Antley-Bixler Syndrome, FGFR2-Related

Mendelian MONDO:0020667 Pathograph 46 Show in embeddings browser FGFR2-related craniosynostosis Craniosynostosis syndrome

FGFR2-related Antley–Bixler syndrome is a rare presentation of FGFR2 craniosynostosis with elbow synostosis or contractures, midface hypoplasia and potentially severe airway and ocular complications. The recurrent p.Ser351Cys allele is also reported in patients labelled Pfeiffer or Crouzon syndrome; elbow fusion does not distinguish these labels. Other extracellular FGFR2 variants have been reported in patients initially diagnosed with Antley–Bixler syndrome. This entry retains the FGFR2-related disease concept while distinguishing it from recessive POR deficiency, which can produce overlapping skeletal abnormalities with disordered steroidogenesis. Normal external genitalia alone do not exclude POR deficiency. Phenotypes below emphasize molecularly confirmed FGFR2 cases, including the same-allele literature under alternative syndrome names; selected, overlapping case reports do not support population frequency estimates.

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1
Inheritance
9
Pathophys.
27
Phenotypes
2
Gaps
46
Pathograph
1
Genes
10
Medical Actions
2
Differentials
2
Models
19
References
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Classifications

ISDS Skeletal Nosology
craniosynostosis syndromes
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous FGFR2 variants can occur de novo. The index p.Ser351Cys case was reported as an apparent de novo occurrence. General FGFR craniosynostosis counseling gives a 50% transmission risk for each child of a heterozygous affected individual; severity cannot be predicted reliably from transmission alone. Negative parental blood testing does not eliminate possible germline mosaicism. Historical recessive Antley–Bixler pedigrees should be reassessed for POR deficiency rather than presumed to establish recessive FGFR2 disease.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:9605588 SUPPORT PRIMARY RESULT Human Clinical
"We report the first case of ABS associated with an apparent dominant de novo mutation in the fibroblast growth factor receptor 2 (FGFR2) gene."
Index clinical inheritance observation.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Each child of an individual with an <i>FGFR</i> craniosynostosis syndrome has a 50% chance of inheriting the <i>FGFR</i> <a class="def" href="/sites/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>."
Complete offspring-transmission sentence from GeneReviews. Literal inline HTML preserves the generated source and the FGFR pathogenic-variant endpoint.
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Discussions and Knowledge Gaps

2
Does the Antley–Bixler label identify a distinct FGFR2 phenotype?
KNOWLEDGE GAP OPEN gap_abs_fgfr2_distinct_entity_status
Attached to
genetic#FGFR2 extracellular variants
The same S351C allele appears under Antley–Bixler, Pfeiffer and Crouzon labels. Elbow ankylosis is not unique to the ABS label, and contractures need not represent bony fusion. Nomenclature proposals differ over whether ABS should be reserved for POR deficiency. This entry retains the existing MONDO concept without treating the clinical labels as distinct molecular mechanisms. A genotype-stratified comparison should deduplicate re-reported patients and record radiographic joint anatomy.
Show evidence (2 references)
PMID:16145814 SUPPORT REVIEW SYNTHESIS Other
"We believe it would be better to reserve the use of the term “ABS” for patients with POR deficiency and clinically significant craniosynostosis and/or radiohumoral synostosis."
Attributed nomenclature proposal, not a binding reclassification.
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III."
Same allele under an alternative clinical label.
How directly does the disulfide-activation mechanism apply to S351C?
KNOWLEDGE GAP OPEN gap_abs_allele_specific_function
Attached to
pathophysiology#Aberrant FGFR2 Disulfide Dimerization pathophysiology#Increased FGFR2 Kinase Activity
The human S351C report predicts aberrant disulfide bonding and altered ligand binding. The cited experiments directly demonstrate dimerization and kinase activation for other alleles, not S351C. Their telokin-based homology model is not a mutant FGFR2 crystal structure or direct bond map. Allele-specific dimerization, ligand dependence and kinase measurements, ideally with expression-matched controls, would strengthen the current class inference. Cranial osteogenic and joint-development effects require separate tissue-level testing.
Show evidence (2 references)
PMID:10406670 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"All three cases were found to have the same FGFR2 Ser351Cys (1231C to G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding."
Explicit predictive wording in the allele-specific report.
PMID:9539778 SUPPORT PRIMARY RESULT Computational
"We used molecular modeling to construct a three-dimensional representation of the Ig-3 domain of FGFR2 based on the crystallographic coordinates of telokin, a myosin light chain kinase homolog"
Homology-model provenance; not an experimental S351C structure.
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Pathophysiology

9
Extracellular FGFR2 Pathogenic Variants
Heterozygous extracellular FGFR2 variants are the initiating genetic lesion. p.Ser351Cys introduces a cysteine in IgIII; C342S and C342R were also reported in an ABS-ascertained cohort. Nucleotide numbering differs among older reports; the contemporary p.Ser351Cys coding designation is c.1052C>G. A syndrome label is not an allele-specific functional assay.
FGFR2 hgnc:3689 ⇑ GAIN OF FUNCTION 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.
Downstream
Aberrant FGFR2 Disulfide Dimerization The variant class is predicted to permit abnormal intermolecular disulfide bonding; p.Ser351Cys has not been directly assayed in this source.
Midfacial Skeletal Hypoplasia The genotype is associated with this developmental abnormality; the tissue-specific causal intermediates are unresolved.
Developmental Joint Synostosis The genotype accompanies radiographically differentiated joint fusion, with unresolved developmental intermediates.
Upper Airway Narrowing Choanal developmental abnormalities accompany the FGFR2 phenotype; the complete embryologic pathway is unresolved.
Multiple joint contractures This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Dislocated radial head This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Peters anomaly This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Corneal opacity This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Hydrocephalus This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Seizures This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Neurodevelopmental delay This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Spinal dysraphism This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Caudal appendage This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Broad hallux This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Hallux varus This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Feeding difficulties This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Intestinal malrotation This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Femoral bowing This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Femur fracture This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Wide anterior fontanel This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Hypertelorism This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Show evidence (1 reference)
PMID:9605588 SUPPORT PRIMARY RESULT Human Clinical
"The patient was found to be heterozygous for a C-->G transversion at nucleotide 1064, which predicts a Ser351Cys amino acid substitution in the IgIII domain of FGFR2."
The index p.Ser351Cys variant; historical nucleotide numbering is quoted as published.
Aberrant FGFR2 Disulfide Dimerization
Mechanism confidence: Provisional
Aberrant intermolecular disulfide bonding is the proposed activating mechanism for p.Ser351Cys and a supported mechanism for the broader extracellular FGFR2 mutation class. Reducible dimers were demonstrated in heterologous assays of other FGFR2 variants; the cited study did not test p.Ser351Cys itself.
Experimental models
Full-length FGFR2 expression in COS-1 cells CELL LINE Related mutant constructs increased dimer formation under nonreducing conditions.
FGFR2/Neu chimeric-receptor transformation in NIH 3T3 cells CELL LINE Removing the two IgIII cysteines abolishes the transforming activity of related mutant extracellular domains in an artificial FGFR2/Neu reporter. This perturbation supports cysteine dependence, with dimer formation measured separately in full-length COS-1 receptors.
Downstream
Increased FGFR2 Kinase Activity Dimerization accompanies kinase activation in related extracellular mutants; cysteine removal suppresses both in the tested constructs.
Show evidence (2 references)
PMID:10406670 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"All three cases were found to have the same FGFR2 Ser351Cys (1231C to G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding."
The human case report explicitly identifies a predicted, not measured, receptor mechanism.
PMID:9539778 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Additionally, the dimerization observed for both of these mutants was reducible, indicating that the dimerization was accomplished by disulfide bond formation."
Reducible dimers in COS-1 experiments with W290G/T341P and cysteine-loss controls support the molecular class mechanism, not a p.Ser351Cys assay.
Increased FGFR2 Kinase Activity
Mechanism confidence: Provisional
Enhanced receptor tyrosine phosphorylation and kinase activity are established for tested activating extracellular FGFR2 variants. Application to p.Ser351Cys is a class-based inference; neither patient suture kinase activity nor the degree of activation of this allele was measured in the cited experiments.
FGFR2 hgnc:3689 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGFR2 (hgnc:3689). hgnc:3689 is a gene from the HUGO Gene Nomenclature Committee.
transmembrane receptor protein tyrosine kinase activity GO:0004714 ↑ INCREASED 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.
Experimental models
Full-length FGFR2 expression in COS-1 cells CELL LINE Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
Downstream
Altered Suture Osteogenic Differentiation Altered receptor signaling is proposed to change osteogenic cell behavior through downstream signaling pathways.
Show evidence (1 reference)
PMID:9539778 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"All of the receptors that formed dimers, as shown in Fig.3A, also exhibited significant phosphorylation of the dimeric form of the receptor, demonstrating activation of the receptor (Fig.4A)."
Full-length receptor kinase assays in transfected COS-1 cells tested related variants.
Altered Suture Osteogenic Differentiation
Mechanism confidence: Provisional
Disordered timing of osteogenic differentiation in cranial suture mesenchyme is a proposed tissue mechanism connecting activated FGFR2 signaling to premature ossification. Much of the evidence comes from other FGFR2 genotypes and models; accelerated differentiation has not been measured in p.Ser351Cys patient sutures in the cited sources.
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 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology.
Downstream
Premature Cranial Suture Fusion Premature osteogenic differentiation is one proposed contributor to suture ossification.
Show evidence (1 reference)
PMID:29230096 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"FGFR2 in cranial sutures is largely expressed in differentiating osteoblasts and osteoprogenitor cells. Via downstream pathways, FGF/FGFR2 signaling mediates osteoprogenitor proliferation, differentiation, and apoptosis 25,40. Early differentiation is thought to be a leading factor involved in..."
The review summarizes FGFR2 biology and a proposed differentiation mechanism; this is not a direct assay in the allele-specific clinical cohort.
Premature Cranial Suture Fusion
Early fusion of one or multiple cranial sutures alters skull growth. The sutures involved and timing of fusion influence head shape; cloverleaf skull is not obligatory. This anatomical event does not by itself explain all facial, ocular and limb malformations.
Downstream
Reduced Bony Orbital Depth Coronal suture and maxillary growth abnormalities contribute to a shallow orbit.
Craniosynostosis This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Cloverleaf skull This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Brachycephaly This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Show evidence (1 reference)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
Craniosynostosis with variable skull shape in three molecularly confirmed p.Ser351Cys cases.
Midfacial Skeletal Hypoplasia
Underdevelopment of midfacial bones contributes to retrusion and upper airway narrowing. It is part of the FGFR2 developmental phenotype, rather than an assumed inevitable downstream consequence of fused calvarial sutures.
Downstream
Reduced Bony Orbital Depth Underdeveloped maxillary arches contribute to orbital shallowness.
Upper Airway Narrowing Reduced nasal skeletal dimensions contribute to obstructed airflow.
Midface retrusion This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Show evidence (1 reference)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
Midface hypoplasia in the p.Ser351Cys clinical series.
Reduced Bony Orbital Depth
Shallow bony orbits contribute to proptosis and, when severe, globe subluxation and inadequate lid closure. Structural anterior chamber abnormalities are a separate ocular manifestation.
Downstream
Proptosis This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Coronal craniosynostosis and underdevelopment of the maxillary arches results in decreased depth of the bony orbit and proptosis."
General FGFR craniosynostosis anatomy explains orbital manifestations seen in p.Ser351Cys cases.
Upper Airway Narrowing
Choanal stenosis or atresia and reduced midfacial dimensions can obstruct airflow. Obstruction may occur at multiple levels, so its anatomical source should be assessed rather than attributed exclusively to the choanae.
Downstream
Choanal atresia This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Upper airway obstruction This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Respiratory distress This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Show evidence (2 references)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
Choanal narrowing in the p.Ser351Cys series.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Narrowed nasal passages as a result of bony atresia or stenosis, including choanal atresia or stenosis."
Anatomical airway contribution in the FGFR clinical baseline.
Developmental Joint Synostosis
Bony fusion at the elbow may involve the humerus and radius or the radius and ulna. Contractures can also occur without synostosis; an unmeasured acceleration of osteoblast differentiation at every affected joint should not be assumed from clinical ankylosis.
Downstream
Elbow ankylosis This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Radioulnar synostosis This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
Show evidence (2 references)
PMID:9605588 SUPPORT PRIMARY RESULT Human Clinical
"Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS."
Index joint observation.
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"Patient 29 had radioulnar—but not radiohumeral—synostosis, knee contractures without synostosis and Peters anomaly, and was subsequently considered to have Crouzon syndrome."
Radioulnar rather than radiohumeral fusion in one p.Ser351Cys patient; knee contractures lacked bony fusion.
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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 Antley-Bixler Syndrome, FGFR2-Related 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

27
Digestive 2
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"Baby graduated from feeding via nasogastric tube to cup feeding."
Observed feeding support in one hospitalized infant.
Intestinal malrotation HP:0002566 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal malrotation (HP:0002566). HP:0002566 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay."
Single case of non-rotation.
Eye 4
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:9714439 SUPPORT PRIMARY RESULT Human Clinical
"We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay."
Genotype-confirmed severe ocular finding.
Peters anomaly HP:0000659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peters anomaly (HP:0000659). HP:0000659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"We evaluated three unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles."
Selected p.Ser351Cys ocular series.
Corneal opacity HP:0007957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal opacity (HP:0007957). HP:0007957 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles."
Primary anatomical finding in the selected ocular series.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"proptosis with ocular hypertelorism (Figure 1), low set ears, protruding tongue"
Direct clinical observation; no prevalence inference.
Head and Neck 6
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:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
Three molecularly confirmed p.Ser351Cys cases.
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:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
Allele-matched series.
Choanal atresia HP:0000453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal atresia (HP:0000453). HP:0000453 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
The series describes choanal stenosis/atresia.
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:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
Explicit with-and-without cloverleaf morphology.
Brachycephaly HP:0000248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachycephaly (HP:0000248). HP:0000248 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"15b | 14506 | Y | Y | Y | Y | Y | Y | Y | | N | N | Y | |"
Positive brachycephaly column for S351C patient 15.
Wide anterior fontanel HP:0000260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide anterior fontanel (HP:0000260). HP:0000260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present."
Large anterior fontanelle reported in the same-allele series.
Limbs 7
Elbow ankylosis HP:0003070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elbow ankylosis (HP:0003070). HP:0003070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9605588 SUPPORT PRIMARY RESULT Human Clinical
"Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS."
Positive index-case observation.
Radioulnar synostosis HP:0002974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Radioulnar synostosis (HP:0002974). HP:0002974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"Patient 29 had radioulnar—but not radiohumeral—synostosis, knee contractures without synostosis and Peters anomaly, and was subsequently considered to have Crouzon syndrome."
Anatomically specified positive observation.
Dislocated radial head HP:0003083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dislocated radial head (HP:0003083). HP:0003083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe."
Single genotype-confirmed clinical case.
Broad hallux HP:0010055 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad hallux (HP:0010055). HP:0010055 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe."
Single case; normal thumbs do not exclude the allele.
Hallux varus HP:0008080 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hallux varus (HP:0008080). HP:0008080 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"wide sandal gap and medially deviated broad great toes"
Direct clinical description; no prevalence inference.
Femoral bowing HP:0002980 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Femoral bowing (HP:0002980). HP:0002980 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"15b | 14506 | Y | Y | Y | Y | Y | Y | Y | | N | N | Y | |"
Table 1 row 15: the femoral-bowing column is positive; Table 4 identifies FGFR2 S351C. Blank cells are unreported, not negative.
Femur fracture HP:0031846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Femur fracture (HP:0031846). HP:0031846 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"15b | 14506 | Y | Y | Y | Y | Y | Y | Y | | N | N | Y | |"
Table 1 femoral-fracture column is positive for patient 15; Table 4 assigns S351C.
Musculoskeletal 2
Multiple joint contractures HP:0002828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple joint contractures (HP:0002828). HP:0002828 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"Patient 28 had a 2.5-cm phallus, contractures of the elbows and knees without synostosis and Peters anomaly, and was subsequently considered to have Pfeiffer syndrome."
One p.Ser351Cys case with non-fused contracted joints.
Caudal appendage HP:0002825 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Caudal appendage (HP:0002825). HP:0002825 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12072807 SUPPORT PRIMARY RESULT Human Clinical
"We report a baby with craniosynostosis and a sacral appendage who has been found to have a Ser351Cys mutation in the fibroblast growth factor receptor 2 gene (FGFR2)."
Genotype-confirmed appendage.
Nervous System 4
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:16465081 SUPPORT PRIMARY RESULT Human Clinical
"He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt."
Single clinical case with documented treatment.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"These patients had airway compromise, seizures, and two died by age 15 months."
Seizures in the selected molecularly confirmed series.
Neurodevelopmental delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay."
Unspecified severe developmental delay in one case.
Spinal dysraphism HP:0010301 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spinal dysraphism (HP:0010301). HP:0010301 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9605588 SUPPORT PRIMARY RESULT Human Clinical
"Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS."
Single index-case observation.
Respiratory 2
Upper airway obstruction HP:0002781 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upper airway obstruction (HP:0002781). HP:0002781 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay."
One allele-matched case.
Respiratory distress HP:0002098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory distress (HP:0002098). HP:0002098 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"The clinical problems identified on initial assessment were respiratory distress which was evidenced by deep laboured breathing with poor oxygen saturation of 55% on room air, seizures of the upper limbs, high-grade fever, and pallor."
Case observation with concurrent neonatal illness.
🧬

Genetic Associations

1
FGFR2 extracellular variants (Causative)
Gene: FGFR2 hgnc:3689 gene page 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:9605588 SUPPORT PRIMARY RESULT Human Clinical
"The patient was found to be heterozygous for a C-->G transversion at nucleotide 1064, which predicts a Ser351Cys amino acid substitution in the IgIII domain of FGFR2."
Index variant.
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"FGFR2 mutation S351C was found in five patients, other FGFR2 mutations (C342S, C342R, and P276V) were found in three other patients"
Selected cohort supports multiple FGFR2 alleles; the source-internal P276V/F276V discrepancy is retained as a limitation.
💊

Medical Actions

10
Cranial vault expansion and reconstruction
Category: Therapeutic Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
A specialist craniofacial team individualizes cranial surgery to suture anatomy, intracranial pressure and respiratory status. General FGFR guidance places multisuture repair in the first year, often with staged posterior expansion and later fronto-orbital procedures. The p.Ser351Cys literature documents treatment use, not comparative surgical efficacy.
Mechanism Target:
MODULATES Premature Cranial Suture Fusion — Release of fused sutures and reconstruction expand the cranial vault; staged anatomy-specific procedures address consequences of premature fusion.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased intracranial pressure and reduce progressive abnormal craniofacial development."
General FGFR clinical baseline, extrapolated to the molecularly confirmed presentation.
PMID:16465081 SUPPORT PRIMARY RESULT Human Clinical
"His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt."
Observed treatment in one allele-matched case.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased intracranial pressure and reduce progressive abnormal craniofacial development."
General FGFR clinical baseline, extrapolated to the molecularly confirmed presentation.
PMID:16465081 SUPPORT PRIMARY RESULT Human Clinical
"His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt."
Observed treatment in one allele-matched case.
Airway stabilization and treatment of obstruction
Category: Therapeutic
Urgent respiratory support and specialist airway assessment are tailored to the obstruction level. Nasal stents, intubation or tracheotomy may be needed. Sleep-apnea interventions depend on severity, age and anatomy; residual obstruction is common. CPAP/BiPAP can be an interim option with craniofacial and ocular precautions. The older GeneReviews concern about prolonged mask pressure is not a ban on acute support.
Mechanism Target:
BYPASSES Upper Airway Narrowing — Stenting, intubation or tracheotomy can bypass the obstructed segment; positive-pressure support is selected according to residual obstruction and gas exchange.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Infants &#x00026; children requiring tracheotomy may also need ventilator-delivered positive pressure to normalize gas exchange &#x00026; achieve normal sleep &#x00026; growth."
General FGFR guidance for bypass and ventilatory support; literal HTML entities retain generated source wording.
PMID:33156164 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Select treatment for OSA based on severity of OSA, age of patient, causal factors, feasibility of treatment and possibly other functional problems (such as increased ICP or exorbitism)."
Syndromic craniosynostosis guideline; not allele-specific comparative evidence.
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"Oxygen support was administered via CPAP and the baby was haemotransfused."
One infant received CPAP during concurrent neonatal illness, not proof of chronic superiority.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Infants &#x00026; children requiring tracheotomy may also need ventilator-delivered positive pressure to normalize gas exchange &#x00026; achieve normal sleep &#x00026; growth."
General FGFR guidance for bypass and ventilatory support; literal HTML entities retain generated source wording.
PMID:33156164 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Select treatment for OSA based on severity of OSA, age of patient, causal factors, feasibility of treatment and possibly other functional problems (such as increased ICP or exorbitism)."
Syndromic craniosynostosis guideline; not allele-specific comparative evidence.
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"Oxygen support was administered via CPAP and the baby was haemotransfused."
One infant received CPAP during concurrent neonatal illness, not proof of chronic superiority.
Midface advancement
Category: Therapeutic Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Midface or combined craniofacial advancement is considered when airway compromise or occlusion justifies it. Severe obstructive sleep apnea can prompt earlier surgery; timing and procedure require a multidisciplinary assessment rather than a fixed allele-based schedule.
Mechanism Target:
MODULATES Midfacial Skeletal Hypoplasia — Advancing the hypoplastic midface changes skeletal position and may enlarge the airway in selected patients with severe obstruction.
Show evidence (1 reference)
PMID:33156164 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Consider Le Fort III surgery or monobloc advancement in children with syndromic craniosynostosis and severe respiratory OSA to treat the respiratory problems. If necessary, combine this procedure with a mandibula advancement."
Guideline recommendation for selected severe syndromic obstruction; evidence is not specific to FGFR2-related ABS.
Show evidence (1 reference)
PMID:33156164 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Consider Le Fort III surgery or monobloc advancement in children with syndromic craniosynostosis and severe respiratory OSA to treat the respiratory problems. If necessary, combine this procedure with a mandibula advancement."
Guideline recommendation for selected severe syndromic obstruction; evidence is not specific to FGFR2-related ABS.
Hydrocephalus management
Category: Therapeutic Action: Ventriculoperitoneal Shunt PlacementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Ventriculoperitoneal Shunt Placement (NCIT:C168483). NCIT:C168483 is a clinical intervention from the NCI Thesaurus. NCIT:C168483
Platform: Surgery
Neurosurgical assessment determines whether cerebrospinal fluid diversion is required. Ventriculoperitoneal shunting was reported in a p.Ser351Cys infant; this is a case-level intervention, not evidence that all enlarged ventricles require shunting.
Mechanism Target:
BYPASSES Hydrocephalus — Ventriculoperitoneal diversion bypasses impaired cerebrospinal-fluid drainage when neurosurgical assessment supports shunting.
Show evidence (1 reference)
PMID:16465081 SUPPORT PRIMARY RESULT Human Clinical
"He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt."
Positive disease-matched intervention.
Show evidence (1 reference)
PMID:16465081 SUPPORT PRIMARY RESULT Human Clinical
"He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt."
Positive disease-matched intervention.
Ocular surface protection
Category: Therapeutic
Ophthalmology assesses exposure, globe subluxation, vision and structural anterior segment abnormalities. Lubrication and, when necessary, tarsorrhaphy protect an inadequately covered cornea; they do not correct congenital Peters anomaly or establish reversal of globe protrusion.
Mechanism Target:
BYPASSES Proptosis — Lubrication or eyelid closure protects the exposed cornea despite persistent globe protrusion; this does not reverse the underlying orbital anatomy.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Tarsorrhaphy may be indicated, e.g., w/globe subluxation or to prevent globe luxation &#x00026;/or exposure keratopathy."
General FGFR guidance provides the preventive indication; raw cache retains the ampersand entity.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Tarsorrhaphy may be indicated, e.g., w/globe subluxation or to prevent globe luxation &#x00026;/or exposure keratopathy."
General FGFR guidance provides the preventive indication; raw cache retains the ampersand entity.
Feeding and swallowing support
Category: Therapeutic
Assess swallowing safety and oral intake, including after craniofacial operations. Feeding therapy and temporary tube support are individualized. The reported transition from nasogastric to cup feeding occurred during recovery from neonatal illness. Evaluate possible intestinal malrotation before gastrostomy as advised in the general FGFR baseline.
Mechanism Target:
BYPASSES Feeding difficulties — Temporary nasogastric or other tube feeding provides intake when oral feeding is unsafe or inadequate; feeding therapy separately supports swallowing and oral intake.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Feeding therapy is helpful to assess swallowing safety &#x00026; support eating by mouth."
Clinical baseline recommendation.
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"Baby graduated from feeding via nasogastric tube to cup feeding."
Observed support and transition in one infant.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Feeding therapy is helpful to assess swallowing safety &#x00026; support eating by mouth."
Clinical baseline recommendation.
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"Baby graduated from feeding via nasogastric tube to cup feeding."
Observed support and transition in one infant.
Seizure treatment
Category: Therapeutic Action: Anticonvulsant TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. NCIT:C64172
Treat seizures according to their cause and clinical course. Phenobarbital and phenytoin were used in the reported neonate with concurrent hypoxic and infectious complications; this does not establish an allele-specific preferred antiseizure drug.
Mechanism Target:
INHIBITS Seizures — Antiseizure medication suppresses clinical seizures; the reported acute neonatal treatment does not demonstrate correction of FGFR2 signaling.
Show evidence (1 reference)
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"IV phenobarbitone and phenytoin were administered to control the seizures"
Disease-matched treatment use with confounding acute illness.
Show evidence (1 reference)
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"IV phenobarbitone and phenytoin were administered to control the seizures"
Disease-matched treatment use with confounding acute illness.
Developmental and rehabilitation support
Category: Therapeutic Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Early intervention, speech assessment and neurodevelopmental review address documented delays and functional needs. Limb evaluation distinguishes fixed bony fusion from soft-tissue contractures; the sources do not establish that physical therapy reverses synostosis.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Consider consultation w/developmental pediatrician or neurodevelopmental specialist."
General FGFR management of developmental delay.
Multidisciplinary surveillance
Category: Monitoring
Monitor head growth and symptoms of raised intracranial pressure, with frequent assessment in infancy and at least annual ophthalmological evaluation. Evaluate hearing, dentition, speech and development. The 2020 craniosynostosis guideline recommends annual type 1 polysomnography through at least age six for syndromic children, in addition to symptom-triggered assessment. Surgical and anesthetic planning should consider airway anatomy, possible cervical anomalies and eye protection.
Show evidence (2 references)
PMID:33156164 SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Screen children with syndromic craniosynostosis annually by type 1 polysomnography at a center of expertise until at least the age of 6 years."
Updated guideline surveillance; not restricted to a genotype.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"Individuals with cervical spine anomalies may be at risk for spinal cord injury with hyperextension and may require fiberoptic intubation and/or sports restrictions for activities that pose a risk for head/neck injury."
Conditional precaution for those with cervical anomalies, not a claim that all have instability.
Genetic counseling and family evaluation
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Explain autosomal-dominant transmission, variable expression and the distinction from recessive POR deficiency. Confirm the familial variant before predictive, prenatal or preimplantation testing, and assess apparently unaffected relatives when appropriate. Negative parental blood testing cannot eliminate possible germline mosaicism.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual"
The full chapter recommends early identification of relatives who may benefit from surveillance.
🔬

Diagnosis

3
Molecular diagnosis with phenotype and variant interpretation
Use craniofacial and limb examination, imaging and molecular testing to establish the FGFR2-related diagnosis. A craniosynostosis panel can address the overlapping FGFR spectrum and alternatives. Sequence-based testing detected p.Ser351Cys after older SSCP screening was negative in one case; that observation does not estimate present-day panel sensitivity.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis."
Actual method limitation in one historical case.
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"sequence analysis using Illumina technology and deletion/duplication testing of 65 genes for variants associated with craniosynostosis syndromes was performed"
Case-level panel approach, not universal diagnostic performance.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/ SUPPORT INDIRECT REVIEW SYNTHESIS Other
"As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing."
GeneReviews recommends molecular confirmation of an FGFR craniosynostosis diagnosis; phenotype and variant interpretation establish its specific scope.
Cranial and joint imaging
Document the sutures and bones involved, and distinguish radiohumeral or radioulnar fusion from non-bony contracture. Evaluate hydrocephalus and other neurological complications as indicated. Neither elbow ankylosis nor a sacral appendage alone specifies the complete anatomical abnormality.
Show evidence (1 reference)
PMID:15793702 SUPPORT PRIMARY RESULT Human Clinical
"craniosynostosis and radioulnar or radiohumeral synostosis were confirmed radiographically."
Method used in the mixed, genotype-stratified cohort.
Steroid assessment when distinguishing POR deficiency
An initial ABS phenotype warrants assessment for steroidogenic disease when the genetic diagnosis is unresolved or endocrine concerns persist. Urinary steroid profiling and specialist adrenal assessment can detect abnormalities missed by genital appearance or limited basal measurements. Established FGFR2 disease alone is not an indication for glucocorticoid replacement.
Show evidence (2 references)
PMID:16145814 SUPPORT REVIEW SYNTHESIS Other
"Steroid abnormalities associated with POR deficiency and ABS are not always recognized without the use of urinary steroid profiling"
Review of the diagnostic distinction.
PMID:16145814 SUPPORT REVIEW SYNTHESIS Other
"The presence of ambiguous genitalia is not necessary for making a diagnosis of POR deficiency."
Normal genital appearance does not exclude the alternative diagnosis.
📈

Progression

1
Congenital and early childhood presentation
Craniofacial, joint and airway abnormalities can be apparent at birth; hydrocephalus and the full craniosynostosis phenotype may become evident later. Severe early morbidity and deaths are described in selected reports, but publication bias, overlapping patients and syndrome-label variation preclude a survival estimate. The 2021 infant died after discharge without autopsy, so a specific terminal mechanism was not established.
Show evidence (3 references)
PMID:16465081 SUPPORT PRIMARY RESULT Human Clinical
"At birth, a male infant had ocular proptosis, a pseudotail, and obstructed respiration. He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints."
Congenital findings and subsequent evolution.
PMID:10406670 SUPPORT PRIMARY RESULT Human Clinical
"These patients had airway compromise, seizures, and two died by age 15 months."
Selected-case outcomes, not a survival cohort.
PMID:34909104 SUPPORT PRIMARY RESULT Human Clinical
"The child was reported to have become lethargic and died some hours after reporting to the district hospital. An autopsy was not done."
Cause of death remains unverified.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Antley-Bixler Syndrome, FGFR2-Related:

P450 oxidoreductase deficiency
Overlapping Features Recessive POR deficiency can share craniosynostosis, elbow synostosis and limb abnormalities, with variable steroidogenic and genital manifestations. Normal genitalia do not exclude it. Genotype and biochemical assessment are more discriminating than the ABS eponym.
Distinguishing Features
  • Biallelic POR variants and characteristic steroid abnormalities support POR deficiency.
  • FGFR2-associated disease generally lacks the primary POR steroidogenic defect.
Show evidence (1 reference)
PMID:16145814 SUPPORT REVIEW SYNTHESIS Other
"The presence of ambiguous genitalia is not necessary for making a diagnosis of POR deficiency."
Diagnostic caution from the nomenclature review.
Pfeiffer and Crouzon syndromes
Overlapping Features These clinical labels overlap with the same p.Ser351Cys genotype, so they are alternative spectrum classifications rather than always genetically separable diagnoses. Normal thumbs do not exclude a severe Pfeiffer-labelled presentation.
Distinguishing Features
  • Assess the complete cranial, limb and ocular phenotype without using elbow fusion as a unique discriminator.
Show evidence (1 reference)
PMID:9714439 SUPPORT PRIMARY RESULT Human Clinical
"The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs."
Same-allele phenotypic overlap.
🧫

Experimental Models

2
Full-length FGFR2 expression in COS-1 cells CELL_LINE
Related extracellular FGFR2 variants formed reducible receptor dimers and showed increased autophosphorylation and phosphotyrosine signal. Combining W290G or T341P with C278A/C342A removed these effects. The assay supports a disulfide-dependent class mechanism, with low translational fidelity to the untested S351C allele and developing human cranial sutures.
Cell source
Immortalized simian COS-1 cells transiently transfected with human FGFR2 constructs
Pathograph links
Aberrant FGFR2 Disulfide Dimerization partially recapitulates fidelity: low observes: molecular Related mutant constructs increased dimer formation under nonreducing conditions.
Limitations: Transient heterologous expression of W290G, T341P, C278F, C342Y and engineered cysteine controls; p.Ser351Cys was not tested. These assays do not measure cranial differentiation, joint fusion, patient tissue signaling or a disease rescue. Reducibility supports disulfide-mediated association without directly mapping individual intermolecular bonds.
Readouts
Reducible FGFR2 dimer bands
Direction: INCREASED
Interpretation: Related mutant constructs increased dimer formation under nonreducing conditions.
Show evidence (1 reference)
PMID:9539778 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Additionally, the dimerization observed for both of these mutants was reducible, indicating that the dimerization was accomplished by disulfide bond formation."
Related mutant constructs increased dimer formation under nonreducing conditions.
Show evidence (1 reference)
PMID:9539778 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Additionally, the dimerization observed for both of these mutants was reducible, indicating that the dimerization was accomplished by disulfide bond formation."
Related mutant constructs increased dimer formation under nonreducing conditions.
Increased FGFR2 Kinase Activity partially recapitulates fidelity: low observes: molecular Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
Limitations: Transient heterologous expression of W290G, T341P, C278F, C342Y and engineered cysteine controls; p.Ser351Cys was not tested. These assays do not measure cranial differentiation, joint fusion, patient tissue signaling or a disease rescue. Reducibility supports disulfide-mediated association without directly mapping individual intermolecular bonds.
Readouts
Receptor autophosphorylation
Direction: INCREASED
Interpretation: Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
Show evidence (1 reference)
PMID:9539778 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"All of the receptors that formed dimers, as shown in Fig.3A, also exhibited significant phosphorylation of the dimeric form of the receptor, demonstrating activation of the receptor (Fig.4A)."
Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
Show evidence (1 reference)
PMID:9539778 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"All of the receptors that formed dimers, as shown in Fig.3A, also exhibited significant phosphorylation of the dimeric form of the receptor, demonstrating activation of the receptor (Fig.4A)."
Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
Show evidence (1 reference)
PMID:9539778 SUPPORT PRIMARY RESULT In Vitro
"COS-1 cells were transfected with full-length FGFR2 constructs described in Fig.1."
Actual full-length receptor preparation.
FGFR2/Neu chimeric-receptor transformation in NIH 3T3 cells CELL_LINE
Focus formation tested FGFR2 extracellular domains fused to the Neu transmembrane and kinase domains. Three to five experiments per construct used activated Neu as a normalization comparator. The transforming output belongs to this artificial reporter, not native FGFR2 kinase or an osteogenic differentiation assay. Removing both IgIII cysteines suppressed transformation by W290G/T341P constructs. No S351C, cranial suture or clinical rescue experiment was reported.
Cell source
Mouse NIH 3T3 fibroblast line
Pathograph links
Aberrant FGFR2 Disulfide Dimerization perturbs fidelity: low observes: cellular Removing the two IgIII cysteines abolishes the transforming activity of related mutant extracellular domains in an artificial FGFR2/Neu reporter. This perturbation supports cysteine dependence, with dimer formation measured separately in full-length COS-1 receptors.
Limitations: Focus formation is a downstream reporter phenotype rather than a direct dimerization readout. The kinase/transmembrane domains are Neu, p.Ser351Cys was not tested, and no cranial differentiation or clinical rescue was measured.
Show evidence (1 reference)
PMID:9539778 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Whereas each of the single mutants W290G and T341P was transforming, as described above, transforming activity was completely lost when these single mutants were combined with the double mutant (C278A, C342A)"
Genetic perturbation of the reporter response.
Show evidence (2 references)
PMID:9539778 SUPPORT PRIMARY RESULT In Vitro
"Chimeric FGFR2/Neu receptors (Fig.1), containing the FGFR2 extracellular domain fused to the transmembrane and kinase domains of Neu, allow the extent of activation to be assayed through focus formation using the intracellular domain of Neu as a reporter"
Construct and reporter context.
PMID:9539778 SUPPORT PRIMARY RESULT In Vitro
"Whereas each of the single mutants W290G and T341P was transforming, as described above, transforming activity was completely lost when these single mutants were combined with the double mutant (C278A, C342A)"
Genetic perturbation of the reporter response.
{ }

Source YAML

click to show 
name: Antley-Bixler Syndrome, FGFR2-Related
synonyms:
- ABS without genital anomalies or disordered steroidogenesis
- Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
- trapezoidocephaly-synostosis syndrome
- FGFR2-related Antley-Bixler syndrome
creation_date: '2026-08-24T00:00:00Z'
category: Mendelian
disease_term:
  preferred_term: Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
  term:
    id: MONDO:0020667
    label: Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
parents:
- FGFR2-related craniosynostosis
- Craniosynostosis syndrome
classifications:
  isds_skeletal_category:
  - classification_value: craniosynostosis_syndromes
    notes: The 2023 skeletal nosology calls the group Syndromes featuring craniosynostosis. This classification does not resolve overlap between FGFR2-related Antley–Bixler and Pfeiffer/Crouzon phenotypes.
description: FGFR2-related Antley–Bixler syndrome is a rare presentation of FGFR2 craniosynostosis with elbow synostosis or contractures, midface hypoplasia and potentially severe airway and ocular complications. The recurrent p.Ser351Cys allele is also reported in patients labelled Pfeiffer or Crouzon syndrome; elbow fusion does not distinguish these labels. Other extracellular FGFR2 variants have been reported in patients initially diagnosed with Antley–Bixler syndrome. This entry retains the FGFR2-related disease concept while distinguishing it from recessive POR deficiency, which can produce overlapping skeletal abnormalities with disordered steroidogenesis. Normal external genitalia alone do not exclude POR deficiency. Phenotypes below emphasize molecularly confirmed FGFR2 cases, including the same-allele literature under alternative syndrome names; selected, overlapping case reports do not support population frequency estimates.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Heterozygous FGFR2 variants can occur de novo. The index p.Ser351Cys case was reported as an apparent de novo occurrence. General FGFR craniosynostosis counseling gives a 50% transmission risk for each child of a heterozygous affected individual; severity cannot be predicted reliably from transmission alone. Negative parental blood testing does not eliminate possible germline mosaicism. Historical recessive Antley–Bixler pedigrees should be reassessed for POR deficiency rather than presumed to establish recessive FGFR2 disease.
  evidence:
  - reference: PMID:9605588
    reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We report the first case of ABS associated with an apparent dominant de novo mutation in the fibroblast growth factor receptor 2 (FGFR2) gene.
    explanation: Index clinical inheritance observation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Each child of an individual with an <i>FGFR</i> craniosynostosis syndrome has a 50% chance of inheriting the <i>FGFR</i> <a class="def" href="/sites/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.
    explanation: Complete offspring-transmission sentence from GeneReviews. Literal inline HTML preserves the generated source and the FGFR pathogenic-variant endpoint.
    directness: INDIRECT
pathophysiology:
- name: Extracellular FGFR2 Pathogenic Variants
  description: Heterozygous extracellular FGFR2 variants are the initiating genetic lesion. p.Ser351Cys introduces a cysteine in IgIII; C342S and C342R were also reported in an ABS-ascertained cohort. Nucleotide numbering differs among older reports; the contemporary p.Ser351Cys coding designation is c.1052C>G. A syndrome label is not an allele-specific functional assay.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:9605588
    reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The patient was found to be heterozygous for a C-->G transversion at nucleotide 1064, which predicts a Ser351Cys amino acid substitution in the IgIII domain of FGFR2.
    explanation: The index p.Ser351Cys variant; historical nucleotide numbering is quoted as published.
  role: trigger
  gene:
    preferred_term: FGFR2
    term:
      id: hgnc:3689
      label: FGFR2
    modifier: GAIN_OF_FUNCTION
  downstream:
  - target: Aberrant FGFR2 Disulfide Dimerization
    description: The variant class is predicted to permit abnormal intermolecular disulfide bonding; p.Ser351Cys has not been directly assayed in this source.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: All three cases were found to have the same FGFR2 Ser351Cys (1231C to G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding.
      explanation: Allele-specific mechanism is a prediction.
      directness: INDIRECT
  - target: Midfacial Skeletal Hypoplasia
    description: The genotype is associated with this developmental abnormality; the tissue-specific causal intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
      explanation: Molecularly confirmed clinical association.
      directness: INDIRECT
  - target: Developmental Joint Synostosis
    description: The genotype accompanies radiographically differentiated joint fusion, with unresolved developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15793702
      reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Patient 29 had radioulnar—but not radiohumeral—synostosis, knee contractures without synostosis and Peters anomaly, and was subsequently considered to have Crouzon syndrome.
      explanation: Positive radioulnar synostosis in an S351C patient.
      directness: INDIRECT
  - target: Upper Airway Narrowing
    description: Choanal developmental abnormalities accompany the FGFR2 phenotype; the complete embryologic pathway is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
      explanation: Genotype-matched clinical association.
      directness: INDIRECT
  - target: Multiple joint contractures
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15793702
      reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Patient 28 had a 2.5-cm phallus, contractures of the elbows and knees without synostosis and Peters anomaly, and was subsequently considered to have Pfeiffer syndrome.
      explanation: One p.Ser351Cys case with non-fused contracted joints.
  - target: Dislocated radial head
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9714439
      reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe.
      explanation: Single genotype-confirmed clinical case.
  - target: Peters anomaly
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We evaluated three unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles.
      explanation: Selected p.Ser351Cys ocular series.
  - target: Corneal opacity
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles.
      explanation: Primary anatomical finding in the selected ocular series.
  - target: Hydrocephalus
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16465081
      reference_title: Syndromic craniosynostosis with elbow joint contracture.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt.
      explanation: Single clinical case with documented treatment.
  - target: Seizures
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: These patients had airway compromise, seizures, and two died by age 15 months.
      explanation: Seizures in the selected molecularly confirmed series.
  - target: Neurodevelopmental delay
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9714439
      reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
      explanation: Unspecified severe developmental delay in one case.
  - target: Spinal dysraphism
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9605588
      reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS.
      explanation: Single index-case observation.
  - target: Caudal appendage
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12072807
      reference_title: Sacral appendage associated with a mutation in FGFR2.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We report a baby with craniosynostosis and a sacral appendage who has been found to have a Ser351Cys mutation in the fibroblast growth factor receptor 2 gene (FGFR2).
      explanation: Genotype-confirmed appendage.
  - target: Broad hallux
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9714439
      reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe.
      explanation: Single case; normal thumbs do not exclude the allele.
  - target: Hallux varus
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34909104
      reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: wide sandal gap and medially deviated broad great toes
      explanation: Direct clinical description; no prevalence inference.
  - target: Feeding difficulties
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34909104
      reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Baby graduated from feeding via nasogastric tube to cup feeding.
      explanation: Observed feeding support in one hospitalized infant.
  - target: Intestinal malrotation
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9714439
      reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
      explanation: Single case of non-rotation.
  - target: Femoral bowing
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15793702
      reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 15b | 14506 | Y | Y | Y | Y | Y | Y | Y |  | N | N | Y |  |
      explanation: 'Table 1 row 15: the femoral-bowing column is positive; Table 4 identifies FGFR2 S351C. Blank cells are unreported, not negative.'
  - target: Femur fracture
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15793702
      reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 15b | 14506 | Y | Y | Y | Y | Y | Y | Y |  | N | N | Y |  |
      explanation: Table 1 femoral-fracture column is positive for patient 15; Table 4 assigns S351C.
  - target: Wide anterior fontanel
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
      explanation: Large anterior fontanelle reported in the same-allele series.
  - target: Hypertelorism
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34909104
      reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: proptosis with ocular hypertelorism (Figure 1), low set ears, protruding tongue
      explanation: Direct clinical observation; no prevalence inference.
- name: Aberrant FGFR2 Disulfide Dimerization
  description: Aberrant intermolecular disulfide bonding is the proposed activating mechanism for p.Ser351Cys and a supported mechanism for the broader extracellular FGFR2 mutation class. Reducible dimers were demonstrated in heterologous assays of other FGFR2 variants; the cited study did not test p.Ser351Cys itself.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: All three cases were found to have the same FGFR2 Ser351Cys (1231C to G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding.
    explanation: The human case report explicitly identifies a predicted, not measured, receptor mechanism.
    directness: INDIRECT
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Additionally, the dimerization observed for both of these mutants was reducible, indicating that the dimerization was accomplished by disulfide bond formation.
    explanation: Reducible dimers in COS-1 experiments with W290G/T341P and cysteine-loss controls support the molecular class mechanism, not a p.Ser351Cys assay.
    directness: INDIRECT
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Increased FGFR2 Kinase Activity
    description: Dimerization accompanies kinase activation in related extracellular mutants; cysteine removal suppresses both in the tested constructs.
    causal_link_type: DIRECT
    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
      quote_role: PRIMARY_RESULT
      snippet: All of the receptors that formed dimers, as shown in Fig.3A, also exhibited significant phosphorylation of the dimeric form of the receptor, demonstrating activation of the receptor (Fig.4A).
      explanation: Heterologous class evidence.
      directness: INDIRECT
- name: Increased FGFR2 Kinase Activity
  genes:
  - preferred_term: FGFR2
    term:
      id: hgnc:3689
      label: FGFR2
  description: Enhanced receptor tyrosine phosphorylation and kinase activity are established for tested activating extracellular FGFR2 variants. Application to p.Ser351Cys is a class-based inference; neither patient suture kinase activity nor the degree of activation of this allele was measured in the cited experiments.
  biological_scale: MOLECULAR
  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
    quote_role: PRIMARY_RESULT
    snippet: All of the receptors that formed dimers, as shown in Fig.3A, also exhibited significant phosphorylation of the dimeric form of the receptor, demonstrating activation of the receptor (Fig.4A).
    explanation: Full-length receptor kinase assays in transfected COS-1 cells tested related variants.
    directness: INDIRECT
  molecular_functions:
  - preferred_term: transmembrane receptor protein tyrosine kinase activity
    term:
      id: GO:0004714
      label: transmembrane receptor protein tyrosine kinase activity
    modifier: INCREASED
  conforms_to: fgfr_gain_of_function_skeletal_dysplasia#Constitutive FGFR Activation
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Altered Suture Osteogenic Differentiation
    description: Altered receptor signaling is proposed to change osteogenic cell behavior through downstream signaling pathways.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29230096
      reference_title: Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: FGFR2 in cranial sutures is largely expressed in differentiating osteoblasts and osteoprogenitor cells. Via downstream pathways, FGF/FGFR2 signaling mediates osteoprogenitor proliferation, differentiation, and apoptosis 25,40. Early differentiation is thought to be a leading factor involved in premature suture fusion 3.
      explanation: Genotype-specific intermediates remain unresolved.
      directness: INDIRECT
- name: Altered Suture Osteogenic Differentiation
  description: Disordered timing of osteogenic differentiation in cranial suture mesenchyme is a proposed tissue mechanism connecting activated FGFR2 signaling to premature ossification. Much of the evidence comes from other FGFR2 genotypes and models; accelerated differentiation has not been measured in p.Ser351Cys patient sutures in the cited sources.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:29230096
    reference_title: Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: FGFR2 in cranial sutures is largely expressed in differentiating osteoblasts and osteoprogenitor cells. Via downstream pathways, FGF/FGFR2 signaling mediates osteoprogenitor proliferation, differentiation, and apoptosis 25,40. Early differentiation is thought to be a leading factor involved in premature suture fusion 3.
    explanation: The review summarizes FGFR2 biology and a proposed differentiation mechanism; this is not a direct assay in the allele-specific clinical cohort.
    directness: INDIRECT
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: ABNORMAL
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  conforms_to: fgfr_gain_of_function_skeletal_dysplasia#Cranial Suture Osteogenic Acceleration
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Premature Cranial Suture Fusion
    description: Premature osteogenic differentiation is one proposed contributor to suture ossification.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29230096
      reference_title: Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: FGFR2 in cranial sutures is largely expressed in differentiating osteoblasts and osteoprogenitor cells. Via downstream pathways, FGF/FGFR2 signaling mediates osteoprogenitor proliferation, differentiation, and apoptosis 25,40. Early differentiation is thought to be a leading factor involved in premature suture fusion 3.
      explanation: Review-level mechanism extrapolated to this presentation.
      directness: INDIRECT
- name: Premature Cranial Suture Fusion
  description: Early fusion of one or multiple cranial sutures alters skull growth. The sutures involved and timing of fusion influence head shape; cloverleaf skull is not obligatory. This anatomical event does not by itself explain all facial, ocular and limb malformations.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: Craniosynostosis with variable skull shape in three molecularly confirmed p.Ser351Cys cases.
  conforms_to: fgfr_gain_of_function_skeletal_dysplasia#Premature Suture Fusion and Craniosynostosis
  downstream:
  - target: Reduced Bony Orbital Depth
    description: Coronal suture and maxillary growth abnormalities contribute to a shallow orbit.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
      reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Coronal craniosynostosis and underdevelopment of the maxillary arches results in decreased depth of the bony orbit and proptosis.
      explanation: Anatomical synthesis from the broader FGFR spectrum.
      directness: INDIRECT
  - target: Craniosynostosis
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
      explanation: Three molecularly confirmed p.Ser351Cys cases.
  - target: Cloverleaf skull
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
      explanation: Explicit with-and-without cloverleaf morphology.
  - target: Brachycephaly
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15793702
      reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: 15b | 14506 | Y | Y | Y | Y | Y | Y | Y |  | N | N | Y |  |
      explanation: Positive brachycephaly column for S351C patient 15.
- name: Midfacial Skeletal Hypoplasia
  description: Underdevelopment of midfacial bones contributes to retrusion and upper airway narrowing. It is part of the FGFR2 developmental phenotype, rather than an assumed inevitable downstream consequence of fused calvarial sutures.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: Midface hypoplasia in the p.Ser351Cys clinical series.
  downstream:
  - target: Reduced Bony Orbital Depth
    description: Underdeveloped maxillary arches contribute to orbital shallowness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
      reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Coronal craniosynostosis and underdevelopment of the maxillary arches results in decreased depth of the bony orbit and proptosis.
      explanation: Anatomical synthesis.
      directness: INDIRECT
  - target: Upper Airway Narrowing
    description: Reduced nasal skeletal dimensions contribute to obstructed airflow.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
      reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Narrowed nasal passages as a result of bony atresia or stenosis, including choanal atresia or stenosis.
      explanation: The contribution varies with airway level and age.
      directness: INDIRECT
  - target: Midface retrusion
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
      explanation: Allele-matched series.
- name: Reduced Bony Orbital Depth
  description: Shallow bony orbits contribute to proptosis and, when severe, globe subluxation and inadequate lid closure. Structural anterior chamber abnormalities are a separate ocular manifestation.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Coronal craniosynostosis and underdevelopment of the maxillary arches results in decreased depth of the bony orbit and proptosis.
    explanation: General FGFR craniosynostosis anatomy explains orbital manifestations seen in p.Ser351Cys cases.
    directness: INDIRECT
  downstream:
  - target: Proptosis
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9714439
      reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
      explanation: Genotype-confirmed severe ocular finding.
- name: Upper Airway Narrowing
  description: Choanal stenosis or atresia and reduced midfacial dimensions can obstruct airflow. Obstruction may occur at multiple levels, so its anatomical source should be assessed rather than attributed exclusively to the choanae.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: Choanal narrowing in the p.Ser351Cys series.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Narrowed nasal passages as a result of bony atresia or stenosis, including choanal atresia or stenosis.
    explanation: Anatomical airway contribution in the FGFR clinical baseline.
    directness: INDIRECT
  downstream:
  - target: Choanal atresia
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10406670
      reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
      explanation: The series describes choanal stenosis/atresia.
  - target: Upper airway obstruction
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9714439
      reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
      explanation: One allele-matched case.
  - target: Respiratory distress
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34909104
      reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The clinical problems identified on initial assessment were respiratory distress which was evidenced by deep laboured breathing with poor oxygen saturation of 55% on room air, seizures of the upper limbs, high-grade fever, and pallor.
      explanation: Case observation with concurrent neonatal illness.
- name: Developmental Joint Synostosis
  description: Bony fusion at the elbow may involve the humerus and radius or the radius and ulna. Contractures can also occur without synostosis; an unmeasured acceleration of osteoblast differentiation at every affected joint should not be assumed from clinical ankylosis.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:9605588
    reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS.
    explanation: Index joint observation.
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patient 29 had radioulnar—but not radiohumeral—synostosis, knee contractures without synostosis and Peters anomaly, and was subsequently considered to have Crouzon syndrome.
    explanation: Radioulnar rather than radiohumeral fusion in one p.Ser351Cys patient; knee contractures lacked bony fusion.
  downstream:
  - target: Elbow ankylosis
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9605588
      reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS.
      explanation: Positive index-case observation.
  - target: Radioulnar synostosis
    description: This clinical finding is reported with the FGFR2 genotype; its intervening developmental or physiological pathway is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15793702
      reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Patient 29 had radioulnar—but not radiohumeral—synostosis, knee contractures without synostosis and Peters anomaly, and was subsequently considered to have Crouzon syndrome.
      explanation: Anatomically specified positive observation.
genetic:
- name: FGFR2 extracellular variants
  gene_term:
    preferred_term: FGFR2
    term:
      id: hgnc:3689
      label: FGFR2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: p.Ser351Cys is recurrent across Antley–Bixler, Pfeiffer and Crouzon labels. The 2005 selected cohort included five p.Ser351Cys cases, C342S and C342R, with earlier cases reanalyzed; this is not an independent population-frequency estimate. The article disagrees between F276V in Table4 and P276V in the narrative for another allele, so that uncertain spelling is not promoted here. A heterozygous variant must be interpreted with phenotype and appropriate classification, not merely the syndrome name.
  evidence:
  - reference: PMID:9605588
    reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The patient was found to be heterozygous for a C-->G transversion at nucleotide 1064, which predicts a Ser351Cys amino acid substitution in the IgIII domain of FGFR2.
    explanation: Index variant.
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: FGFR2 mutation S351C was found in five patients, other FGFR2 mutations (C342S, C342R, and P276V) were found in three other patients
    explanation: Selected cohort supports multiple FGFR2 alleles; the source-internal P276V/F276V discrepancy is retained as a limitation.
phenotypes:
- name: Craniosynostosis
  category: Craniofacial
  description: Premature fusion may involve multiple sutures; the shape and extent vary.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: Three molecularly confirmed p.Ser351Cys cases.
- name: Elbow ankylosis
  category: Skeletal
  description: Elbow ankylosis is reported in allele-matched cases. The abstract does not always resolve humeroradial versus radioulnar fusion; the term does not convert non-bony contracture into proven synostosis.
  phenotype_term:
    preferred_term: Elbow ankylosis
    term:
      id: HP:0003070
      label: Elbow ankylosis
  evidence:
  - reference: PMID:9605588
    reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS.
    explanation: Positive index-case observation.
- name: Radioulnar synostosis
  category: Skeletal
  description: Documented in one p.Ser351Cys individual initially ascertained as ABS and later labelled Crouzon syndrome; radiohumeral fusion was absent.
  phenotype_term:
    preferred_term: Radioulnar synostosis
    term:
      id: HP:0002974
      label: Radioulnar synostosis
  evidence:
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patient 29 had radioulnar—but not radiohumeral—synostosis, knee contractures without synostosis and Peters anomaly, and was subsequently considered to have Crouzon syndrome.
    explanation: Anatomically specified positive observation.
- name: Multiple joint contractures
  category: Skeletal
  description: Elbow and knee contractures can occur without synostosis, so contracture and bony fusion are represented separately.
  phenotype_term:
    preferred_term: Multiple joint contractures
    term:
      id: HP:0002828
      label: Multiple joint contractures
  evidence:
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patient 28 had a 2.5-cm phallus, contractures of the elbows and knees without synostosis and Peters anomaly, and was subsequently considered to have Pfeiffer syndrome.
    explanation: One p.Ser351Cys case with non-fused contracted joints.
- name: Dislocated radial head
  category: Skeletal
  description: Reported in a p.Ser351Cys case labelled Pfeiffer type III; not a defining or obligatory finding.
  phenotype_term:
    preferred_term: Dislocated radial head
    term:
      id: HP:0003083
      label: Dislocated radial head
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe.
    explanation: Single genotype-confirmed clinical case.
- name: Midface retrusion
  category: Craniofacial
  description: Midfacial hypoplasia contributes to reduced nasal dimensions and the characteristic facial profile.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: Allele-matched series.
- name: Choanal atresia
  category: Respiratory
  description: Atresia or stenosis was reported in selected p.Ser351Cys cases. The combined source wording is not a separate atresia frequency.
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: The series describes choanal stenosis/atresia.
- name: Upper airway obstruction
  category: Respiratory
  description: May present at birth and can involve more than one airway level.
  phenotype_term:
    preferred_term: Upper airway obstruction
    term:
      id: HP:0002781
      label: Upper airway obstruction
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
    explanation: One allele-matched case.
- name: Respiratory distress
  category: Respiratory
  description: Severe respiratory difficulty has been reported in infancy. Infection and perinatal illness can contribute, so not every respiratory event is assigned to structural obstruction alone.
  phenotype_term:
    preferred_term: Respiratory distress
    term:
      id: HP:0002098
      label: Respiratory distress
  evidence:
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The clinical problems identified on initial assessment were respiratory distress which was evidenced by deep laboured breathing with poor oxygen saturation of 55% on room air, seizures of the upper limbs, high-grade fever, and pallor.
    explanation: Case observation with concurrent neonatal illness.
- name: Proptosis
  category: Ophthalmologic
  description: Prominent globes may be severe enough for subluxation or luxation and inadequate lid closure.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
    explanation: Genotype-confirmed severe ocular finding.
- name: Peters anomaly
  category: Ophthalmologic
  description: Anterior segment dysgenesis was reported in two of three patients selected for ocular investigation. This ascertainment does not provide a general disease frequency.
  phenotype_term:
    preferred_term: Peters anomaly
    term:
      id: HP:0000659
      label: Peters anomaly
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We evaluated three unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles.
    explanation: Selected p.Ser351Cys ocular series.
- name: Corneal opacity
  category: Ophthalmologic
  description: Structural corneal opacity was reported with anterior segment dysgenesis. It should not automatically be attributed to exposure injury from proptosis.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles.
    explanation: Primary anatomical finding in the selected ocular series.
- name: Cloverleaf skull
  category: Craniofacial
  description: Present in some severe presentations but absent in others, including patients labelled Pfeiffer type III.
  phenotype_term:
    preferred_term: Cloverleaf skull
    term:
      id: HP:0002676
      label: Cloverleaf skull
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: Explicit with-and-without cloverleaf morphology.
- name: Hydrocephalus
  category: Neurologic
  description: Reported in several allele-matched cases; some required cerebrospinal fluid diversion.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:16465081
    reference_title: Syndromic craniosynostosis with elbow joint contracture.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt.
    explanation: Single clinical case with documented treatment.
- name: Seizures
  category: Neurologic
  description: Reported in severe p.Ser351Cys presentations. Perinatal hypoxia and intercurrent infection confound the 2021 case; the available reports do not establish a primary allele-specific epilepsy mechanism.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: These patients had airway compromise, seizures, and two died by age 15 months.
    explanation: Seizures in the selected molecularly confirmed series.
- name: Neurodevelopmental delay
  category: Neurologic
  description: Severe developmental delay is reported, but domains, ages and secondary neurological complications vary. It is not an obligatory intellectual-disability phenotype.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
    explanation: Unspecified severe developmental delay in one case.
- name: Spinal dysraphism
  category: Neurologic
  description: A severe spinal closure abnormality was reported in the index p.Ser351Cys case. A sacral appendage or dimple alone does not establish this finding.
  phenotype_term:
    preferred_term: Spinal dysraphism
    term:
      id: HP:0010301
      label: Spinal dysraphism
  evidence:
  - reference: PMID:9605588
    reference_title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS.
    explanation: Single index-case observation.
- name: Caudal appendage
  category: Skeletal
  description: A sacral appendage or pseudotail is reported in separate p.Ser351Cys case reports. Its underlying spinal anatomy requires assessment rather than inference.
  phenotype_term:
    preferred_term: Caudal appendage
    term:
      id: HP:0002825
      label: Caudal appendage
  evidence:
  - reference: PMID:12072807
    reference_title: Sacral appendage associated with a mutation in FGFR2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We report a baby with craniosynostosis and a sacral appendage who has been found to have a Ser351Cys mutation in the fibroblast growth factor receptor 2 gene (FGFR2).
    explanation: Genotype-confirmed appendage.
- name: Broad hallux
  category: Skeletal
  description: Broad great toes may occur despite normal-appearing thumbs, explaining overlap with Pfeiffer syndrome.
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe.
    explanation: Single case; normal thumbs do not exclude the allele.
- name: Hallux varus
  category: Skeletal
  description: Medial deviation of broad great toes was reported in the 2021 p.Ser351Cys case.
  phenotype_term:
    preferred_term: Hallux varus
    term:
      id: HP:0008080
      label: Hallux varus
  evidence:
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: wide sandal gap and medially deviated broad great toes
    explanation: Direct clinical description; no prevalence inference.
- name: Feeding difficulties
  category: Gastrointestinal
  description: Feeding support may be required during neonatal respiratory illness; the reported nasogastric feeding requirement does not establish chronic dysphagia in every affected person.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Baby graduated from feeding via nasogastric tube to cup feeding.
    explanation: Observed feeding support in one hospitalized infant.
- name: Intestinal malrotation
  category: Gastrointestinal
  description: Intestinal non-rotation was reported in one p.Ser351Cys case; the association does not establish a recurrent penetrance estimate.
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay.
    explanation: Single case of non-rotation.
- name: Femoral bowing
  category: Skeletal
  description: Femoral bowing was recorded in the 2005 cohort, including patient 15 with S351C. The reused, selected cohort is not a prevalence sample.
  phenotype_term:
    preferred_term: Femoral bowing
    term:
      id: HP:0002980
      label: Femoral bowing
  evidence:
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 15b | 14506 | Y | Y | Y | Y | Y | Y | Y |  | N | N | Y |  |
    explanation: 'Table 1 row 15: the femoral-bowing column is positive; Table 4 identifies FGFR2 S351C. Blank cells are unreported, not negative.'
- name: Femur fracture
  category: Skeletal
  description: Femoral fractures were recorded in selected FGFR2 cases, including S351C patient 15. Their timing, injury mechanism and general fracture risk cannot be established from the summary row.
  phenotype_term:
    preferred_term: Femur fracture
    term:
      id: HP:0031846
      label: Femur fracture
  evidence:
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 15b | 14506 | Y | Y | Y | Y | Y | Y | Y |  | N | N | Y |  |
    explanation: Table 1 femoral-fracture column is positive for patient 15; Table 4 assigns S351C.
- name: Brachycephaly
  category: Craniofacial
  description: Recorded cranial shape in the selected FGFR2 cohort; different suture patterns can produce different skull shapes.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 15b | 14506 | Y | Y | Y | Y | Y | Y | Y |  | N | N | Y |  |
    explanation: Positive brachycephaly column for S351C patient 15.
- name: Wide anterior fontanel
  category: Craniofacial
  description: A large anterior fontanelle can coexist with fusion of other sutures; it does not exclude craniosynostosis.
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanelle, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/ atresia, midface hypoplasia, and elbow contractures were also present.
    explanation: Large anterior fontanelle reported in the same-allele series.
- name: Hypertelorism
  category: Craniofacial
  description: Widely spaced orbits were described in the genotype-confirmed 2021 infant.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: proptosis with ocular hypertelorism (Figure 1), low set ears, protruding tongue
    explanation: Direct clinical observation; no prevalence inference.
progression:
- phase: Congenital and early childhood presentation
  notes: Craniofacial, joint and airway abnormalities can be apparent at birth; hydrocephalus and the full craniosynostosis phenotype may become evident later. Severe early morbidity and deaths are described in selected reports, but publication bias, overlapping patients and syndrome-label variation preclude a survival estimate. The 2021 infant died after discharge without autopsy, so a specific terminal mechanism was not established.
  evidence:
  - reference: PMID:16465081
    reference_title: Syndromic craniosynostosis with elbow joint contracture.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At birth, a male infant had ocular proptosis, a pseudotail, and obstructed respiration. He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints.
    explanation: Congenital findings and subsequent evolution.
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: These patients had airway compromise, seizures, and two died by age 15 months.
    explanation: Selected-case outcomes, not a survival cohort.
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The child was reported to have become lethargic and died some hours after reporting to the district hospital. An autopsy was not done.
    explanation: Cause of death remains unverified.
treatments:
- name: Cranial vault expansion and reconstruction
  description: A specialist craniofacial team individualizes cranial surgery to suture anatomy, intracranial pressure and respiratory status. General FGFR guidance places multisuture repair in the first year, often with staged posterior expansion and later fronto-orbital procedures. The p.Ser351Cys literature documents treatment use, not comparative surgical efficacy.
  action_category: THERAPEUTIC
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased intracranial pressure and reduce progressive abnormal craniofacial development.
    explanation: General FGFR clinical baseline, extrapolated to the molecularly confirmed presentation.
    directness: INDIRECT
  - reference: PMID:16465081
    reference_title: Syndromic craniosynostosis with elbow joint contracture.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt.
    explanation: Observed treatment in one allele-matched case.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Premature Cranial Suture Fusion
    treatment_effect: MODULATES
    description: Release of fused sutures and reconstruction expand the cranial vault; staged anatomy-specific procedures address consequences of premature fusion.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
      reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased intracranial pressure and reduce progressive abnormal craniofacial development.
      explanation: General FGFR clinical baseline, extrapolated to the molecularly confirmed presentation.
      directness: INDIRECT
    - reference: PMID:16465081
      reference_title: Syndromic craniosynostosis with elbow joint contracture.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt.
      explanation: Observed treatment in one allele-matched case.
- name: Airway stabilization and treatment of obstruction
  description: Urgent respiratory support and specialist airway assessment are tailored to the obstruction level. Nasal stents, intubation or tracheotomy may be needed. Sleep-apnea interventions depend on severity, age and anatomy; residual obstruction is common. CPAP/BiPAP can be an interim option with craniofacial and ocular precautions. The older GeneReviews concern about prolonged mask pressure is not a ban on acute support.
  action_category: THERAPEUTIC
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Infants &#x00026; children requiring tracheotomy may also need ventilator-delivered positive pressure to normalize gas exchange &#x00026; achieve normal sleep &#x00026; growth.
    explanation: General FGFR guidance for bypass and ventilatory support; literal HTML entities retain generated source wording.
    directness: INDIRECT
  - reference: PMID:33156164
    reference_title: Updated Guideline on Treatment and Management of Craniosynostosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Select treatment for OSA based on severity of OSA, age of patient, causal factors, feasibility of treatment and possibly other functional problems (such as increased ICP or exorbitism).
    explanation: Syndromic craniosynostosis guideline; not allele-specific comparative evidence.
    directness: INDIRECT
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Oxygen support was administered via CPAP and the baby was haemotransfused.
    explanation: One infant received CPAP during concurrent neonatal illness, not proof of chronic superiority.
  target_mechanisms:
  - target: Upper Airway Narrowing
    treatment_effect: BYPASSES
    description: Stenting, intubation or tracheotomy can bypass the obstructed segment; positive-pressure support is selected according to residual obstruction and gas exchange.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
      reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Infants &#x00026; children requiring tracheotomy may also need ventilator-delivered positive pressure to normalize gas exchange &#x00026; achieve normal sleep &#x00026; growth.
      explanation: General FGFR guidance for bypass and ventilatory support; literal HTML entities retain generated source wording.
      directness: INDIRECT
    - reference: PMID:33156164
      reference_title: Updated Guideline on Treatment and Management of Craniosynostosis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Select treatment for OSA based on severity of OSA, age of patient, causal factors, feasibility of treatment and possibly other functional problems (such as increased ICP or exorbitism).
      explanation: Syndromic craniosynostosis guideline; not allele-specific comparative evidence.
      directness: INDIRECT
    - reference: PMID:34909104
      reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Oxygen support was administered via CPAP and the baby was haemotransfused.
      explanation: One infant received CPAP during concurrent neonatal illness, not proof of chronic superiority.
- name: Midface advancement
  description: Midface or combined craniofacial advancement is considered when airway compromise or occlusion justifies it. Severe obstructive sleep apnea can prompt earlier surgery; timing and procedure require a multidisciplinary assessment rather than a fixed allele-based schedule.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:33156164
    reference_title: Updated Guideline on Treatment and Management of Craniosynostosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Consider Le Fort III surgery or monobloc advancement in children with syndromic craniosynostosis and severe respiratory OSA to treat the respiratory problems. If necessary, combine this procedure with a mandibula advancement.
    explanation: Guideline recommendation for selected severe syndromic obstruction; evidence is not specific to FGFR2-related ABS.
    directness: INDIRECT
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Midfacial Skeletal Hypoplasia
    treatment_effect: MODULATES
    description: Advancing the hypoplastic midface changes skeletal position and may enlarge the airway in selected patients with severe obstruction.
    evidence:
    - reference: PMID:33156164
      reference_title: Updated Guideline on Treatment and Management of Craniosynostosis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Consider Le Fort III surgery or monobloc advancement in children with syndromic craniosynostosis and severe respiratory OSA to treat the respiratory problems. If necessary, combine this procedure with a mandibula advancement.
      explanation: Guideline recommendation for selected severe syndromic obstruction; evidence is not specific to FGFR2-related ABS.
      directness: INDIRECT
- name: Hydrocephalus management
  description: Neurosurgical assessment determines whether cerebrospinal fluid diversion is required. Ventriculoperitoneal shunting was reported in a p.Ser351Cys infant; this is a case-level intervention, not evidence that all enlarged ventricles require shunting.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:16465081
    reference_title: Syndromic craniosynostosis with elbow joint contracture.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt.
    explanation: Positive disease-matched intervention.
  treatment_term:
    preferred_term: Ventriculoperitoneal Shunt Placement
    term:
      id: NCIT:C168483
      label: Ventriculoperitoneal Shunt Placement
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Hydrocephalus
    treatment_effect: BYPASSES
    description: Ventriculoperitoneal diversion bypasses impaired cerebrospinal-fluid drainage when neurosurgical assessment supports shunting.
    evidence:
    - reference: PMID:16465081
      reference_title: Syndromic craniosynostosis with elbow joint contracture.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: He developed craniosynostosis, craniofacial dysmorphism, hydrocephalus, and bilateral contracture of his elbow joints. His treatment included fronto-orbital advancements and a ventriculoperitoneal shunt.
      explanation: Positive disease-matched intervention.
- name: Ocular surface protection
  description: Ophthalmology assesses exposure, globe subluxation, vision and structural anterior segment abnormalities. Lubrication and, when necessary, tarsorrhaphy protect an inadequately covered cornea; they do not correct congenital Peters anomaly or establish reversal of globe protrusion.
  action_category: THERAPEUTIC
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Tarsorrhaphy may be indicated, e.g., w/globe subluxation or to prevent globe luxation &#x00026;/or exposure keratopathy.
    explanation: General FGFR guidance provides the preventive indication; raw cache retains the ampersand entity.
    directness: INDIRECT
  target_mechanisms:
  - target: Proptosis
    treatment_effect: BYPASSES
    description: Lubrication or eyelid closure protects the exposed cornea despite persistent globe protrusion; this does not reverse the underlying orbital anatomy.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
      reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Tarsorrhaphy may be indicated, e.g., w/globe subluxation or to prevent globe luxation &#x00026;/or exposure keratopathy.
      explanation: General FGFR guidance provides the preventive indication; raw cache retains the ampersand entity.
      directness: INDIRECT
- name: Feeding and swallowing support
  description: Assess swallowing safety and oral intake, including after craniofacial operations. Feeding therapy and temporary tube support are individualized. The reported transition from nasogastric to cup feeding occurred during recovery from neonatal illness. Evaluate possible intestinal malrotation before gastrostomy as advised in the general FGFR baseline.
  action_category: THERAPEUTIC
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Feeding therapy is helpful to assess swallowing safety &#x00026; support eating by mouth.
    explanation: Clinical baseline recommendation.
    directness: INDIRECT
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Baby graduated from feeding via nasogastric tube to cup feeding.
    explanation: Observed support and transition in one infant.
  target_mechanisms:
  - target: Feeding difficulties
    treatment_effect: BYPASSES
    description: Temporary nasogastric or other tube feeding provides intake when oral feeding is unsafe or inadequate; feeding therapy separately supports swallowing and oral intake.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
      reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Feeding therapy is helpful to assess swallowing safety &#x00026; support eating by mouth.
      explanation: Clinical baseline recommendation.
      directness: INDIRECT
    - reference: PMID:34909104
      reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Baby graduated from feeding via nasogastric tube to cup feeding.
      explanation: Observed support and transition in one infant.
- name: Seizure treatment
  description: Treat seizures according to their cause and clinical course. Phenobarbital and phenytoin were used in the reported neonate with concurrent hypoxic and infectious complications; this does not establish an allele-specific preferred antiseizure drug.
  action_category: THERAPEUTIC
  evidence:
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: IV phenobarbitone and phenytoin were administered to control the seizures
    explanation: Disease-matched treatment use with confounding acute illness.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_mechanisms:
  - target: Seizures
    treatment_effect: INHIBITS
    description: Antiseizure medication suppresses clinical seizures; the reported acute neonatal treatment does not demonstrate correction of FGFR2 signaling.
    evidence:
    - reference: PMID:34909104
      reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: IV phenobarbitone and phenytoin were administered to control the seizures
      explanation: Disease-matched treatment use with confounding acute illness.
- name: Developmental and rehabilitation support
  description: Early intervention, speech assessment and neurodevelopmental review address documented delays and functional needs. Limb evaluation distinguishes fixed bony fusion from soft-tissue contractures; the sources do not establish that physical therapy reverses synostosis.
  action_category: THERAPEUTIC
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Consider consultation w/developmental pediatrician or neurodevelopmental specialist.
    explanation: General FGFR management of developmental delay.
    directness: INDIRECT
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
- name: Multidisciplinary surveillance
  description: Monitor head growth and symptoms of raised intracranial pressure, with frequent assessment in infancy and at least annual ophthalmological evaluation. Evaluate hearing, dentition, speech and development. The 2020 craniosynostosis guideline recommends annual type 1 polysomnography through at least age six for syndromic children, in addition to symptom-triggered assessment. Surgical and anesthetic planning should consider airway anatomy, possible cervical anomalies and eye protection.
  action_category: MONITORING
  evidence:
  - reference: PMID:33156164
    reference_title: Updated Guideline on Treatment and Management of Craniosynostosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Screen children with syndromic craniosynostosis annually by type 1 polysomnography at a center of expertise until at least the age of 6 years.
    explanation: Updated guideline surveillance; not restricted to a genotype.
    directness: INDIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Individuals with cervical spine anomalies may be at risk for spinal cord injury with hyperextension and may require fiberoptic intubation and/or sports restrictions for activities that pose a risk for head/neck injury.
    explanation: Conditional precaution for those with cervical anomalies, not a claim that all have instability.
    directness: INDIRECT
- name: Genetic counseling and family evaluation
  description: Explain autosomal-dominant transmission, variable expression and the distinction from recessive POR deficiency. Confirm the familial variant before predictive, prenatal or preimplantation testing, and assess apparently unaffected relatives when appropriate. Negative parental blood testing cannot eliminate possible germline mosaicism.
  action_category: COUNSELING_INFORMATIONAL
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual
    explanation: The full chapter recommends early identification of relatives who may benefit from surveillance.
    directness: INDIRECT
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
diagnosis:
- name: Molecular diagnosis with phenotype and variant interpretation
  description: Use craniofacial and limb examination, imaging and molecular testing to establish the FGFR2-related diagnosis. A craniosynostosis panel can address the overlapping FGFR spectrum and alternatives. Sequence-based testing detected p.Ser351Cys after older SSCP screening was negative in one case; that observation does not estimate present-day panel sensitivity.
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis.
    explanation: Actual method limitation in one historical case.
  - reference: PMID:34909104
    reference_title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: sequence analysis using Illumina technology and deletion/duplication testing of 65 genes for variants associated with craniosynostosis syndromes was performed
    explanation: Case-level panel approach, not universal diagnostic performance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
    reference_title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing.
    explanation: GeneReviews recommends molecular confirmation of an FGFR craniosynostosis diagnosis; phenotype and variant interpretation establish its specific scope.
    directness: INDIRECT
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
- name: Cranial and joint imaging
  description: Document the sutures and bones involved, and distinguish radiohumeral or radioulnar fusion from non-bony contracture. Evaluate hydrocephalus and other neurological complications as indicated. Neither elbow ankylosis nor a sacral appendage alone specifies the complete anatomical abnormality.
  evidence:
  - reference: PMID:15793702
    reference_title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: craniosynostosis and radioulnar or radiohumeral synostosis were confirmed radiographically.
    explanation: Method used in the mixed, genotype-stratified cohort.
- name: Steroid assessment when distinguishing POR deficiency
  description: An initial ABS phenotype warrants assessment for steroidogenic disease when the genetic diagnosis is unresolved or endocrine concerns persist. Urinary steroid profiling and specialist adrenal assessment can detect abnormalities missed by genital appearance or limited basal measurements. Established FGFR2 disease alone is not an indication for glucocorticoid replacement.
  evidence:
  - reference: PMID:16145814
    reference_title: 'Use of the term "Antley-Bixler syndrome": minimizing confusion.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Steroid abnormalities associated with POR deficiency and ABS are not always recognized without the use of urinary steroid profiling
    explanation: Review of the diagnostic distinction.
  - reference: PMID:16145814
    reference_title: 'Use of the term "Antley-Bixler syndrome": minimizing confusion.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The presence of ambiguous genitalia is not necessary for making a diagnosis of POR deficiency.
    explanation: Normal genital appearance does not exclude the alternative diagnosis.
differential_diagnoses:
- name: P450 oxidoreductase deficiency
  description: Recessive POR deficiency can share craniosynostosis, elbow synostosis and limb abnormalities, with variable steroidogenic and genital manifestations. Normal genitalia do not exclude it. Genotype and biochemical assessment are more discriminating than the ABS eponym.
  distinguishing_features:
  - Biallelic POR variants and characteristic steroid abnormalities support POR deficiency.
  - FGFR2-associated disease generally lacks the primary POR steroidogenic defect.
  evidence:
  - reference: PMID:16145814
    reference_title: 'Use of the term "Antley-Bixler syndrome": minimizing confusion.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The presence of ambiguous genitalia is not necessary for making a diagnosis of POR deficiency.
    explanation: Diagnostic caution from the nomenclature review.
- name: Pfeiffer and Crouzon syndromes
  description: These clinical labels overlap with the same p.Ser351Cys genotype, so they are alternative spectrum classifications rather than always genetically separable diagnoses. Normal thumbs do not exclude a severe Pfeiffer-labelled presentation.
  distinguishing_features:
  - Assess the complete cranial, limb and ocular phenotype without using elbow fusion as a unique discriminator.
  evidence:
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs.
    explanation: Same-allele phenotypic overlap.
experimental_models:
- name: Full-length FGFR2 expression in COS-1 cells
  experimental_model_type: CELL_LINE
  cell_source: Immortalized simian COS-1 cells transiently transfected with human FGFR2 constructs
  description: Related extracellular FGFR2 variants formed reducible receptor dimers and showed increased autophosphorylation and phosphotyrosine signal. Combining W290G or T341P with C278A/C342A removed these effects. The assay supports a disulfide-dependent class mechanism, with low translational fidelity to the untested S351C allele and developing human cranial sutures.
  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
    quote_role: PRIMARY_RESULT
    snippet: COS-1 cells were transfected with full-length FGFR2 constructs described in Fig.1.
    explanation: Actual full-length receptor preparation.
  modeled_mechanisms:
  - target: Aberrant FGFR2 Disulfide Dimerization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: Related mutant constructs increased dimer formation under nonreducing conditions.
    limitations: Transient heterologous expression of W290G, T341P, C278F, C342Y and engineered cysteine controls; p.Ser351Cys was not tested. These assays do not measure cranial differentiation, joint fusion, patient tissue signaling or a disease rescue. Reducibility supports disulfide-mediated association without directly mapping individual intermolecular bonds.
    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
      quote_role: PRIMARY_RESULT
      snippet: Additionally, the dimerization observed for both of these mutants was reducible, indicating that the dimerization was accomplished by disulfide bond formation.
      explanation: Related mutant constructs increased dimer formation under nonreducing conditions.
      directness: INDIRECT
    readouts:
    - name: Reducible FGFR2 dimer bands
      target: Aberrant FGFR2 Disulfide Dimerization
      direction: INCREASED
      interpretation: Related mutant constructs increased dimer formation under nonreducing conditions.
      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
        quote_role: PRIMARY_RESULT
        snippet: Additionally, the dimerization observed for both of these mutants was reducible, indicating that the dimerization was accomplished by disulfide bond formation.
        explanation: Related mutant constructs increased dimer formation under nonreducing conditions.
        directness: INDIRECT
  - target: Increased FGFR2 Kinase Activity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
    limitations: Transient heterologous expression of W290G, T341P, C278F, C342Y and engineered cysteine controls; p.Ser351Cys was not tested. These assays do not measure cranial differentiation, joint fusion, patient tissue signaling or a disease rescue. Reducibility supports disulfide-mediated association without directly mapping individual intermolecular bonds.
    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
      quote_role: PRIMARY_RESULT
      snippet: All of the receptors that formed dimers, as shown in Fig.3A, also exhibited significant phosphorylation of the dimeric form of the receptor, demonstrating activation of the receptor (Fig.4A).
      explanation: Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
      directness: INDIRECT
    readouts:
    - name: Receptor autophosphorylation
      target: Increased FGFR2 Kinase Activity
      direction: INCREASED
      interpretation: Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
      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
        quote_role: PRIMARY_RESULT
        snippet: All of the receptors that formed dimers, as shown in Fig.3A, also exhibited significant phosphorylation of the dimeric form of the receptor, demonstrating activation of the receptor (Fig.4A).
        explanation: Dimer-forming receptors showed phosphorylation in immunoprecipitate kinase assays.
        directness: INDIRECT
- name: FGFR2/Neu chimeric-receptor transformation in NIH 3T3 cells
  experimental_model_type: CELL_LINE
  cell_source: Mouse NIH 3T3 fibroblast line
  description: Focus formation tested FGFR2 extracellular domains fused to the Neu transmembrane and kinase domains. Three to five experiments per construct used activated Neu as a normalization comparator. The transforming output belongs to this artificial reporter, not native FGFR2 kinase or an osteogenic differentiation assay. Removing both IgIII cysteines suppressed transformation by W290G/T341P constructs. No S351C, cranial suture or clinical rescue experiment was reported.
  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
    quote_role: PRIMARY_RESULT
    snippet: Chimeric FGFR2/Neu receptors (Fig.1), containing the FGFR2 extracellular domain fused to the transmembrane and kinase domains of Neu, allow the extent of activation to be assayed through focus formation using the intracellular domain of Neu as a reporter
    explanation: Construct and reporter context.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Whereas each of the single mutants W290G and T341P was transforming, as described above, transforming activity was completely lost when these single mutants were combined with the double mutant (C278A, C342A)
    explanation: Genetic perturbation of the reporter response.
  modeled_mechanisms:
  - target: Aberrant FGFR2 Disulfide Dimerization
    relationship: PERTURBS
    fidelity: LOW
    model_scale: CELLULAR
    description: Removing the two IgIII cysteines abolishes the transforming activity of related mutant extracellular domains in an artificial FGFR2/Neu reporter. This perturbation supports cysteine dependence, with dimer formation measured separately in full-length COS-1 receptors.
    limitations: Focus formation is a downstream reporter phenotype rather than a direct dimerization readout. The kinase/transmembrane domains are Neu, p.Ser351Cys was not tested, and no cranial differentiation or clinical rescue was measured.
    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
      quote_role: PRIMARY_RESULT
      snippet: Whereas each of the single mutants W290G and T341P was transforming, as described above, transforming activity was completely lost when these single mutants were combined with the double mutant (C278A, C342A)
      explanation: Genetic perturbation of the reporter response.
      directness: INDIRECT
discussions:
- discussion_id: gap_abs_fgfr2_distinct_entity_status
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does the Antley–Bixler label identify a distinct FGFR2 phenotype?
  attaches_to:
  - genetic#FGFR2 extracellular variants
  rationale: The same S351C allele appears under Antley–Bixler, Pfeiffer and Crouzon labels. Elbow ankylosis is not unique to the ABS label, and contractures need not represent bony fusion. Nomenclature proposals differ over whether ABS should be reserved for POR deficiency. This entry retains the existing MONDO concept without treating the clinical labels as distinct molecular mechanisms. A genotype-stratified comparison should deduplicate re-reported patients and record radiographic joint anatomy.
  evidence:
  - reference: PMID:16145814
    reference_title: 'Use of the term "Antley-Bixler syndrome": minimizing confusion.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: We believe it would be better to reserve the use of the term “ABS” for patients with POR deficiency and clinically significant craniosynostosis and/or radiohumoral synostosis.
    explanation: Attributed nomenclature proposal, not a binding reclassification.
  - reference: PMID:9714439
    reference_title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III.
    explanation: Same allele under an alternative clinical label.
- discussion_id: gap_abs_allele_specific_function
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How directly does the disulfide-activation mechanism apply to S351C?
  attaches_to:
  - pathophysiology#Aberrant FGFR2 Disulfide Dimerization
  - pathophysiology#Increased FGFR2 Kinase Activity
  rationale: The human S351C report predicts aberrant disulfide bonding and altered ligand binding. The cited experiments directly demonstrate dimerization and kinase activation for other alleles, not S351C. Their telokin-based homology model is not a mutant FGFR2 crystal structure or direct bond map. Allele-specific dimerization, ligand dependence and kinase measurements, ideally with expression-matched controls, would strengthen the current class inference. Cranial osteogenic and joint-development effects require separate tissue-level testing.
  evidence:
  - reference: PMID:10406670
    reference_title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: All three cases were found to have the same FGFR2 Ser351Cys (1231C to G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding.
    explanation: Explicit predictive wording in the allele-specific report.
    directness: INDIRECT
  - 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: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    snippet: We used molecular modeling to construct a three-dimensional representation of the Ig-3 domain of FGFR2 based on the crystallographic coordinates of telokin, a myosin light chain kinase homolog
    explanation: Homology-model provenance; not an experimental S351C structure.
notes: Clinical care is based on the broader FGFR craniosynostosis baseline plus genotype-matched case reports. Established steroidogenic disease belongs to the POR differential rather than an assumed FGFR2 mechanism. No allele-specific drug efficacy, clinical trial or whole-animal S351C model was established by the reviewed sources. Other FGFR2 model genotypes are not silently substituted for this allele.
review_notes: 'Comprehensive source review used all original cached abstracts and available full scientific bodies, the complete FGFR GeneReviews clinical chapter, regenerated 2005 cohort tables, and the relevant 2020 guideline methodology and respiratory recommendations. No matching deep-research report was found. Selected reports overlap: the 2005 cohort reuses earlier cases, including two from the 1999 ocular series. Clinical frequencies and a numeric prevalence class are therefore omitted. The 2005 article conflicts between F276V in its table and P276V in the narrative; that spelling is not resolved by assumption. Its joint column combines radiohumeral and radioulnar fusion; individual unspecific ankylosis is kept at the broader elbow term. Genital appearance does not exclude POR deficiency. The 2021 report has perinatal hypoxic/infectious confounding, a source-internal intron designation for a coding missense variant, and an unverified terminal event. The unavailable correspondence is bibliographic context only. The 1998 model cache contains the main scientific text and captions but omits Table 1 rows; no table-specific conclusion was inferred. The full GeneReviews HTML is genuinely
  available; a separate PDF route returned a challenge page and was quarantined, not cited. Literal HTML entities in a few chapter excerpts preserve the generated source text.'
references:
- reference: PMID:10076886
  title: Patient described by Chun et al. may not present Antley-Bixler syndrome.
  findings: []
- reference: PMID:10076887
  title: Not Antley-Bixler syndrome.
  findings: []
- reference: PMID:10406670
  title: Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
  findings:
  - statement: Full available abstract read. Three ocular-selected S351C cases, two reused in the 2005 cohort; anterior chamber findings and predicted receptor mechanism are distinguished.
- reference: PMID:11430730
  title: Further evidence that fibroblast growth factor receptor 2 mutations cause Antley-Bixler syndrome.
  findings: []
- reference: PMID:12072807
  title: Sacral appendage associated with a mutation in FGFR2.
  findings:
  - statement: Full available abstract read. Genotype-confirmed sacral appendage; not proof of underlying spinal dysraphism.
- reference: PMID:15793702
  title: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
  findings:
  - statement: Complete main text, clinical and genetic tables read. Selected mixed ABS cohort separates FGFR and POR disease, records overlapping cases and distinguishes radioulnar fusion from contracture. POR functional assays are not FGFR2 experiments.
- reference: PMID:16145814
  title: 'Use of the term "Antley-Bixler syndrome": minimizing confusion.'
  findings:
  - statement: Full correspondence consumed. Nomenclature disagreement and normal-genitalia POR cases correct phenotype-only discrimination.
- reference: PMID:16465081
  title: Syndromic craniosynostosis with elbow joint contracture.
  findings:
  - statement: Full available abstract read. Congenital presentation and fronto-orbital/shunt treatment use; selected literature review does not establish survival.
- reference: PMID:20301628
  title: FGFR Craniosynostosis Syndromes Overview.
  findings:
  - statement: GeneReviews overview identity; its abstract gives scope only. The generated complete chapter is separately cited for clinical care and counseling.
  tags:
  - GeneReviews
- reference: PMID:20818252
  title: Spectrum of Antley-Bixler syndrome.
  findings:
  - statement: Full available abstract read. Four mixed ABS cases; unstratified clinical and management summaries cannot provide FGFR2-specific frequencies or efficacy.
- reference: PMID:29230096
  title: Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis.
  findings:
  - statement: Full FGFR2 review consumed; differentiation biology and other-genotype models do not establish S351C-specific functional or treatment effects.
- reference: PMID:33156164
  title: Updated Guideline on Treatment and Management of Craniosynostosis.
  findings:
  - statement: Full guideline retrieved; methodology and complete respiratory-disorder chapter reviewed. Syndromic OSA surveillance and severity-based intervention are applied with their broader population and observational evidence limits.
- reference: PMID:34909104
  title: 'Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.'
  findings:
  - statement: Full case body consumed. Genotype-confirmed severe Pfeiffer-labelled presentation; concurrent neonatal illness and lack of autopsy constrain seizure, organ-injury and mortality attribution.
- reference: PMID:36779427
  title: 'Nosology of genetic skeletal disorders: 2023 revision.'
  findings:
  - statement: Full nosology narrative read, including updated craniosynostosis group name; cache does not expose the complete group-table rows.
- reference: PMID:8946174
  title: Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus.
  findings:
  - statement: Full available abstract read. Earlier FGFR2 variant spectrum includes S351C before the ABS-index report.
- reference: PMID:9539778
  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.
  findings:
  - statement: Complete scientific main body, methods and captions read. Native COS1 receptor dimer/kinase assays and NIH3T3 FGFR2/Neu transformation are distinct; S351C is not an assayed construct. Cached Table 1 rows were unavailable.
- reference: PMID:9605588
  title: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
  findings:
  - statement: Full available abstract read. Index de novo S351C case with elbow ankylosis and spinal dysraphism; no functional receptor experiment.
- reference: PMID:9714439
  title: 'Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.'
  findings:
  - statement: Full available abstract read. Same-allele Pfeiffer type III phenotype and historical SSCP false-negative result; no population penetrance inference.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
  title: FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
  findings:
  - statement: Complete GeneReviews clinical chapter consumed for clinical spectrum, diagnosis, management, surveillance and family counseling, with syndrome and genotype scope retained.
  tags:
  - GeneReviews
📚

References & Deep Research

References

19
PMID:10076886
Patient described by Chun et al. may not present Antley-Bixler syndrome.
No top-level findings curated for this source.
PMID:10076887
Not Antley-Bixler syndrome.
No top-level findings curated for this source.
PMID:10406670
Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.
1 finding
Full available abstract read. Three ocular-selected S351C cases, two reused in the 2005 cohort; anterior chamber findings and predicted receptor mechanism are distinguished.
PMID:11430730
Further evidence that fibroblast growth factor receptor 2 mutations cause Antley-Bixler syndrome.
No top-level findings curated for this source.
PMID:12072807
Sacral appendage associated with a mutation in FGFR2.
1 finding
Full available abstract read. Genotype-confirmed sacral appendage; not proof of underlying spinal dysraphism.
PMID:15793702
Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
1 finding
Complete main text, clinical and genetic tables read. Selected mixed ABS cohort separates FGFR and POR disease, records overlapping cases and distinguishes radioulnar fusion from contracture. POR functional assays are not FGFR2 experiments.
PMID:16145814
Use of the term "Antley-Bixler syndrome": minimizing confusion.
1 finding
Full correspondence consumed. Nomenclature disagreement and normal-genitalia POR cases correct phenotype-only discrimination.
PMID:16465081
Syndromic craniosynostosis with elbow joint contracture.
1 finding
Full available abstract read. Congenital presentation and fronto-orbital/shunt treatment use; selected literature review does not establish survival.
PMID:20301628
FGFR Craniosynostosis Syndromes Overview.
1 finding
GeneReviews overview identity; its abstract gives scope only. The generated complete chapter is separately cited for clinical care and counseling.
PMID:20818252
Spectrum of Antley-Bixler syndrome.
1 finding
Full available abstract read. Four mixed ABS cases; unstratified clinical and management summaries cannot provide FGFR2-specific frequencies or efficacy.
PMID:29230096
Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis.
1 finding
Full FGFR2 review consumed; differentiation biology and other-genotype models do not establish S351C-specific functional or treatment effects.
PMID:33156164
Updated Guideline on Treatment and Management of Craniosynostosis.
1 finding
Full guideline retrieved; methodology and complete respiratory-disorder chapter reviewed. Syndromic OSA surveillance and severity-based intervention are applied with their broader population and observational evidence limits.
PMID:34909104
Pfeiffer syndrome type 3 with FGR2 c.1052C>G (p.Ser351Cys) variant in West Africa: a case report.
1 finding
Full case body consumed. Genotype-confirmed severe Pfeiffer-labelled presentation; concurrent neonatal illness and lack of autopsy constrain seizure, organ-injury and mortality attribution.
PMID:36779427
Nosology of genetic skeletal disorders: 2023 revision.
1 finding
Full nosology narrative read, including updated craniosynostosis group name; cache does not expose the complete group-table rows.
PMID:8946174
Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus.
1 finding
Full available abstract read. Earlier FGFR2 variant spectrum includes S351C before the ABS-index report.
PMID:9539778
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.
1 finding
Complete scientific main body, methods and captions read. Native COS1 receptor dimer/kinase assays and NIH3T3 FGFR2/Neu transformation are distinct; S351C is not an assayed construct. Cached Table 1 rows were unavailable.
PMID:9605588
FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.
1 finding
Full available abstract read. Index de novo S351C case with elbow ankylosis and spinal dysraphism; no functional receptor experiment.
PMID:9714439
Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III.
1 finding
Full available abstract read. Same-allele Pfeiffer type III phenotype and historical SSCP false-negative result; no population penetrance inference.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1455/
FGFR Craniosynostosis Syndromes Overview - GeneReviews® - NCBI Bookshelf
1 finding
Complete GeneReviews clinical chapter consumed for clinical spectrum, diagnosis, management, surveillance and family counseling, with syndrome and genotype scope retained.