Beare-Stevenson Cutis Gyrata Syndrome

Mendelian MONDO:0007412 Pathograph 25 Show in embeddings browser FGFR2-related craniosynostosis Craniosynostosis syndrome

Beare-Stevenson cutis gyrata syndrome (BSS) is an ultra-rare autosomal dominant craniosynostosis syndrome caused by heterozygous cysteine-creating gain-of-function variants in FGFR2 — most often p.Tyr375Cys in the transmembrane domain or p.Ser372Cys in the juxtamembrane linker. It combines multisuture craniosynostosis (frequently cloverleaf skull) and midface hypoplasia with a distinctive skin phenotype that no other FGFR2 craniosynostosis syndrome shares: cutis gyrata, furrowed corrugated skin of the scalp, face, palms and soles, together with acanthosis nigricans, skin tags and a prominent umbilical stump. Anogenital anomalies, choanal stenosis, ear defects and dental anomalies complete the picture. BSS occupies a specific position in the FGFR-related skeletal dysplasia family. Mechanistically it belongs with the craniosynostosis arm, but its causal alleles are cysteine substitutions of the kind that produce ligand-independent, disulfide-mediated receptor dimerization — the same activation class that drives thanatophoric dysplasia type 1 on the FGFR3 chondrodysplasia side. It is therefore the member that links the two arms of the group at the level of how the receptor is switched on, rather than by which tissue responds. Clinically the defining fact is prognosis. BSS carries a substantially higher rate of sudden unexplained death than Apert, Pfeiffer or Crouzon syndrome, and roughly half of reported patients die in the first year of life. A tracheal cartilaginous sleeve — a continuous cartilage tube replacing the normal tracheal rings, difficult to detect without direct visualization of the airway and frequently found only at autopsy — is reported in BSS and in other FGFR2 craniosynostosis syndromes, and carries about a 90% risk of death by two years of age without tracheostomy. Because BSS overlaps phenotypically with Crouzon syndrome but has a markedly worse prognosis, distinguishing the two is a consequential diagnostic act rather than a nosological one.

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1
Inheritance
7
Pathophys.
19
Phenotypes
3
Gaps
25
Pathograph
1
Genes
2
Variants
3
Medical Actions
1
References
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Classifications

ISDS Skeletal Nosology
craniosynostosis syndromes
👪

Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant. Every molecularly confirmed case reported to date has been sporadic, arising as a de novo variant in an unaffected family, and advanced paternal age has been noted repeatedly — the pattern expected of a paternal-age-effect FGFR allele, as also seen in Apert and Crouzon syndrome. The practical consequence is that recurrence risk for the parents is low, while the affected individual's own transmission risk would be 50%; survival to reproductive age is rare enough that this has not been observed.
Autosomal dominant inheritance
Show evidence (3 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 original clinical delineation records the sporadic occurrence and the paternal-age observation that later proved characteristic of activating FGFR alleles.
PMID:16531735 SUPPORT Human Clinical
"The paternal age at the time of conception was 62 years consistent with a paternal age effect."
A specific documented instance of the paternal age effect in a molecularly confirmed case.
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Discussions and Knowledge Gaps

3
Does p38 MAPK inhibition, which reverses the skin phenotype in the Fgfr2 Beare-Stevenson mouse, have any prospect of translating to human BSS — and would treating the skin arm matter if the mortality is driven by the airway?
HUMAN MODEL MISMATCH OPEN gap_bss_p38_inhibition_translation
Attached to
pathophysiology#Sustained FGFR2 Signaling with p38 MAPK Activation pathophysiology#Epidermal Hyperplasia and Cutis Gyrata
The Fgfr2 p.Tyr394Cys mouse is an unusually faithful model: it carries the murine equivalent of the commonest human allele and reproduces both arms of the syndrome, epidermal hyperplasia and craniosynostosis. Treating those mice with a p38 kinase inhibitor attenuated the skin abnormalities by returning proliferation and differentiation toward normal, which the authors advance as a therapeutic direction for BSS and for acanthosis nigricans and craniosynostosis generally. Three things stand between that and a human therapy, and they differ in kind rather than degree. First, the demonstrated reversal is of skin; craniosynostosis in a human is established at birth rather than progressive in the way a mouse suture phenotype is, so the window the mouse result occupies may not exist postnatally. Second, systemic p38 inhibition is a broad intervention with no defined dose, route or developmental window for a neonate. Third, and most consequential for how this entry should be read: the cause of death in BSS is airway and cardiorespiratory, and nothing links p38 activity to the tracheal cartilaginous sleeve. A therapy that normalized the skin would leave the survival problem untouched. This should not be curated anywhere as an emerging BSS treatment.
Proposed experiments
Airway phenotype of the Fgfr2 Y394C mouse under p38 inhibition
exp_bss_p38_airway_phenotype
Determine whether the BSS mouse develops a tracheal cartilage abnormality at all, and if so whether p38 inhibition alters it. This is the measurement that would tell whether the p38 axis touches the arm of the syndrome that kills, or only the arm that is visible.
Developmental window for suture rescue
exp_bss_p38_developmental_window
Establish the latest gestational or postnatal point at which p38 inhibition still prevents suture fusion in the model, since a window that closes before birth would rule out postnatal human treatment regardless of efficacy.
Show evidence (3 references)
PMID:22585574 SUPPORT Model Organism
"Treating Fgfr2+/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels."
The rescue result, and the fact that what was reversed is the skin phenotype.
PMID:22585574 SUPPORT Model Organism
"The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis."
The authors' own forward-looking claim, marked PARTIAL because it is a prospect rather than a result.
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."
Establishes that the outcome any BSS therapy must move is cardiorespiratory, which the p38 skin result does not address.
How often does a tracheal cartilaginous sleeve actually occur in Beare-Stevenson syndrome, and is it caused by the FGFR2 variant or merely co-occurring with it?
KNOWLEDGE GAP OPEN gap_bss_tracheal_sleeve_frequency_and_causation
Attached to
pathophysiology#Tracheal Cartilaginous Sleeve and Airway Compromise
Both halves of this question are open, and the entry deliberately stops short of answering either. On frequency: the sleeve is described as often found only incidentally at autopsy because it cannot be diagnosed without direct visualization of the trachea, so every published frequency is a lower bound drawn from a case literature of fewer than thirty patients, most of whom died before any airway endoscopy would have been considered. On causation: the sleeve is reported across FGFR2-related craniosynostosis syndromes, which is consistent with an FGFR2-driven cartilage phenotype but equally consistent with shared ascertainment in severely affected, tracheostomized infants. No model system in the cited literature reproduces it, and the BSS mouse work characterizes skin and calvaria only. This matters practically rather than academically: if the sleeve is FGFR2-driven it should be sought in every patient with a cysteine-class allele, whereas if it tracks severity it should be sought in every severely affected infant regardless of genotype. The surveillance recommendation is the same either way, which is why the entry curates the recommendation as established and the mechanism as open.
Proposed experiments
Prospective airway endoscopy in FGFR2 craniosynostosis
exp_bss_prospective_airway_endoscopy
Direct airway visualization in every infant with a molecularly confirmed FGFR2 craniosynostosis syndrome, reported by genotype, to replace an autopsy-ascertained lower bound with a real frequency and to test whether cysteine-class alleles carry excess risk.
Tracheal cartilage phenotyping in the BSS mouse
exp_fgfr2_tracheal_cartilage_model
Characterize tracheal ring segmentation in the Fgfr2 Y394C mouse, which would establish whether the lesion is a direct consequence of the allele.
Show evidence (2 references)
PMID:25706251 SUPPORT Human Clinical
"Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea."
The ascertainment problem underlying the frequency half of the gap.
PMID:25706251 SUPPORT Human Clinical
"Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy."
The cross-syndrome occurrence that is compatible with either an FGFR2-driven mechanism or shared ascertainment.
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 and Cloverleaf Skull
This is a diagnostic gap with immediate consequences for counselling and delivery planning. Cloverleaf skull identified prenatally in a BSS patient led to an initial concern for Crouzon syndrome, and in that case 3D ultrasound was performed but the cutis gyrata — the feature that separates the two — was visible only on retrospective review after the postnatal diagnosis. Since BSS carries markedly higher mortality than Crouzon syndrome, a prenatal misassignment is not a naming error but a prognostic one. The authors' proposed answer is to add molecular testing to suspected prenatal Crouzon cases rather than to rely on imaging, but no study has tested whether that changes outcomes, and the 2026 prenatal report identified BSS through a presentation — hydrops fetalis with increased nuchal translucency — that a craniofacial-led pathway would not have been triggered by.
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."
Shows that the discriminating feature was present but not prospectively detectable, which is what makes this a gap rather than a training problem.
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 Cysteine-Creating Activating Variant
A de novo heterozygous missense variant in FGFR2 that substitutes a cysteine for the wild-type residue. Two recurrent alleles account for nearly all molecularly confirmed cases: p.Tyr375Cys in the transmembrane domain and p.Ser372Cys at the carboxyl-terminal end of the linker between the third immunoglobulin-like (Ig-III) domain and the transmembrane segment. A p.Ser372Tyr variant and, in a 2026 prenatal case, a p.Phe276Cys variant have also been reported, and the original series noted two clinically typical patients in whom neither recurrent allele was found — so genetic heterogeneity within the clinical syndrome is documented rather than excluded.
FGFR2 hgnc:3689 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGFR2 (hgnc:3689), qualified as gain of function. hgnc:3689 is a gene from the HUGO Gene Nomenclature Committee. ⇑ GAIN OF FUNCTION
transmembrane receptor protein tyrosine kinase activity GO:0004714 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased transmembrane receptor protein tyrosine kinase activity (GO:0004714). GO:0004714 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Ligand-Independent Disulfide-Mediated Receptor Dimerization A newly introduced unpaired cysteine provides a partner for intermolecular disulfide bonding between receptor monomers.
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."
Records that the two recurrent alleles do not account for every clinically diagnosed case, so a negative FGFR2 hotspot result does not exclude the diagnosis.
PMID:41775672 SUPPORT Human Clinical
"This is the first report of a variant at this position (p.Phe276Cys) in association with BSS, thus expanding the known genotype"
A 2026 prenatal case extending the allelic spectrum with a third cysteine-creating substitution, consistent with the shared cysteine mechanism.
Ligand-Independent Disulfide-Mediated Receptor Dimerization
The mechanistic step that makes BSS a cysteine-allele disorder rather than simply another FGFR2 craniosynostosis. A free, unpaired cysteine residue introduced by the variant forms an intermolecular disulfide bond between two receptor monomers, locking them into a covalent dimer and activating the kinase without any FGF ligand present. This is the same activation route used by the extracellular-cysteine alleles of thanatophoric dysplasia type 1 on FGFR3, and it is mechanistically distinct from the Ig-II/III linker alleles of Apert and Muenke syndrome, which instead increase FGF-ligand affinity and alter specificity while leaving the receptor ligand-dependent.
protein homodimerization activity GO:0042803 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased protein homodimerization activity (GO:0042803). GO:0042803 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Sustained FGFR2 Signaling with p38 MAPK Activation Covalently dimerized receptor autophosphorylates and drives sustained downstream signaling in the absence of ligand.
Show evidence (2 references)
PMID:9539778 SUPPORT In Vitro
"Many of these mutations create a free cysteine residue that potentially leads to abnormal disulfide bond formation and receptor activation"
States the cysteine-creating activation mechanism shared by this class of FGFR2 craniosynostosis alleles.
PMID:9539778 SUPPORT In Vitro
"This allows the unbonded cysteine residues to participate in intermolecular disulfide bonding, resulting in constitutive activation of the receptor."
The demonstrated biochemical route from an unpaired cysteine to constitutive, ligand-independent receptor activation.
Sustained FGFR2 Signaling with p38 MAPK Activation
Constitutively dimerized FGFR2 sustains downstream signaling in both skin and calvarial tissue. In the Fgfr2 p.Tyr394Cys mouse — the murine equivalent of the human p.Tyr375Cys allele — ligand-independent receptor phosphorylation is accompanied by activation of the p38 MAPK branch specifically, in both mutant skin and mutant calvaria. p38 is the branch this module's shared MAPK/STAT effector axis is realized through in BSS, and it is the node at which pharmacological rescue has been demonstrated in the model.
p38MAPK cascade GO:0038066 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased p38MAPK cascade (GO:0038066). GO:0038066 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cranial Suture Osteogenic Acceleration Sustained signaling in suture mesenchyme accelerates osteogenic differentiation.
Epidermal Hyperplasia and Cutis Gyrata The same sustained signaling in skin drives keratinocyte hyperproliferation and abnormal differentiation, producing the furrowed skin phenotype.
Show evidence (2 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.
Cranial Suture Osteogenic Acceleration
Premature osteogenic differentiation at the suture margins, driven by abnormal proliferation and differentiation of suture cells rather than by a mechanical or secondary cause.
Osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Premature Cranial Suture Fusion and Cloverleaf Skull
Show evidence (1 reference)
PMID:22585574 SUPPORT Model Organism
"Fgfr2+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation."
Attributes suture closure in the model to abnormal cell proliferation and differentiation, the cellular step this node represents.
Premature Cranial Suture Fusion and Cloverleaf Skull
Multisuture craniosynostosis, in a large fraction of cases severe enough to produce the cloverleaf (Kleeblattschädel) skull. The original clinical series recorded cloverleaf skull in three of four patients with craniosynostosis and noted that outcome tracked with its presence — the earliest statement of what remains the main prognostic split within BSS. Restricted cranial volume drives the associated hydrocephalus, Chiari malformation and proptosis.
cranial suture morphogenesis GO:0060363 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cranial suture morphogenesis (GO:0060363). GO:0060363 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Craniosynostosis
Cloverleaf skull
Hydrocephalus
Chiari malformation
Midface retrusion
Proptosis
Choanal stenosis
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."
Establishes cloverleaf skull as the prognostic discriminator within the syndrome, recognized before the molecular cause was known.
PMID:12900900 SUPPORT Human Clinical
"The radiologic examination showed a cloverleaf-form craniosynostosis."
Independent radiological confirmation in molecularly confirmed p.Tyr375Cys patients.
Epidermal Hyperplasia and Cutis Gyrata
The skin arm, and the feature that names the syndrome. Sustained FGFR2-p38 signaling in the epidermis produces keratinocyte hyperplasia, expressed clinically as cutis gyrata — thickened skin thrown into convoluted, cerebriform folds and furrows — along with acanthosis nigricans and skin tags. The distribution is characteristically wide, involving scalp, forehead, face, preauricular area, neck, trunk, palms and soles. This node is deliberately not given a module `conforms_to` anchor: the FGFR module's consequence nodes cover growth plate and cranial suture, and an epidermal hyperproliferation arm is not among them. Curating it as conforming would assert membership in a node that does not describe it.
Keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
keratinocyte proliferation GO:0043616 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased keratinocyte proliferation (GO:0043616). GO:0043616 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cutis gyrata of scalp
Palmoplantar cutis gyrata
Acanthosis nigricans
Skin tags
Show evidence (2 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.
Tracheal Cartilaginous Sleeve and Airway Compromise
A continuous cartilaginous tube replacing the normal segmented tracheal rings. It is reported in BSS and in other FGFR2-related craniosynostosis syndromes, and it is the leading candidate explanation for the syndrome's excess sudden unexplained death. It is almost impossible to diagnose without direct visualization of the airway, so it is frequently discovered only at autopsy — which means its true frequency in BSS is unknown and is likely underestimated. This node records an association with an identified structural lesion and a management consequence, not a demonstrated causal chain from the FGFR2 allele: no experiment cited here shows that the variant produces the sleeve.
Downstream
Tracheal cartilaginous sleeve
Show evidence (3 references)
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 first report of a tracheal cartilaginous sleeve in BSS, and the proposed link to the syndrome's sudden-death excess — phrased by the authors as a possibility.
PMID:25706251 SUPPORT Human Clinical
"Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy."
Quantifies the mortality risk of an unmanaged sleeve, which is what makes detection actionable rather than descriptive.
PMID:25706251 SUPPORT Human Clinical
"Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea."
The ascertainment problem that makes any frequency estimate in BSS a lower bound.
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Pathograph

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

19
Eye 1
Proptosis HP:0000520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proptosis (HP:0000520). HP:0000520 is a phenotype from the Human Phenotype Ontology.
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.
Head and Neck 4
Craniosynostosis HP:0001363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
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.
Cloverleaf skull HP:0002676 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cloverleaf skull (HP:0002676). HP:0002676 is a phenotype from the Human Phenotype Ontology.
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.
Midface retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
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.
Hypodontia HP:0000668 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypodontia (HP:0000668). HP:0000668 is a phenotype from the Human Phenotype Ontology.
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.
Integument 2
Acanthosis nigricans HP:0000956 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acanthosis nigricans (HP:0000956). HP:0000956 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
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.
Skin tags HP:0010609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin tags (HP:0010609). HP:0010609 is a phenotype from the Human Phenotype Ontology.
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.
Nervous System 2
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
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.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
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:21397175 SUPPORT Human Clinical
"The patients exhibited a simplified gyral pattern, an abnormal posterior fossa, and an abnormal hippocampus on cranial magnetic resonance imaging."
Supplies the structural brain findings in two p.Tyr375Cys patients, indicating the delay is not attributable to raised intracranial pressure alone.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 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.
Other 9
Cutis gyrata of scalp HP:0010541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutis gyrata of scalp (HP:0010541). HP:0010541 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 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.
Palmoplantar cutis gyrata HP:0007469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Palmoplantar cutis gyrata (HP:0007469). HP:0007469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12900900 SUPPORT Human Clinical
"Furrowed palms and soles were also observed."
Direct observation in two molecularly confirmed patients.
Abnormal umbilicus morphology HP:0001551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal umbilicus morphology (HP:0001551). HP:0001551 is a phenotype from the Human Phenotype Ontology.
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.
Choanal stenosis HP:0000452 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal stenosis (HP:0000452). HP:0000452 is a phenotype from the Human Phenotype Ontology.
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.
Tracheal cartilaginous sleeve HP:0005347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tracheal cartilaginous sleeve (HP:0005347). HP:0005347 is a phenotype from the Human Phenotype Ontology.
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.
Chiari malformation HP:0002308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari malformation (HP:0002308). HP:0002308 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
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.
Natal tooth HP:0000695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Natal tooth (HP:0000695). HP:0000695 is a phenotype from the Human Phenotype Ontology.
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.
Bifid scrotum HP:0000048 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bifid scrotum (HP:0000048). HP:0000048 is a phenotype from the Human Phenotype Ontology.
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 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Perineal hypospadias (HP:0000051). HP:0000051 is a phenotype from the Human Phenotype Ontology.
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.
🧬

Genetic Associations

1
FGFR2 cysteine-creating gain-of-function variants (Causative)
Gene: FGFR2 hgnc:3689 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FGFR2 (hgnc:3689). hgnc:3689 is a gene from the HUGO Gene Nomenclature Committee. 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."
Extends the allelic series with p.Ser372Tyr, a non-cysteine substitution at the same codon as the recurrent p.Ser372Cys.
Variants (2)
c.1124A>G (p.Tyr375Cys)
The commonest allele, in the transmembrane domain. Reported repeatedly across independent series and populations, and the allele modeled in the Fgfr2 Y394C mouse.
Show evidence (1 reference)
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.
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.
💊

Medical Actions

3
Tracheostomy and airway surveillance for tracheal cartilaginous sleeve
Category: Therapeutic Action: TracheostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Tracheostomy, annotated with Tracheotomy (NCIT:C15341). NCIT:C15341 is a clinical intervention from the NCI Thesaurus. Ontology label: Tracheotomy NCIT:C15341
The intervention with the clearest survival rationale in this syndrome. An unmanaged tracheal cartilaginous sleeve carries about a 90% risk of death by two years of age without tracheostomy, and because the lesion is difficult to detect without direct visualization of the trachea, the recommendation is to evaluate for it actively rather than await symptoms. Tracheostomy in infancy is reported as routine in surgically managed BSS patients.
Mechanism Target:
INHIBITS Tracheal Cartilaginous Sleeve and Airway Compromise — Bypasses the fixed cartilaginous segment, removing the airway obstruction that is the proposed route to sudden death. It does not modify the lesion itself.
Show evidence (1 reference)
PMID:25706251 SUPPORT Human Clinical
"Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy."
The survival difference that motivates tracheostomy.
Show evidence (1 reference)
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.
Cranial vault expansion and cerebrospinal fluid diversion
Category: Therapeutic Action: Cranial vault expansionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cranial vault expansion, annotated with Craniotomy (NCIT:C15214). NCIT:C15214 is a clinical intervention from the NCI Thesaurus. Ontology label: Craniotomy NCIT:C15214
Staged neurosurgical management of the restricted cranial vault: ventriculoperitoneal shunting for hydrocephalus, then posterior or occipital cranial expansion, then fronto-orbital advancement. In the reported course these precede any midface procedure by years.
Target Phenotypes: Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
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.
Midface advancement (Le Fort III distraction)
Category: Therapeutic Action: Midface advancementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Midface advancement, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
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 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology. Proptosis HP:0000520 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proptosis (HP:0000520). HP:0000520 is a phenotype from the Human Phenotype Ontology.
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.
📈

Progression

2
Infancy
Age: Birth through the first year
The period in which the syndrome's excess mortality is concentrated. Roughly half of reported patients die in the first year from cardiorespiratory arrest or unexpected sudden death, and reported deaths have occurred within weeks of birth from respiratory complications requiring mechanical ventilation from birth. A tracheal cartilaginous sleeve is the leading candidate mechanism for the sudden-death excess, but a causal contribution has not been demonstrated and other contributors — severe midface hypoplasia, choanal stenosis, micrognathia and raised intracranial pressure — are present in the same patients.
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."
Quantifies first-year mortality and names the reported mechanisms of death.
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
Survivors face significant developmental delay and a staged surgical course — tracheostomy, cerebrospinal fluid diversion, cranial expansion, and later midface advancement — extending across the first decade. Reported patients have reached at least 8 years of age.
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."
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.
📊

Prevalence

1
Worldwide, published-case literature
Cases In Literature <1 in 1,000,000
No population prevalence estimate exists. The entire evidence base is a few dozen published cases — 21 reported as of 2015, fewer than 30 as of 2024 — which is the practical ceiling on any frequency claim made anywhere in this entry, and the reason no phenotype below is given a frequency band. The authors of both counts state explicitly that this limits prognostication.
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.
{ }

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 (BSS) is an ultra-rare autosomal dominant
  craniosynostosis syndrome caused by heterozygous cysteine-creating gain-of-function
  variants in FGFR2 — most often p.Tyr375Cys in the transmembrane domain or
  p.Ser372Cys in the juxtamembrane linker. It combines multisuture craniosynostosis
  (frequently cloverleaf skull) and midface hypoplasia with a distinctive skin
  phenotype that no other FGFR2 craniosynostosis syndrome shares: cutis gyrata,
  furrowed corrugated skin of the scalp, face, palms and soles, together with
  acanthosis nigricans, skin tags and a prominent umbilical stump. Anogenital
  anomalies, choanal stenosis, ear defects and dental anomalies complete the picture.

  BSS occupies a specific position in the FGFR-related skeletal dysplasia family.
  Mechanistically it belongs with the craniosynostosis arm, but its causal alleles are
  cysteine substitutions of the kind that produce ligand-independent, disulfide-mediated
  receptor dimerization — the same activation class that drives thanatophoric dysplasia
  type 1 on the FGFR3 chondrodysplasia side. It is therefore the member that links the
  two arms of the group at the level of how the receptor is switched on, rather than
  by which tissue responds.

  Clinically the defining fact is prognosis. BSS carries a substantially higher rate of
  sudden unexplained death than Apert, Pfeiffer or Crouzon syndrome, and roughly half of
  reported patients die in the first year of life. A tracheal cartilaginous sleeve — a
  continuous cartilage tube replacing the normal tracheal rings, difficult to detect
  without direct visualization of the airway and frequently found only at autopsy — is
  reported in BSS and in other FGFR2 craniosynostosis syndromes, and carries about a 90%
  risk of death by two years of age without tracheostomy. Because BSS overlaps
  phenotypically with Crouzon syndrome but has a markedly worse prognosis, distinguishing
  the two is a consequential diagnostic act rather than a nosological one.
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. Every molecularly confirmed case reported to date has been
    sporadic, arising as a de novo variant in an unaffected family, and advanced
    paternal age has been noted repeatedly — the pattern expected of a paternal-age-effect
    FGFR allele, as also seen in Apert and Crouzon syndrome. The practical consequence is
    that recurrence risk for the parents is low, while the affected individual's own
    transmission risk would be 50%; survival to reproductive age is rare enough that this
    has not been observed.
  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 original clinical delineation records the sporadic occurrence and the
      paternal-age observation that later proved characteristic of activating FGFR alleles.
  - 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 specific documented instance of the paternal age effect in a molecularly confirmed case.
prevalence:
- population: Worldwide, published-case literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    No population prevalence estimate exists. The entire evidence base is a few dozen
    published cases — 21 reported as of 2015, fewer than 30 as of 2024 — which is the
    practical ceiling on any frequency claim made anywhere in this entry, and the reason
    no phenotype below is given a frequency band. The authors of both counts state
    explicitly that this limits prognostication.
  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 Cysteine-Creating Activating Variant
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "fgfr_gain_of_function_skeletal_dysplasia#Constitutive FGFR Activation"
  description: >
    A de novo heterozygous missense variant in FGFR2 that substitutes a cysteine for the
    wild-type residue. Two recurrent alleles account for nearly all molecularly confirmed
    cases: p.Tyr375Cys in the transmembrane domain and p.Ser372Cys at the carboxyl-terminal
    end of the linker between the third immunoglobulin-like (Ig-III) domain and the
    transmembrane segment. A p.Ser372Tyr variant and, in a 2026 prenatal case, a
    p.Phe276Cys variant have also been reported, and the original series noted two
    clinically typical patients in whom neither recurrent allele was found — so genetic
    heterogeneity within the clinical syndrome is documented rather than excluded.
  gene:
    preferred_term: FGFR2
    description: >-
      Fibroblast growth factor receptor 2, constitutively activated by cysteine-creating
      substitutions in Beare-Stevenson cutis gyrata syndrome.
    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."
    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.
  - reference: PMID:8696350
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two patients, neither of these mutations were found suggesting further genetic heterogeneity."
    explanation: >-
      Records that the two recurrent alleles do not account for every clinically
      diagnosed case, so a negative FGFR2 hotspot result does not exclude the diagnosis.
  - 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 is the first report of a variant at this position (p.Phe276Cys) in association with BSS, thus expanding the known genotype"
    explanation: >-
      A 2026 prenatal case extending the allelic spectrum with a third cysteine-creating
      substitution, consistent with the shared cysteine mechanism.
  downstream:
  - target: Ligand-Independent Disulfide-Mediated Receptor Dimerization
    description: >
      A newly introduced unpaired cysteine provides a partner for intermolecular
      disulfide bonding between receptor monomers.
    causal_link_type: DIRECT

- name: Ligand-Independent Disulfide-Mediated Receptor Dimerization
  biological_scale: MOLECULAR
  description: >
    The mechanistic step that makes BSS a cysteine-allele disorder rather than simply
    another FGFR2 craniosynostosis. A free, unpaired cysteine residue introduced by the
    variant forms an intermolecular disulfide bond between two receptor monomers,
    locking them into a covalent dimer and activating the kinase without any FGF ligand
    present. This is the same activation route used by the extracellular-cysteine alleles
    of thanatophoric dysplasia type 1 on FGFR3, and it is mechanistically distinct from
    the Ig-II/III linker alleles of Apert and Muenke syndrome, which instead increase
    FGF-ligand affinity and alter specificity while leaving the receptor
    ligand-dependent.
  molecular_functions:
  - preferred_term: protein homodimerization activity
    term:
      id: GO:0042803
      label: protein homodimerization activity
    modifier: INCREASED
  evidence:
  - 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: "Many of these mutations create a free cysteine residue that potentially leads to abnormal disulfide bond formation and receptor activation"
    explanation: >-
      States the cysteine-creating activation mechanism shared by this class of FGFR2
      craniosynostosis alleles.
  - reference: PMID:9539778
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This allows the unbonded cysteine residues to participate in intermolecular disulfide bonding, resulting in constitutive activation of the receptor."
    explanation: >-
      The demonstrated biochemical route from an unpaired cysteine to constitutive,
      ligand-independent receptor activation.
  downstream:
  - target: Sustained FGFR2 Signaling with p38 MAPK Activation
    description: >
      Covalently dimerized receptor autophosphorylates and drives sustained downstream
      signaling in the absence of ligand.
    causal_link_type: DIRECT

- name: Sustained FGFR2 Signaling with p38 MAPK Activation
  biological_scale: CELLULAR
  conforms_to: "fgfr_gain_of_function_skeletal_dysplasia#Sustained MAPK/STAT Signaling"
  description: >
    Constitutively dimerized FGFR2 sustains downstream signaling in both skin and
    calvarial tissue. In the Fgfr2 p.Tyr394Cys mouse — the murine equivalent of the human
    p.Tyr375Cys allele — ligand-independent receptor phosphorylation is accompanied by
    activation of the p38 MAPK branch specifically, in both mutant skin and mutant
    calvaria. p38 is the branch this module's shared MAPK/STAT effector axis is realized
    through in BSS, and it is the node at which pharmacological rescue has been
    demonstrated in the model.
  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.
  downstream:
  - target: Cranial Suture Osteogenic Acceleration
    description: >
      Sustained signaling in suture mesenchyme accelerates osteogenic differentiation.
    causal_link_type: DIRECT
  - target: Epidermal Hyperplasia and Cutis Gyrata
    description: >
      The same sustained signaling in skin drives keratinocyte hyperproliferation and
      abnormal differentiation, producing the furrowed skin phenotype.
    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: >
    Premature osteogenic differentiation at the suture margins, driven by abnormal
    proliferation and differentiation of suture cells rather than by a mechanical or
    secondary cause.
  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
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Fgfr2+/Y394C mice exhibited epidermal hyperplasia and premature closure of cranial sutures (craniosynostosis) due to abnormal cell proliferation and differentiation."
    explanation: >-
      Attributes suture closure in the model to abnormal cell proliferation and
      differentiation, the cellular step this node represents.
  downstream:
  - target: Premature Cranial Suture Fusion and Cloverleaf Skull
    causal_link_type: DIRECT

- name: Premature Cranial Suture Fusion and Cloverleaf Skull
  biological_scale: TISSUE
  conforms_to: "fgfr_gain_of_function_skeletal_dysplasia#Premature Suture Fusion and Craniosynostosis"
  description: >
    Multisuture craniosynostosis, in a large fraction of cases severe enough to produce
    the cloverleaf (Kleeblattschädel) skull. The original clinical series recorded
    cloverleaf skull in three of four patients with craniosynostosis and noted that
    outcome tracked with its presence — the earliest statement of what remains the main
    prognostic split within BSS. Restricted cranial volume drives the associated
    hydrocephalus, Chiari malformation and proptosis.
  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: 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: >-
      Establishes cloverleaf skull as the prognostic discriminator within the syndrome,
      recognized before the molecular cause was known.
  - 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
  - target: Hydrocephalus
  - target: Chiari malformation
  - target: Midface retrusion
  - target: Proptosis
  - target: Choanal stenosis

- name: Epidermal Hyperplasia and Cutis Gyrata
  biological_scale: TISSUE
  description: >
    The skin arm, and the feature that names the syndrome. Sustained FGFR2-p38 signaling
    in the epidermis produces keratinocyte hyperplasia, expressed clinically as cutis
    gyrata — thickened skin thrown into convoluted, cerebriform folds and furrows — along
    with acanthosis nigricans and skin tags. The distribution is characteristically wide,
    involving scalp, forehead, face, preauricular area, neck, trunk, palms and soles. This
    node is deliberately not given a module `conforms_to` anchor: the FGFR module's
    consequence nodes cover growth plate and cranial suture, and an epidermal
    hyperproliferation arm is not among them. Curating it as conforming would assert
    membership in a node that does not describe it.
  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: 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.
  downstream:
  - target: Cutis gyrata of scalp
  - target: Palmoplantar cutis gyrata
  - target: Acanthosis nigricans
  - target: Skin tags

- name: Tracheal Cartilaginous Sleeve and Airway Compromise
  biological_scale: TISSUE
  description: >
    A continuous cartilaginous tube replacing the normal segmented tracheal rings. It is
    reported in BSS and in other FGFR2-related craniosynostosis syndromes, and it is the
    leading candidate explanation for the syndrome's excess sudden unexplained death. It
    is almost impossible to diagnose without direct visualization of the airway, so it is
    frequently discovered only at autopsy — which means its true frequency in BSS is
    unknown and is likely underestimated. This node records an association with an
    identified structural lesion and a management consequence, not a demonstrated causal
    chain from the FGFR2 allele: no experiment cited here shows that the variant produces
    the 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 first report of a tracheal cartilaginous sleeve in BSS, and the proposed link
      to the syndrome's sudden-death excess — phrased by the authors as a possibility.
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy."
    explanation: >-
      Quantifies the mortality risk of an unmanaged sleeve, which is what makes detection
      actionable rather than descriptive.
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea."
    explanation: >-
      The ascertainment problem that makes any frequency estimate in BSS a lower bound.
  downstream:
  - target: Tracheal cartilaginous sleeve
phenotypes:
- category: Craniofacial
  name: Craniosynostosis
  description: >
    Premature fusion of cranial sutures, typically multisutural. Present in essentially
    all reported patients and one of the three cardinal features of the syndrome.
  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.
- category: Craniofacial
  name: Cloverleaf skull
  description: >
    Trilobar (Kleeblattschädel) skull deformity from severe multisuture fusion. Reported
    in the majority of patients with craniosynostosis in the original series, and the
    feature that best separates the severe from the milder end of the syndrome.
  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.
- category: Dermatologic
  name: Cutis gyrata of scalp
  description: >
    Convoluted, cerebriform folds and furrows of thickened scalp skin. The eponymous
    feature, and the finding that distinguishes BSS from Crouzon syndrome on inspection.
  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: 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.
- 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.
- 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.
- 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.
- category: Gastrointestinal
  name: Abnormal umbilicus morphology
  description: >
    A prominent umbilical stump is a consistent and distinctive feature, recorded in the
    original delineation and in molecularly confirmed cases since.
  phenotype_term:
    preferred_term: Abnormal umbilicus morphology
    term:
      id: HP:0001551
      label: Abnormal umbilicus morphology
  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.
- category: Craniofacial
  name: Midface retrusion
  description: >
    Severe midface hypoplasia, which in reported surgical experience can be extreme
    enough to leave a very narrow temporal fossa and to prevent decannulation even after
    midface advancement.
  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: >
    Shallow orbits from midface and cranial base involvement produce marked globe
    protrusion, up to ocular herniation in severe cases.
  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.
- 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.
- category: Respiratory
  name: Tracheal cartilaginous sleeve
  description: >
    A continuous cartilage tube replacing the normal tracheal rings. Recorded here as a
    phenotype because it is the single most actionable finding in the syndrome: it is
    associated with about a 90% risk of death by two years without tracheostomy, and it
    is generally invisible without direct airway visualization. Its frequency in BSS is
    unknown, and the published figure is a lower bound.
  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.
- category: Neurologic
  name: Hydrocephalus
  description: >
    Ventricular enlargement requiring cerebrospinal fluid diversion in reported patients,
    a consequence of the restricted and distorted cranial vault.
  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.
- 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.
- category: Neurologic
  name: Global developmental delay
  description: >
    Significant developmental delay is reported in most patients who survive infancy.
    Structural correlates on MRI include a simplified gyral pattern, abnormal posterior
    fossa and abnormal hippocampus.
  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: 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: >-
      Supplies the structural brain findings in two p.Tyr375Cys patients, indicating the
      delay is not attributable to raised intracranial pressure alone.
- 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.
- category: Genitourinary
  name: Bifid scrotum
  description: >
    Anogenital anomalies are a cardinal feature of the syndrome; bifid scrotum with
    perineal hypospadias is the reported pattern in male patients.
  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.
- 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.
- category: Growth
  name: Failure to thrive
  description: >
    Severe failure to thrive is reported, and a 2026 autopsy identified a candidate
    structural explanation that had not previously been described: a small intestine much
    shorter than expected for body size. This is a single case and is recorded as a
    hypothesis-generating observation, not an established component of the syndrome.
  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.
genetic:
- name: FGFR2 cysteine-creating gain-of-function variants
  gene_term:
    preferred_term: FGFR2
    term:
      id: hgnc:3689
      label: FGFR2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Heterozygous de novo missense variants introducing an unpaired cysteine. The two
    recurrent alleles, p.Tyr375Cys (transmembrane) and p.Ser372Cys (Ig-III/transmembrane
    linker), account for most molecularly confirmed cases; p.Ser372Tyr and p.Phe276Cys
    have each been reported once. A subset of clinically typical patients carry neither
    recurrent allele.
  variants:
  - name: c.1124A>G (p.Tyr375Cys)
    description: >-
      The commonest allele, in the transmembrane domain. Reported repeatedly across
      independent series and populations, and the allele modeled in the Fgfr2 Y394C
      mouse.
    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.
  - 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.
  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: 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: >-
      Extends the allelic series with p.Ser372Tyr, a non-cysteine substitution at the
      same codon as the recurrent p.Ser372Cys.
progression:
- phase: Infancy
  age_range: Birth through the first year
  notes: >-
    The period in which the syndrome's excess mortality is concentrated. Roughly half of
    reported patients die in the first year from cardiorespiratory arrest or unexpected
    sudden death, and reported deaths have occurred within weeks of birth from
    respiratory complications requiring mechanical ventilation from birth. A tracheal
    cartilaginous sleeve is the leading candidate mechanism for the sudden-death excess,
    but a causal contribution has not been demonstrated and other contributors — severe
    midface hypoplasia, choanal stenosis, micrognathia and raised intracranial pressure —
    are present in the same patients.
  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: 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: Quantifies first-year mortality and names the reported mechanisms of death.
  - 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.
- phase: Childhood
  age_range: Beyond infancy, in survivors
  notes: >-
    Survivors face significant developmental delay and a staged surgical course —
    tracheostomy, cerebrospinal fluid diversion, cranial expansion, and later midface
    advancement — extending across the first decade. Reported patients have reached at
    least 8 years of age.
  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: 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.
treatments:
- name: Tracheostomy and airway surveillance for tracheal cartilaginous sleeve
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >
    The intervention with the clearest survival rationale in this syndrome. An unmanaged
    tracheal cartilaginous sleeve carries about a 90% risk of death by two years of age
    without tracheostomy, and because the lesion is difficult to detect without direct
    visualization of the trachea, the recommendation is to evaluate for it actively
    rather than await symptoms. Tracheostomy in infancy is reported as routine in
    surgically managed BSS patients.
  treatment_term:
    preferred_term: Tracheostomy
    term:
      id: NCIT:C15341
      label: Tracheotomy
  target_mechanisms:
  - target: Tracheal Cartilaginous Sleeve and Airway Compromise
    treatment_effect: INHIBITS
    description: >
      Bypasses the fixed cartilaginous segment, removing the airway obstruction that is
      the proposed route to sudden death. It does not modify the lesion itself.
    evidence:
    - reference: PMID:25706251
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy."
      explanation: The survival difference that motivates tracheostomy.
  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.
- name: Cranial vault expansion and cerebrospinal fluid diversion
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >
    Staged neurosurgical management of the restricted cranial vault: ventriculoperitoneal
    shunting for hydrocephalus, then posterior or occipital cranial expansion, then
    fronto-orbital advancement. In the reported course these precede any midface
    procedure by years.
  treatment_term:
    preferred_term: Cranial vault expansion
    term:
      id: NCIT:C15214
      label: Craniotomy
  target_phenotypes:
  - 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: Documents the staged sequence and its timing in a BSS patient.
- 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
  notes: >-
    treatment_term is left at the generic Surgical Procedure deliberately. NCIT was
    searched for a midface-advancement, Le Fort or distraction-osteogenesis clinical
    action and has none; NCIT:C51903 Osteotomy names the bone cut but not the staged
    advancement, and NCIT:C15214 Craniotomy is the wrong compartment. Pfeiffer_Syndrome
    carries NCIT:C15329 for the same procedure, so this is also the consistent choice.
  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: 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.
discussions:
- discussion_id: gap_bss_p38_inhibition_translation
  prompt: >-
    Does p38 MAPK inhibition, which reverses the skin phenotype in the Fgfr2
    Beare-Stevenson mouse, have any prospect of translating to human BSS — and would
    treating the skin arm matter if the mortality is driven by the airway?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Sustained FGFR2 Signaling with p38 MAPK Activation
  - pathophysiology#Epidermal Hyperplasia and Cutis Gyrata
  rationale: >-
    The Fgfr2 p.Tyr394Cys mouse is an unusually faithful model: it carries the murine
    equivalent of the commonest human allele and reproduces both arms of the syndrome,
    epidermal hyperplasia and craniosynostosis. Treating those mice with a p38 kinase
    inhibitor attenuated the skin abnormalities by returning proliferation and
    differentiation toward normal, which the authors advance as a therapeutic direction
    for BSS and for acanthosis nigricans and craniosynostosis generally. Three things
    stand between that and a human therapy, and they differ in kind rather than degree.
    First, the demonstrated reversal is of skin; craniosynostosis in a human is
    established at birth rather than progressive in the way a mouse suture phenotype is,
    so the window the mouse result occupies may not exist postnatally. Second, systemic
    p38 inhibition is a broad intervention with no defined dose, route or developmental
    window for a neonate. Third, and most consequential for how this entry should be
    read: the cause of death in BSS is airway and cardiorespiratory, and nothing links
    p38 activity to the tracheal cartilaginous sleeve. A therapy that normalized the skin
    would leave the survival problem untouched. This should not be curated anywhere as an
    emerging BSS treatment.
  evidence:
  - reference: PMID:22585574
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treating Fgfr2+/Y394C mice with a p38 kinase inhibitor attenuated skin abnormalities by reversing cell proliferation and differentiation to near normal levels."
    explanation: The rescue result, and the fact that what was reversed is the skin phenotype.
  - reference: PMID:22585574
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The demonstration of a pathogenic role for p38 activation may lead to the development of therapeutic strategies for BSS and related conditions, such as acanthosis nigricans or craniosynostosis."
    explanation: >-
      The authors' own forward-looking claim, marked PARTIAL because it is a prospect
      rather than a result.
  - 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: >-
      Establishes that the outcome any BSS therapy must move is cardiorespiratory, which
      the p38 skin result does not address.
  proposed_experiments:
  - experiment_id: exp_bss_p38_airway_phenotype
    name: Airway phenotype of the Fgfr2 Y394C mouse under p38 inhibition
    description: >-
      Determine whether the BSS mouse develops a tracheal cartilage abnormality at all,
      and if so whether p38 inhibition alters it. This is the measurement that would tell
      whether the p38 axis touches the arm of the syndrome that kills, or only the arm
      that is visible.
  - experiment_id: exp_bss_p38_developmental_window
    name: Developmental window for suture rescue
    description: >-
      Establish the latest gestational or postnatal point at which p38 inhibition still
      prevents suture fusion in the model, since a window that closes before birth would
      rule out postnatal human treatment regardless of efficacy.
- discussion_id: gap_bss_tracheal_sleeve_frequency_and_causation
  prompt: >-
    How often does a tracheal cartilaginous sleeve actually occur in Beare-Stevenson
    syndrome, and is it caused by the FGFR2 variant or merely co-occurring with it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Tracheal Cartilaginous Sleeve and Airway Compromise
  rationale: >-
    Both halves of this question are open, and the entry deliberately stops short of
    answering either. On frequency: the sleeve is described as often found only
    incidentally at autopsy because it cannot be diagnosed without direct visualization
    of the trachea, so every published frequency is a lower bound drawn from a case
    literature of fewer than thirty patients, most of whom died before any airway
    endoscopy would have been considered. On causation: the sleeve is reported across
    FGFR2-related craniosynostosis syndromes, which is consistent with an FGFR2-driven
    cartilage phenotype but equally consistent with shared ascertainment in severely
    affected, tracheostomized infants. No model system in the cited literature reproduces
    it, and the BSS mouse work characterizes skin and calvaria only. This matters
    practically rather than academically: if the sleeve is FGFR2-driven it should be
    sought in every patient with a cysteine-class allele, whereas if it tracks severity
    it should be sought in every severely affected infant regardless of genotype. The
    surveillance recommendation is the same either way, which is why the entry curates
    the recommendation as established and the mechanism as open.
  evidence:
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea."
    explanation: The ascertainment problem underlying the frequency half of the gap.
  - reference: PMID:25706251
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, tracheal cartilaginous sleeves have been reported in other FGFR2-related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy."
    explanation: >-
      The cross-syndrome occurrence that is compatible with either an FGFR2-driven
      mechanism or shared ascertainment.
  proposed_experiments:
  - experiment_id: exp_bss_prospective_airway_endoscopy
    name: Prospective airway endoscopy in FGFR2 craniosynostosis
    description: >-
      Direct airway visualization in every infant with a molecularly confirmed FGFR2
      craniosynostosis syndrome, reported by genotype, to replace an autopsy-ascertained
      lower bound with a real frequency and to test whether cysteine-class alleles carry
      excess risk.
  - experiment_id: exp_fgfr2_tracheal_cartilage_model
    name: Tracheal cartilage phenotyping in the BSS mouse
    description: >-
      Characterize tracheal ring segmentation in the Fgfr2 Y394C mouse, which would
      establish whether the lesion is a direct consequence of the allele.
- 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 and Cloverleaf Skull
  rationale: >-
    This is a diagnostic gap with immediate consequences for counselling and delivery
    planning. Cloverleaf skull identified prenatally in a BSS patient led to an initial
    concern for Crouzon syndrome, and in that case 3D ultrasound was performed but the
    cutis gyrata — the feature that separates the two — was visible only on retrospective
    review after the postnatal diagnosis. Since BSS carries markedly higher mortality
    than Crouzon syndrome, a prenatal misassignment is not a naming error but a
    prognostic one. The authors' proposed answer is to add molecular testing to suspected
    prenatal Crouzon cases rather than to rely on imaging, but no study has tested
    whether that changes outcomes, and the 2026 prenatal report identified BSS through a
    presentation — hydrops fetalis with increased nuchal translucency — that a
    craniofacial-led pathway would not have been triggered by.
  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: 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: >-
      Shows that the discriminating feature was present but not prospectively detectable,
      which is what makes this a gap rather than a training problem.
  - 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.
  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.
notes: >
  Curated de novo from primary literature during a completeness review of the
  FGFR-Related Skeletal Dysplasias grouping (issue #9257), which identified BSS as the
  only member of the classical FGFR2 craniosynostosis series with no dismech entry.

  Two curation decisions worth recording. First, the Epidermal Hyperplasia and Cutis
  Gyrata node carries no `conforms_to` anchor even though it is downstream of an anchored
  node: the FGFR module's consequence nodes cover growth plate and cranial suture only,
  and there is no epidermal arm for it to conform to. Rather than force a bad anchor or
  drop the node, it is left unanchored and the reason is stated in the node description.
  If a second FGFR disorder with a keratinocyte arm is curated — Crouzon syndrome with
  acanthosis nigricans already has one — an epidermal consequence node in the module
  would be worth proposing.

  Second, the tracheal cartilaginous sleeve is modeled as a node and a phenotype but its
  causal link to the FGFR2 variant is explicitly not asserted; see
  gap_bss_tracheal_sleeve_frequency_and_causation. It is included because it is the most
  actionable finding in the syndrome, not because the mechanism is established.

  PMID:38265560 (mosaic FGFR2 p.Asn549Lys neurocutaneous syndrome) was reviewed and
  deliberately not cited: it describes a different, postzygotic FGFR2 disorder and is a
  differential-diagnosis consideration rather than BSS evidence. PMID:31373082 (tracheal
  cartilaginous sleeve in Beare-Stevenson) is the most on-topic paper found for the
  airway arm but caches with no abstract, so the sleeve evidence is drawn from
  PMID:25706251 instead rather than quoting a title.
references:
- reference: PMID:20301628
  title: "FGFR Craniosynostosis Syndromes Overview."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301628
FGFR Craniosynostosis Syndromes Overview.
No top-level findings curated for this source.