypic features including craniosynostosis, cutis gyrata, choanal stenosis, bifid scrotum with perineal hypospadias and a caudal appendage.
    explanation: The clinical case abstract explicitly includes a caudal appendage in its observed phenotype.
  phenotype_term:
    preferred_term: Caudal appendage
    term:
      id: HP:0002825
      label: Caudal appendage
- name: Small nails
  category: Nails
  description: Nail hypoplasia is recorded in the report’s genotype-stratified clinical compilation and in its deletion-associated patient.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Nail hypoplasia | 1/9 | 2/2 | + |'
    explanation: Table I records nail hypoplasia in the historical p.Tyr375Cys/p.Ser372Cys groups and the propositus; no population frequency is inferred.
  phenotype_term:
    preferred_term: Small nail
    term:
      id: HP:0001792
      label: Small nail
- name: Hypoplastic labia minora
  category: Genitourinary
  description: Hypoplastic labia minora are recorded in the female p.Tyr375Cys and p.Ser372Cys groups of the clinical compilation.
  evidence:
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Hypoplastic labia minora | 1/5 | 1/1 | NA |'
    explanation: The genotype-stratified table records this finding in historical female cases; the male deletion patient is not applicable.
  phenotype_term:
    preferred_term: Hypoplastic labia minora
    term:
      id: HP:0000064
      label: Hypoplastic labia minora
- name: Short small intestine
  category: Gastrointestinal
  description: At autopsy, one p.Tyr375Cys child had a 75 cm small intestine, shorter than age- and weight-matched reference values. The report did not establish whether impaired development, chronic illness or other factors accounted for the finding, so congenital shortened-intestine HPO binding is not asserted.
  evidence:
  - reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The lengths of the total intestinal tract, small intestine, and colon were 120, 75, and 45 cm, respec- tively (Table 1B).
    explanation: The autopsy measurement supports a short small intestine but does not establish congenital origin.
- name: Ascites
  category: Gastrointestinal
  description: Progressive refractory ascites occurred in the p.Tyr375Cys autopsy case. The cause remained uncertain.
  evidence:
  - reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abdominal distention due to ascites gradually wors- ened from 12 months of age. Tragically, the patient died of severe, uncontrollable ascites and respiratory failure at 2 years and 2 months of age (Fig. 3)." # codespell:ignore-line
    explanation: The clinical course documents progressively worsening ascites before death in one patient.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
- name: Broad fingers
  category: Limbs
  description: Broad fingers were noted on examination in the p.Tyr375Cys autopsy case.
  evidence:
  - reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional findings in- cluded low-set ears, a prominent umbilical stump, and broad fingers and toes (Fig. 1).
    explanation: The autopsy case examination explicitly identifies broad fingers.
  phenotype_term:
    preferred_term: Broad finger
    term:
      id: HP:0001500
      label: Broad finger
genetic:
- name: FGFR2-associated allelic spectrum
  gene_term:
    preferred_term: FGFR2
    term:
      id: hgnc:3689
      label: FGFR2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Recurrent p.Tyr375Cys and p.Ser372Cys substitutions are accompanied by rarer reported
    alleles. The
    2015 abstract reports p.Ser372Tyr, while later case compilations list p.Ser372Cys
    for that patient;
    without the primary full-text sequence result this discrepancy should not be treated
    as a confirmed
    additional mechanism. A de novo p.Phe276Cys variant was classified as likely pathogenic
    in 2026. The
    c.859del63 deletion was reported in a Beare-Stevenson-like presentation; its proposed
    splice effect
    was not demonstrated.
  variants:
  - name: c.1124A>G (p.Tyr375Cys)
    description: >-
      Recurrent p.Tyr375Cys substitution near the membrane. The c.1124A>G notation
      is documented on NM_000141.5
      in the 2026 autopsy report; mouse p.Tyr394Cys is the corresponding experimental
      allele.
    evidence:
    - reference: PMID:12900900
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The molecular analysis of these patients identified the mutation Tyr375Cys in the FGFR2 gene.
      explanation: Molecular confirmation of the recurrent transmembrane allele.
      reference_title: 'Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis.'
    - reference: PMID:41882888
      reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Trio-based whole-exome sequencing and a filtering analy- sis subsequently identified a c.1124A>G pathogenic variant in FGFR2 (NM_000141.5), resulting in a p.Tyr375Cys sub- stitution.
      explanation: The report identifies c.1124A>G on NM_000141.5 and its p.Tyr375Cys consequence; the source line-break hyphens are retained.
  - name: p.Ser372Cys
    description: >-
      The second recurrent allele, at the carboxyl-terminal end of the Ig-III to transmembrane
      linker.
    evidence:
    - reference: PMID:18247426
      reference_title: Second case of Beare-Stevenson syndrome with an FGFR2 Ser372Cys mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Reported causes are an FGFR2 Tyr375Cys mutation in nine cases and an FGFR2 Ser372Cys mutation in one case. Here, we report on a second patient with the FGFR2 Ser372Cys mutation.
      explanation: >-
        A second independent report of the p.Ser372Cys allele, establishing it as
        recurrent rather than
        private, and quantifying the relative frequency of the two recurrent alleles
        at the time: nine
        p.Tyr375Cys to two p.Ser372Cys.
  - name: c.827T>G (p.Phe276Cys)
    description: Heterozygous de novo variant classified as likely pathogenic in one fetus with a postnatally concordant BSS phenotype; no functional assay was reported.
    evidence:
    - reference: PMID:41775672
      reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: GS resulted at 30 weeks 5 days and revealed a heterozygous, de novo, likely pathogenic FGFR2 variant (c.827 T > G, p.Phe276Cys) (Table 1B).
      explanation: The prenatal variant was classified as likely pathogenic; this case report does not experimentally establish disulfide bonding or gain of function.
  - name: c.859del63 (reported nomenclature)
    description: De novo 63-nucleotide intragenic deletion predicting loss of 21 amino acids, reported in a child with Beare-Stevenson-like syndrome. The proposed altered-splicing mechanism remains unproven.
    evidence:
    - reference: PMID:19610084
      reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: a de novo, intragenic deletion of 63 nucleotides starting in exon 8 of the gene, c.859del63, was detected (Fig. 2). This deletion predicts the loss of 21 amino acids from the FGFR2 protein.
      explanation: Direct molecular identification in the Beare-Stevenson-like case; preserve the authors’ nomenclature without inventing a normalized HGVS interval.
    - reference: PMID:19610084
      reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A similar activating mechanism, although unproven, could be present in this child.
      explanation: The splicing-based gain-of-function interpretation was proposed by analogy, not established by a functional assay.
  evidence:
  - reference: PMID:8696350
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome.
    explanation: The original assignment of the syndrome to FGFR2.
    reference_title: Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report on two additional patients with molecularly confirmed BSS, one each with p.Ser372Tyr and p.Tyr375Cys mutations in FGFR2.
    explanation: >-
      The abstract reports p.Ser372Tyr; a later case table reports p.Ser372Cys. This
      unresolved nomenclature
      discrepancy is retained explicitly rather than interpreted as established non-cysteine
      disease biology.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
progression:
- phase: Infancy
  age_range: Birth through the first year
  notes: >-
    Published case literature records respiratory distress and deaths in early infancy.
    A 2024 surgical
    case report summarizes historical first-year mortality as about half, but this
    selected literature
    is not a contemporary survival cohort. Multilevel airway obstruction, tracheal
    cartilage abnormalities
    and neurologic complications require individual assessment.
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Beare-Stevenson syndrome (BSS) is a rare FGFR2-associated craniosynostosis syndrome with a higher rate of sudden unexplained death than related conditions such as Apert, Pfeiffer, and Crouzon syndromes.
    explanation: >-
      States the excess mortality relative to the other members of the FGFR2 craniosynostosis
      group, which
      is the entry's central clinical claim.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  - reference: PMID:38445861
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Half of patients with BSS died within the first year of life due to cardiorespiratory arrest or unexpected sudden death.
    explanation: A historical summary in a surgical case report, not a prospective BSS survival estimate.
    reference_title: Pitfall of Monobloc Advancement in Beare-Stevenson Syndrome.
  - reference: PMID:12900900
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: They were born with respiratory distress and were connected to mechanical ventilation for ventilatory support. Both of them died in 50 days after birth due to secondary complications.
    explanation: A concrete instance of the early respiratory course in two confirmed patients.
    reference_title: 'Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis.'
- phase: Childhood
  age_range: Beyond infancy, in survivors
  notes: >-
    Surviving children may require staged airway, cranial and midface procedures and
    developmental support.
    An eight-year-old survivor is described in the 2024 surgical report. Airway cartilage
    deformation
    and Chiari-related tonsillar herniation can progress during childhood, as observed
    in a three-year-old
    with p.Tyr375Cys.
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy.
    explanation: The developmental outcome that characterizes the surviving group.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  - reference: PMID:38445861
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We currently have an 8-year-old patient who is being followed up. She underwent tracheostomy, cranioplasty, and shunting.
    explanation: Documents survival beyond infancy and the staged surgical burden.
    reference_title: Pitfall of Monobloc Advancement in Beare-Stevenson Syndrome.
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 3 years of age, rigid bronchoscopy revealed progressive tracheal cartilage deformity with inward protrusion.
    explanation: Serial imaging demonstrates progression in one child; it does not define the course of all BSS sleeves.
treatments:
- name: Tracheostomy for clinically significant airway obstruction
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Airway support may require tracheostomy, with ventilation when indicated by the
    level and severity
    of obstruction. A tracheal cartilaginous sleeve remains present after tracheostomy;
    progressive deformation,
    tube malposition and granulation require continued specialist surveillance.
  treatment_term:
    preferred_term: Tracheostomy
    term:
      id: NCIT:C15341
      label: Tracheotomy
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This association and our experience suggests that BSS patients be evaluated for tracheal cartilaginous sleeve to prevent airway compromise.
    explanation: The authors' explicit surveillance recommendation.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Importantly, sudden and life-threatening airway obstruction can occur despite the presence of a tracheostomy tube due to severe deformity of the tracheal cartilage.
    explanation: Tracheostomy does not remove the structural lesion or eliminate airway risk.
- name: Cranial vault expansion
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Cranial expansion addresses craniosynostosis and inadequate intracranial volume.
    GeneReviews recommends
    repair of multisuture synostosis generally within the first year, with timing
    and technique guided
    by anatomy, intracranial pressure and respiratory status. The sequence is individualized
    rather than
    fixed by one published surgical case.
  treatment_term:
    preferred_term: Cranial vault expansion
    term:
      id: NCIT:C15214
      label: Craniotomy
  target_phenotypes:
  - preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:42495986
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 2 months of age, she underwent a ventriculoperitoneal shunt placement, followed by occipital cranial expansion at 1 year and fronto-orbital distraction at 2 years of age.
    explanation: Documents the staged sequence and its timing in a BSS patient.
    reference_title: First Successful Le Fort III Distraction in a Patient With Beare-Stevenson Cutis Gyrata Syndrome.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In general, multisuture craniosynostosis should be surgically repaired in 1st yr of life.
    explanation: The FGFR overview provides general timing, qualified by the individual anatomy and clinical status.
    quote_role: REVIEW_SYNTHESIS
- name: Midface advancement (Le Fort III distraction)
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >
    Halo-type external distraction osteogenesis to advance the severely hypoplastic
    midface, correcting
    proptosis and occlusion. The first successful Le Fort III distraction in BSS was
    reported in 2026
    in a 5-year-old, achieving roughly 25 mm of distraction without major complications
    and sustained
    improvement at two years. Reported experience with the alternative monobloc advancement
    is more cautionary:
    in one BSS patient the temporal fossa was too narrow for the procedure to work
    well, and unrecognized
    micrognathia meant decannulation remained impossible despite the advancement.
    Prior shunt tubing and
    skull defects constrain the operative approach.
  treatment_term:
    preferred_term: Midface advancement
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  - preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:42495986
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two uneventful years after surgery, the patient showed significant improvements in proptosis, occlusion, and facial profile, with an excellent clinical course.
    explanation: Medium-term outcome of the procedure.
    reference_title: First Successful Le Fort III Distraction in a Patient With Beare-Stevenson Cutis Gyrata Syndrome.
  - reference: PMID:38445861
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, even though midface advancement, it was difficult to remove tracheostomy. This was because midfacial hypoplasia was so severe that it was hard to notice, but there was also micrognathia.
    explanation: >-
      The counter-case: midface advancement did not achieve decannulation, because
      coexisting micrognathia
      was masked by the severity of the midface hypoplasia.
    reference_title: Pitfall of Monobloc Advancement in Beare-Stevenson Syndrome.
- name: Cerebrospinal fluid diversion for hydrocephalus
  description: Ventriculoperitoneal shunting has been used for progressive hydrocephalus in reported patients. Indication and timing require neurosurgical assessment.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Ventriculoperitoneal shunt placement
    term:
      id: NCIT:C168483
      label: Ventriculoperitoneal Shunt Placement
  target_phenotypes:
  - preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a ventriculoperitoneal shunt was placed at 6 months of age to treat hydrocephalus.
    explanation: Case-level use of CSF diversion in molecularly confirmed BSS.
- name: Airway assessment and tracheostomy surveillance
  description: Assess multilevel obstruction with otolaryngology. The FGFR overview advises operative airway evaluation at the first anesthetic, or during infancy if no procedure is planned, because a sleeve may otherwise be missed. Continued evaluation after tracheostomy should account for progressive cartilage deformation, tube position and granulation. The optimal repeat-endoscopy schedule is individualized.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: eval should occur in infancy because of risk of sudden death if tracheal cartilaginous sleeve is present.
    explanation: GeneReviews Table 6 supports infant airway evaluation; it does not prescribe a fixed repeat-bronchoscopy interval.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This case underscores the importance of thorough preoperative airway assessment and meticulous attention to tube placement in patients with BSS and TCS.
    explanation: Direct BSS case evidence for continued airway precautions.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the time of 1st anesthesia, performed by otolaryngologist. Craniofacial otolaryngologist should direct timing of operative airway eval if no sedation is planned, but eval should occur in infancy because of risk of sudden death if tracheal cartilaginous sleeve is present.
    explanation: GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.
    quote_role: REVIEW_SYNTHESIS
- name: Sleep-disordered breathing surveillance
  description: Evaluate sleep-apnea symptoms at least every three months during infancy and annually thereafter under the FGFR overview, with polysomnography when indicated. Central apnea can prompt evaluation for Chiari I malformation. The choice of respiratory support is individualized; prolonged mask pressure from CPAP or BiPAP can worsen midface retrusion.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Avoid use of CPAP/BiPAP for long-term treatment of sleep apnea when possible, as pressure on midface exacerbates midface retrusion.
    explanation: This is an FGFR craniosynostosis precaution, not a prohibition on necessary ventilation.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical eval for symptoms of sleep apnea At least every 3 mos in 1st year & annually thereafter
    explanation: GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: OTHER
- name: Ocular protection and ophthalmic follow-up
  description: Assess corneal exposure, globe protection, eye alignment and optic nerves. GeneReviews recommends at least annual ophthalmic review, with urgent assessment for concerns. Inadequate lid closure can require lubrication, and severe exposure or globe subluxation may require tarsorrhaphy. Protective eyewear may be appropriate for activities posing an eye-injury risk.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early initiation of topical eye lubrication if inadequate lid closure
    explanation: The FGFR management table supports ocular-surface protection in patients with proptosis.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmologic exam of optic nerves; eval for sclerocornea, orbital protection, strabismus &/or amblyopia At least annually, & urgently if any concern arises
    explanation: GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with exophthalmos may require protective eyewear during activities with risk of eye injury (e.g., ball sports).
    explanation: The precaution applies when proptosis increases eye-injury risk.
    quote_role: REVIEW_SYNTHESIS
- name: Audiologic surveillance and hearing support
  description: Evaluate hearing at diagnosis and at least annually. Conductive hearing loss is part of the BSS phenotype; hearing aids, bone-conduction devices or middle-ear procedures are selected according to the lesion and degree of loss. Optimizing hearing supports language development.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Optimization of hearing facilitates language & communication development.
    explanation: The FGFR treatment table provides the rationale for hearing support.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hearing loss Audiology eval At least annually
    explanation: GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: OTHER
- name: Developmental and speech support
  description: Arrange early-intervention and developmental assessment, with continued speech-language evaluation and individualized therapies. GeneReviews recommends developmental evaluation at least every three months in the first year and annually thereafter; speech assessment begins around 18 months and continues annually, with additional assessment around midface surgery.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Referral for early intervention services. Consider referral to a neurodevelopmental specialist.
    explanation: The initial-evaluation table supports developmental referral rather than assuming a fixed developmental outcome.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neurodevelopment Early intervention &/or neurodevelopmental pediatrics eval At least every 3 mos in 1st yr & annually thereafter
    explanation: GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Speech issues Speech pathology eval • At age ~18 mos, then annually • Additional speech assessments before & after midface surgeries
    explanation: Table 6 specifies speech surveillance beginning around 18 months and around midface surgery.
    quote_role: REVIEW_SYNTHESIS
- name: Feeding assessment and nutritional support
  description: Assess swallowing safety and growth, and provide feeding therapy and enteral support when needed. Reassess swallowing after craniofacial surgery. Persistent poor growth requires evaluation of multiple possible contributors; the short-intestine autopsy observation does not establish a universal mechanism.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Feeding therapy is helpful to assess swallowing safety & support eating by mouth.
    explanation: The FGFR management table supports feeding evaluation and therapy.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Feeding assessment and nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- name: Dental and orthodontic care
  description: Coordinate pediatric dentistry and craniofacial orthodontics for hypodontia, natal teeth, occlusion and eruption problems. Timing of orthodontic and surgical interventions depends on anatomy and growth.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pediatric dental care & eval by craniofacial orthodontist as part of coordinated craniofacial team care
    explanation: Shared FGFR craniosynostosis management is relevant to the documented BSS dental phenotype.
    quote_role: REVIEW_SYNTHESIS
- name: Cervical spine assessment and positioning precautions
  description: Assess cervical fusion and instability, particularly before surgery. If cervical anomalies are present, positioning, intubation technique and activity restrictions should minimize spinal cord injury risk.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with cervical spine anomalies may be at risk for spinal cord injury with hyperextension and may require fiberoptic intubation and/or sports restrictions for activities that pose a risk for head/neck injury.
    explanation: GeneReviews qualifies these precautions by the presence of cervical spine anomalies.
    quote_role: REVIEW_SYNTHESIS
- name: Intracranial pressure surveillance
  description: Monitor head growth and symptoms of raised intracranial pressure. The FGFR overview advises clinical assessment at least every three months during the first year and ophthalmic assessment for papilledema at least annually or with concerning symptoms. Imaging and neurosurgical reassessment are guided by concern for hydrocephalus or Chiari malformation.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eval for signs of ↑ intracranial pressure (e.g., headaches, vomiting)
    explanation: The surveillance table supports symptom-directed reassessment in addition to head-growth monitoring.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical eval at least every 3 mos in 1st year of life; can be done in conjunction w/team visits to assess for craniosynostosis Ophthalmologic exam for papilledema At least annually, & w/any concerning symptoms
    explanation: GeneReviews Table 6 specifies the assessment and timing for FGFR craniosynostosis syndromes.
    quote_role: REVIEW_SYNTHESIS
- name: Genetic counseling and reproductive testing
  description: Offer counseling with parental testing, residual mosaic recurrence risk and the 50% variant-transmission risk for an affected heterozygous individual. Once a familial pathogenic variant is identified, prenatal and preimplantation testing are possible; genotype alone cannot reliably predict individual clinical severity.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Once the FGFR pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
    explanation: GeneReviews supports reproductive testing after variant identification.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Genetic counseling and reproductive testing
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Delivery planning for an affected fetus
  description: Coordinate delivery at a center with pediatric airway, craniofacial and neurosurgical expertise. A clinician skilled in neonatal intubation and resuscitation should be present because airway obstruction can require immediate intervention.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a health care provider skilled in endotracheal intubation and resuscitation should be present at the delivery.
    explanation: GeneReviews recommends specialist preparedness for FGFR craniosynostosis pregnancies.
    quote_role: REVIEW_SYNTHESIS
- name: Psychosocial and family support
  description: Provide ongoing psychosocial assessment, educational support and attention to the family’s practical needs and the child’s social experience. Care goals and elective reconstruction should be individualized.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Psychosocial assessments & mental health support throughout childhood
    explanation: The shared FGFR management table supports longitudinal psychosocial care.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Psychosocial and family support
    term:
      id: NCIT:C15747
      label: Supportive Care
discussions:
- discussion_id: gap_bss_p38_inhibition_translation
  prompt: >-
    What aspects of the p38-inhibitor response in Fgfr2+/Y394C mice could translate
    to human BSS?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#p38 MAPK Activation
  - pathophysiology#Epidermal Hyperplasia
  rationale: >-
    Prenatal systemic SB203580 and early postnatal topical treatment improved epidermal
    hyperplasia in
    mice. Systemic treatment produced slight coronal-suture improvement in a minority
    of pups, but quantitative
    skull morphology did not significantly improve and survival was unchanged. This
    is preclinical evidence
    for pathway involvement, with unresolved developmental timing, efficacy and safety
    in humans. The
    mouse model does not reliably reproduce human tracheal sleeves, so an airway benefit
    cannot be inferred
    from skin rescue.
  evidence:
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Only a small portion of drug-treated mutant pups (20% of mutants from 2 litters) showed slight improvement and increased patency in coronal sutures.
    explanation: The full paper reports limited suture benefit rather than skin-only efficacy.
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: subsequent landmark-based quantification of skull morphology did not show significant differences between treated and untreated mutants
    explanation: Qualitative head-shape observations did not translate to significant quantitative morphology improvement.
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The SB203580 treatment did not improve the survival rate of Fgfr2+/Y394C mice
    explanation: The tested regimen did not improve survival.
  proposed_experiments:
  - experiment_id: exp_bss_p38_developmental_window
    name: Timing and tissue specificity of p38 inhibition
    description: Compare developmental treatment windows and tissue-specific delivery with prespecified skin, suture, growth and survival outcomes; evaluate toxicity and pathways that remain active despite p38 inhibition.
- discussion_id: gap_bss_tracheal_sleeve_frequency_and_causation
  prompt: >-
    Why does the newborn Fgfr2+/Y394C mouse incompletely reproduce the human tracheal
    cartilage phenotype?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Tracheal Cartilage Ring Fusion
  rationale: >-
    Human p.Tyr375Cys cases have tracheal cartilaginous sleeves, but a systematic
    study found none among
    five newborn Fgfr2+/Y394C tracheas examined by whole-mount morphology. Sleeves
    occurred in Fgfr2C342Y
    mice. The small BSS sample, single time point and genetic-background differences
    limit inference.
    This is a demonstrated model limitation, not an experiment that has yet to be
    attempted. Human frequency
    and genotype-specific longitudinal airway risks remain uncertain.
  evidence:
  - reference: PMID:32886384
    reference_title: Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Though TCS has been seen in the human FGFR2Y375C variant, our results suggest that they are not present or are present at low frequency in the mouse model.
    explanation: Directly states the human-model mismatch.
  - reference: PMID:32886384
    reference_title: Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: There were substantially fewer Fgfr2+/Y394C, Fgfr2+/S252W and Fgfr2+/P253R specimens than Fgfr2C342Y/+. It is possible that more severely affected tracheas would have been present in other groups, had greater numbers of specimens been available.
    explanation: The negative finding is limited by sample size.
  proposed_experiments:
  - experiment_id: exp_bss_longitudinal_airway_model
    name: Longitudinal tracheal morphology in larger BSS mouse cohorts
    description: Extend the existing newborn study to larger, age-stratified cohorts and controlled genetic backgrounds, and compare cartilage segmentation and airway dimensions with human serial imaging.
- discussion_id: gap_bss_versus_crouzon_prenatal_discrimination
  prompt: >-
    Can Beare-Stevenson syndrome be distinguished from Crouzon syndrome prenatally,
    given that the two
    overlap in appearance but differ sharply in prognosis?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Premature Cranial Suture Fusion
  rationale: >-
    Prenatal craniosynostosis syndromes overlap. In the 2015 report, cutis gyrata
    was recognized retrospectively
    on prenatal imaging after a postnatal BSS diagnosis. A 2026 case with hydrops
    and multiple anomalies
    used genome sequencing to identify p.Phe276Cys and inform delivery planning before
    craniosynostosis
    was confidently recognized. These cases support combined imaging and molecular
    evaluation; they do
    not establish diagnostic sensitivity or a survival benefit.
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome.
    explanation: A concrete instance of the prenatal misassignment this gap concerns.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth.
    explanation: >-
      The skin finding was missed prospectively in this case; the observation does
      not establish that
      prospective detection is impossible.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Due to phenotypic overlap with Crouzon syndrome, but worse prognosis, we recommend consideration of prenatal 3D ultrasound and mutation testing for patients with suspected Crouzon to allow for prenatal diagnosis of BSS and to enable appropriate genetic counseling and postnatal care.
    explanation: The proposed but untested solution.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  proposed_experiments:
  - experiment_id: exp_bss_prenatal_fgfr2_panel_yield
    name: Diagnostic yield of FGFR2 testing in prenatally suspected Crouzon syndrome
    description: >-
      Apply FGFR2 sequencing to a consecutive series of fetuses with prenatally suspected
      syndromic craniosynostosis
      and report how often the result reassigns the diagnosis to BSS, which is the
      measurement the recommendation
      currently lacks.
references:
- reference: PMID:20301628
  title: FGFR Craniosynostosis Syndromes Overview.
  tags:
  - GeneReviews
  findings: []
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
  tags:
  - GeneReviews
diagnosis:
- name: Clinical assessment and molecular confirmation
  description: Assess cranial sutures, characteristic skin folds, umbilical and anogenital findings, and airway involvement. Because craniosynostosis syndromes overlap and no formal clinical criteria exist, confirm the suspected diagnosis with FGFR2 testing. A craniosynostosis multigene panel or genomic testing can be appropriate when the phenotype is atypical or initial testing is unrevealing. Hotspot-only testing will miss rarer alleles.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing.
    explanation: The FGFR overview recommends molecular confirmation in the overlapping syndromic spectrum.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Approaches include gene-targeted testing (targeted analysis, single-gene testing, multigene panel) or comprehensive genomic testing (exome sequencing, exome array, genome sequencing).
    explanation: Provides the diagnostic options; selection depends on phenotype and prior results.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: was performed on DNA extracted from peripheral blood lymphocytes from the propositus, and was negative.
    explanation: A deletion-associated BSS-like case illustrates the limitation of testing only the two recurrent substitutions.
  - reference: PMID:19610084
    reference_title: Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: targeted re-sequencing for the two previously known FGFR2 mutations, p.Y375 C and p.S372 C
    explanation: The preceding portion of the diagnostic passage identifies the negative assay as testing only the recurrent substitutions.
- name: Prenatal imaging with molecular evaluation
  description: Prenatal ultrasound may identify cloverleaf skull, abnormal skin folding or additional anomalies, but suggestive craniosynostosis can emerge late and imaging findings overlap other syndromes. In one 2026 case, amniocyte genome sequencing identified de novo p.Phe276Cys and informed delivery planning. Molecular results require interpretation with detailed fetal and postnatal phenotyping.
  evidence:
  - reference: PMID:41775672
    reference_title: Prenatally Diagnosed Beare-Stevenson Cutis Gyrata Syndrome With a Novel FGFR2 Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This case expands the genotype–phenotype correlation of BSS and demonstrates the clinical utility of prenatal SNV analysis available via modalities such as GS, given that the genetic diagnosis had direct implications for delivery planning.
    explanation: A single prenatal case supports clinical utility without establishing diagnostic sensitivity.
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth.
    explanation: >-
      The skin finding was missed prospectively in this case; the observation does
      not establish that
      prospective detection is impossible.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
animal_models:
- name: Fgfr2 Y394C heterozygous knock-in mouse
  species: Mus musculus
  genotype: Fgfr2+/Y394C
  background: C57BL/6J
  publication: PMID:22585574
  description: Knock-in of the murine allele corresponding to human p.Tyr375Cys. The model develops epidermal hyperplasia, premature suture fusion, midface hypoplasia, reduced growth and early mortality. p38 inhibition improves skin histology, with limited suture benefit and no survival improvement under the reported regimen.
  modeled_mechanisms:
  - target: Epidermal Hyperplasia
    relationship: RECAPITULATES
    model_scale: TISSUE
    description: Reproduces epidermal acanthosis, papillomatosis and hyperproliferation.
    limitations: Pigmentation was not increased; this is not a complete reproduction of human acanthosis nigricans.
    evidence:
    - reference: PMID:22585574
      reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Histologically, the skin of E16.5, P0, and P5 Fgfr2+/Y394C mice displayed cutis gyrata, epidermal acanthosis, and papillomatosis (Figure 2, A–D).
      explanation: Mouse tissue histology supports the epidermal phenotype.
  - target: Cranial Suture Osteogenic Acceleration
    relationship: RECAPITULATES
    model_scale: TISSUE
    description: Shows increased osteogenic differentiation at coronal sutures.
    limitations: The model carries one recurrent allele and does not establish equivalent effects for every reported FGFR2 variant.
    evidence:
    - reference: PMID:22585574
      reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These data indicated increased osteogenic differentiation as well as abnormal bone growth at the coronal suture in Fgfr2+/Y394 mice.
      explanation: ALP, Runx2 and osteonectin observations support increased differentiation; the source omits the final C in this genotype occurrence.
  - target: Tracheal Cartilage Ring Fusion
    relationship: FAILS_TO_RECAPITULATE
    model_scale: TISSUE
    description: No tracheal sleeves were detected in the newborn Y394C sample in the later comparative study.
    limitations: Whole-mount morphology included five newborn Y394C mice; low-frequency or later abnormalities cannot be excluded.
    evidence:
    - reference: PMID:32886384
      reference_title: Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Though TCS has been seen in the human FGFR2Y375C variant, our results suggest that they are not present or are present at low frequency in the mouse model.
      explanation: Directly states the human-model mismatch.
  evidence:
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: with age the mutants showed reduced growth and early death, usually within 2 weeks
    explanation: The initial model study records growth and survival limitations.
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The SB203580 treatment did not improve the survival rate of Fgfr2+/Y394C mice
    explanation: The tested regimen did not improve survival.
experimental_models:
- name: RCS chondrocytes expressing human FGFR2 Y375C
  experimental_model_type: CELL_LINE
  publication: PMID:22585574
  description: Rat chondrosarcoma cells transfected with wild-type or mutant human FGFR2; receptor and FRS2 phosphorylation were measured.
  modeled_mechanisms:
  - target: Ligand-Independent FGFR2 Activation
    relationship: MEASURES
    model_scale: MOLECULAR
    description: Measures increased phosphorylation with the human disease allele.
    limitations: Heterologous overexpression in a tumor-derived rat cell line does not reproduce endogenous expression in human skin or cranial sutures.
    evidence:
    - reference: PMID:22585574
      reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Our results showed constitutive activation of FGFR2 receptor and FRS2, a major FGFR downstream mediator (52), in rat chondrosarcoma (RCS) chondrocytes transfected with human FGFR2 Y375C as compared with WT FGFR2 (Figure 4A).
      explanation: Direct receptor-signaling measurements in cells expressing the human disease allele.
  evidence:
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our results showed constitutive activation of FGFR2 receptor and FRS2, a major FGFR downstream mediator (52), in rat chondrosarcoma (RCS) chondrocytes transfected with human FGFR2 Y375C as compared with WT FGFR2 (Figure 4A).
    explanation: Direct receptor-signaling measurements in cells expressing the human disease allele.
- name: Primary keratinocytes from Fgfr2 Y394C mice
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:22585574
  description: Mouse-derived epidermal keratinocytes used to assess FGFR2 phosphorylation without added FGF ligand.
  modeled_mechanisms:
  - target: Ligand-Independent FGFR2 Activation
    relationship: MEASURES
    model_scale: MOLECULAR
    description: Measures receptor activation in cells bearing the knock-in allele.
    limitations: Mouse-derived culture is informative about ligand-independent signaling, not human clinical efficacy.
    evidence:
    - reference: PMID:22585574
      reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We confirmed this result in vivo by demonstrating increased phosphorylation of FGFR2 in epidermal keratinocytes derived from our Fgfr2+/Y394C mice without the addition of FGF ligand as compared with that of controls (Supplemental Figure 4), indicating that the Y394C mutation causes constitutive or ligand-independent activation of the receptor.
      explanation: Mouse-derived keratinocytes support ligand-independent activation.
  evidence:
  - reference: PMID:22585574
    reference_title: p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We confirmed this result in vivo by demonstrating increased phosphorylation of FGFR2 in epidermal keratinocytes derived from our Fgfr2+/Y394C mice without the addition of FGF ligand as compared with that of controls (Supplemental Figure 4), indicating that the Y394C mutation causes constitutive or ligand-independent activation of the receptor.
    explanation: Mouse-derived keratinocytes support ligand-independent activation.
histopathology:
- name: Intestinal fibroblast proliferation and smooth-muscle thickening
  description: In one p.Tyr375Cys autopsy case, jejunal tissue showed fibroblast proliferation from the submucosa into muscularis and thickened smooth muscle. A contribution to dysmotility was proposed, but recurrent infection, malnutrition and altered perfusion were potential secondary contributors.
  evidence:
  - reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fibroblast proliferation was observed extending from the submucosal layer to the muscularis, accompanied by marked thick- ening of the smooth muscle.
    explanation: The figure legend describes the tissue finding; causation and generalizability remain uncertain.
- name: Reduced neuronal density and thin superficial myelin
  description: The same autopsy case showed reduced neuronal density and a thin myelin sheath in the superficial brain layer. This isolated histologic observation does not establish a universal primary neurodevelopmental mechanism.
  evidence:
  - reference: PMID:41882888
    reference_title: An Autopsy Case of Beare-Stevenson Cutis Gyrata Syndrome Presenting with an Extremely Short Small Intestine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The brain exhibited hypertrophy, characterized by a reduced neural density and a thin myelin sheath in the superficial layer.
    explanation: Direct autopsy observation in a single severely ill child.
differential_diagnoses:
- name: Crouzon syndrome
  disease_term:
    preferred_term: Crouzon syndrome
    term:
      id: MONDO:0007405
      label: Crouzon syndrome
  description: Craniosynostosis, proptosis and midface retrusion overlap with BSS, including prenatal cloverleaf presentations.
  distinguishing_features:
  - BSS characteristically combines cutis gyrata with umbilical and anogenital findings; skin redundancy can also occur in some Crouzon genotypes, so it is not an absolute discriminator.
  - Detailed phenotyping and molecular testing are needed because the craniofacial appearances overlap.
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome.
    explanation: A concrete instance of the prenatal misassignment this gap concerns.
    reference_title: 'Beare-Stevenson syndrome: two new patients, including a novel finding of tracheal cartilaginous sleeve.'
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Linear skin rugations, deep creases, and redundant scalp skin (similar to those seen in Beare-Stevenson cutis gyrata syndrome) were reported
    explanation: The Crouzon section documents skin overlap, limiting claims that skin folds alone establish BSS.
- name: Pfeiffer syndrome
  disease_term:
    preferred_term: Pfeiffer syndrome
    term:
      id: MONDO:0007043
      label: Pfeiffer syndrome
  description: Severe craniosynostosis, midface hypoplasia, airway abnormalities and broad digits can resemble BSS.
  distinguishing_features:
  - Cutis gyrata may be inconspicuous in infancy; a p.Tyr375Cys child initially suspected to have Pfeiffer syndrome was reassigned to BSS after genetic testing.
  evidence:
  - reference: PMID:41112086
    reference_title: 'Anesthetic Management of Progressive Deformity of Tracheal Cartilaginous Sleeve in a Pediatric Patient With Beare-Stevenson Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This patient was initially suspected to have Pfeiffer syndrome from her clinical features because cutis gyrata (which is indicative of BSS) was not apparent in infancy.
    explanation: A molecularly confirmed case demonstrates the clinical diagnostic overlap.

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References & Deep Research

References

2

PMID:20301628

FGFR Craniosynostosis Syndromes Overview.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf

https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/pdf/Bookshelf_NBK1455.pdf

No top-level findings curated for this source.

Beare-Stevenson Cutis Gyrata Syndrome

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