Atelosteogenesis Type I

Mendelian MONDO:0007167 Pathograph 24 Show in embeddings browser Skeletal Dysplasia Lethal Skeletal Dysplasia

Atelosteogenesis type I (FLNB-AO1) is the perinatal-lethal end of the monoallelic FLNB gain-of-function skeletal-dysplasia spectrum. It is characterized by severe short-limbed dwarfism, incomplete or regionally absent ossification, vertebral and long-bone abnormalities, congenital joint dislocations, clubfeet, distinctive craniofacial findings, and respiratory compromise from thoracic, pulmonary, and laryngotracheal abnormalities.

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1
Mappings
1
Definitions
1
Inheritance
3
Pathophys.
20
Phenotypes
24
Pathograph
1
Genes
2
Medical Actions
3
Differentials
1
Deep Research
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Classifications

ISDS Skeletal Nosology
filamin and related
🔗

Mappings

MONDO
MONDO:0007167 atelosteogenesis type I
skos:exactMatch Orphadata ORPHA:1190
The current Orphadata cross-reference record lists MONDO:0007167 as a validated exact mapping for ORPHA:1190.
📘

Definitions

1
FLNB-AO1 spectrum definition
A monoallelic FLNB gain-of-function disorder at the perinatal-lethal end of the FLNB skeletal-dysplasia spectrum; contemporary GeneReviews scope also subsumes the historically named boomerang and Piepkorn dysplasias under the FLNB-AO1 spectrum.
OTHER
Show evidence (2 references)
PMID:20301736 SUPPORT Other
"Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum of phenotypic severity ranging from apparently isolated clubfoot to Larsen syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal."
The current GeneReviews update defines FLNB-AO1 within the monoallelic gain-of-function spectrum and states its perinatal lethality.
PMID:20301736 SUPPORT Other
"For the purposes of this GeneReview, the previously described entities Piepkorn dysplasia and boomerang dysplasia are subsumed under the FLNB-AO1 spectrum."
The current GeneReviews scope supplies the historical-entity boundary used here.
👪

Inheritance

1
Autosomal dominant FLNB disorder HP:0000006
The disease model is autosomal dominant and is caused by a heterozygous gain-of-function FLNB pathogenic variant. Most lethal FLNB conditions arise de novo, but transmission from a heterozygous or mosaic parent is possible.
Autosomal dominant inheritance De novo rate: The vast majority of lethal FLNB conditions result from de novo pathogenic variants.
Show evidence (2 references)
PMID:16752402 SUPPORT Human Clinical
"AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations."
This directly supports dominant inheritance and lethal disease severity in AOI.
PMID:20301736 SUPPORT Other
"Some individuals have the disorder as the result of a de novo pathogenic variant (the vast majority of lethal FLNB conditions are the result of de novo pathogenic variants)."
GeneReviews supports the usual de novo origin while preserving the possibility of familial or mosaic transmission.
⚙

Pathophysiology

3
Monoallelic FLNB gain-of-function and abnormal actin binding
FLNB-AO1 is caused by heterozygous gain-of-function FLNB variants, commonly clustered in the CH2 actin-binding domain or repeats 14-15. Biochemical work on the actin-binding-domain substitutions W148R and M202V showed increased F-actin affinity, and cellular work on W148R showed F-actin clustering, focal-adhesion rearrangement, and delayed directional migration. These experiments establish a plausible cytoskeletal mechanism for an important variant subset; they do not demonstrate that every AO1 variant has the same biochemical effect or fully resolve the bridge from altered FLNB to fetal cartilage pathology.
Chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
FLNB hgnc:3755 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FLNB (hgnc:3755). hgnc:3755 is a gene from the HUGO Gene Nomenclature Committee.
Actin filament organization GO:0007015 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Actin filament organization (GO:0007015). GO:0007015 is a biological process from the Gene Ontology. ⚠ ABNORMAL Cytoskeleton organization GO:0007010 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cytoskeleton organization (GO:0007010). GO:0007010 is a biological process from the Gene Ontology. ⚠ ABNORMAL
actin filament binding GO:0051015 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves actin filament binding (GO:0051015). GO:0051015 is a molecular function from the Gene Ontology.
Downstream
Abnormal growth-plate cartilage and endochondral ossification Altered FLNB-actin behavior is proposed to disturb chondrocyte organization and skeletal development, but the intervening in-vivo steps are not fully established.
Show evidence (4 references)
PMID:20301736 SUPPORT Other
"Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum of phenotypic severity ranging from apparently isolated clubfoot to Larsen syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal."
GeneReviews classifies FLNB-AO1 as a monoallelic gain-of-function disorder.
PMID:16752402 SUPPORT Human Clinical
"The majority of the mutations resided in exon 2 and exon 3, which encode the CH2 domain of the actin-binding region of filamin B. The remaining mutations were found in exon 28 and exon 29, which encode repeats 14 and 15 of filamin B."
The AOI/AOIII series identifies two recurrent variant clusters, including the actin-binding domain.
PMID:19505475 SUPPORT In Vitro
"Characterisation of the wild type and mutant ABD F-actin binding activities via co-sedimentation assays shows that the mutant FLNB ABDs have increased F-actin binding affinities, with dissociation constants of 2.0 microM (W148R) and 0.56 microM (M202V), compared to the wild type ABD K(d) of 7.0 microM."
Purified-protein assays demonstrate increased F-actin affinity for two disease-associated actin-binding-domain substitutions.
+ 1 more reference
Abnormal growth-plate cartilage and endochondral ossification
AO1 cartilage shows irregular clusters that can include giant chondrocytes, while cartilage anlagen undergo incomplete ossification. The pathological observations support abnormal cartilage organization and endochondral bone formation, although they do not identify a single universal cellular step.
Growth plate chondrocyte CL:1000217 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Growth plate chondrocyte, annotated with growth plate cartilage chondrocyte (CL:1000217). CL:1000217 is a cell type from the Cell Ontology.
Cartilage development GO:0051216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cartilage development (GO:0051216). GO:0051216 is a biological process from the Gene Ontology. ⚠ ABNORMAL Chondrocyte differentiation GO:0002062 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Chondrocyte differentiation (GO:0002062). GO:0002062 is a biological process from the Gene Ontology. ⚠ ABNORMAL Endochondral ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology. ↓ DECREASED Bone mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Bone mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Thoracic and upper-airway cartilage insufficiency Thoracic restriction, pulmonary hypoplasia, and malformed upper-airway cartilage combine to produce severe respiratory compromise.
Disproportionate Short-Limb Short Stature
Rhizomelia
Joint Dislocation
Abnormality of the Vertebral Column
Platyspondyly
Fibular Aplasia
Talipes Equinovarus
Brachydactyly
Broad Thumb
Pectus Excavatum
Thoracic Hypoplasia
Prominent Forehead
Hypertelorism
Proptosis
Downslanting Palpebral Fissures
Micrognathia
Cleft Palate
Show evidence (3 references)
PMID:16752402 SUPPORT Human Clinical
"These results show that clustering of mutations in two regions of FLNB produce AOI/AOIII, and highlight the important role of this cytoskeletal protein in normal skeletogenesis."
Human genetic data connect clustered FLNB variants to abnormal skeletogenesis.
PMID:9779808 SUPPORT Human Clinical
"Atelosteogenesis type 1 (AO1) is a rare lethal chondrodysplasia characterized by incomplete ossification of cartilage anlagen."
Directly supports incomplete endochondral ossification as a defining AOI pathophysiologic feature.
PMID:9779808 SUPPORT Human Clinical
"Histologically, the cartilage contains irregular clusters that occasionally include giant chondrocytes."
Postnatal pathology links AOI to abnormal chondrocyte organization and maturation.
Thoracic and upper-airway cartilage insufficiency
Perinatal lethality reflects combined skeletal thoracic restriction, pulmonary hypoplasia, and primary upper-airway cartilage failure. In reported AOI neonates, severe subglottic hypoplasia and tracheomalacia allowed tracheal collapse and contributed to death independently of pulmonary hypoplasia.
Airway chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Airway chondrocyte, annotated with chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology. Respiratory tract epithelial cell CL:0002368 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Respiratory tract epithelial cell (CL:0002368). CL:0002368 is a cell type from the Cell Ontology.
Trachea development GO:0060438 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Trachea development (GO:0060438). GO:0060438 is a biological process from the Gene Ontology. ⚠ ABNORMAL Lung development GO:0030324 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Lung development (GO:0030324). GO:0030324 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Thoracic Hypoplasia
Pulmonary Hypoplasia
Tracheomalacia
Laryngeal Stenosis
Show evidence (3 references)
PMID:9779808 SUPPORT Human Clinical
"Although pulmonary hypoplasia was present, it was moderate and considered unlikely to be the sole cause of death."
Establishes that lethality is not explained by pulmonary hypoplasia alone.
PMID:9779808 SUPPORT Human Clinical
"The marked luminal narrowing, tracheomalacia, and temporal proximity of extubation to demise support tracheal collapse as a major contributor to the death in AO1."
Directly supports tracheomalacia and airway collapse as a primary lethal mechanism in AOI.
PMID:23401428 SUPPORT Human Clinical
"Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis, and pulmonary hypoplasia have all been described in patients with AO type I and we conclude that compromised pulmonary function is a major contributor to morbidity and mortality in this condition."
Confirms airway and pulmonary abnormalities as major contributors to AOI morbidity and mortality.
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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 Atelosteogenesis Type I 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

20
Eye 2
Hypertelorism OCCASIONAL 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 (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0000316", "HPOTerm": "Hypertelorism" }, "HPOFrequency": "Occasional (29-5%)""
Current Orphadata classifies hypertelorism as occasional (29-5%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports hypertelorism as part of the AOI craniofacial phenotype.
Proptosis OCCASIONAL 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 (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0000520", "HPOTerm": "Proptosis" }, "HPOFrequency": "Occasional (29-5%)""
Current Orphadata classifies proptosis as occasional (29-5%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports proptosis as part of the AOI craniofacial phenotype.
Head and Neck 4
Prominent Forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301736 SUPPORT Other
"At its most severe, the spectrum of phenotypes assigned FLNB-AO1 can present with perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal..."
The current GeneReviews update includes prominent forehead in the severe FLNB-AO1 spectrum.
Downslanting Palpebral Fissures Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanting palpebral fissures, annotated with Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports downslanting palpebral fissures as part of the AOI craniofacial phenotype.
Micrognathia OCCASIONAL HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0000347", "HPOTerm": "Micrognathia" }, "HPOFrequency": "Occasional (29-5%)""
Current Orphadata classifies micrognathia as occasional (29-5%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports retromicrognathia/micrognathia in AOI.
Cleft Palate OCCASIONAL HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0000175", "HPOTerm": "Cleft palate" }, "HPOFrequency": "Occasional (29-5%)""
Current Orphadata classifies cleft palate as occasional (29-5%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports cleft palate in AOI.
Limbs 4
Fibular Aplasia HP:0002990 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fibular aplasia (HP:0002990). HP:0002990 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12454961 SUPPORT Human Clinical
"Fetal ultrasonography (US) revealed absent or deficient ossification of the posterior neural arches of the thoracic spine, humeri, radii, ulnae, fibulae, and short tubular bones other than the distal phalanges, in addition to extremely short, thick femora."
This prenatal AOI case directly documents absent/deficient fibular ossification.
Talipes Equinovarus FREQUENT HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0001762", "HPOTerm": "Talipes equinovarus" }, "HPOFrequency": "Frequent (79-30%)""
Current Orphadata classifies talipes equinovarus as frequent (79-30%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports bilateral talipes equinovarus in AOI.
Brachydactyly FREQUENT HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0001156", "HPOTerm": "Brachydactyly" }, "HPOFrequency": "Frequent (79-30%)""
Current Orphadata classifies brachydactyly as frequent (79-30%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports brachydactyly as part of the distal limb phenotype.
Broad Thumb HP:0011304 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad thumb (HP:0011304). HP:0011304 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports broad thumbs in AOI.
Musculoskeletal 5
Joint Dislocation OCCASIONAL HP:0001373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint dislocation (HP:0001373). HP:0001373 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0001373", "HPOTerm": "Joint dislocation" }, "HPOFrequency": "Occasional (29-5%)""
Current Orphadata classifies joint dislocation as occasional (29-5%) in Atelosteogenesis type I.
PMID:24624349 SUPPORT Human Clinical
"Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows."
This directly supports congenital large-joint dislocation in AOI.
Abnormality of the Vertebral Column HP:0000925 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the vertebral column (HP:0000925). HP:0000925 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16752402 SUPPORT Human Clinical
"AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations."
This multi-patient FLNB series supports vertebral abnormalities as a core AOI feature.
PMID:12454961 SUPPORT Human Clinical
"Fetal ultrasonography (US) revealed absent or deficient ossification of the posterior neural arches of the thoracic spine, humeri, radii, ulnae, fibulae, and short tubular bones other than the distal phalanges, in addition to extremely short, thick femora."
This directly documents deficient thoracic vertebral ossification in a prenatally diagnosed AOI fetus.
Platyspondyly OCCASIONAL HP:0000926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Platyspondyly (HP:0000926). HP:0000926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0000926", "HPOTerm": "Platyspondyly" }, "HPOFrequency": "Occasional (29-5%)""
Current Orphadata classifies platyspondyly as occasional (29-5%) in Atelosteogenesis type I.
Pectus Excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports pectus excavatum in AOI.
Thoracic Hypoplasia FREQUENT HP:0005257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thoracic hypoplasia (HP:0005257). HP:0005257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0005257", "HPOTerm": "Thoracic hypoplasia" }, "HPOFrequency": "Frequent (79-30%)""
Current Orphadata classifies thoracic hypoplasia as frequent (79-30%) in Atelosteogenesis type I.
Respiratory 2
Pulmonary Hypoplasia FREQUENT HP:0002089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypoplasia (HP:0002089). HP:0002089 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0002089", "HPOTerm": "Pulmonary hypoplasia" }, "HPOFrequency": "Frequent (79-30%)""
Current Orphadata classifies pulmonary hypoplasia as frequent (79-30%) in Atelosteogenesis type I.
PMID:12454961 SUPPORT Human Clinical
"Fetal magnetic resonance imaging (MRI) using an ultrafast imaging sequence depicted dysmorphic features, pulmonary hypoplasia, and large cisterna magna."
This case provides direct evidence of pulmonary hypoplasia in AOI.
PMID:9779808 SUPPORT Human Clinical
"Pulmonary hypoplasia is a characteristic finding that has been presumed to be the cause of neonatal lethality."
This supports pulmonary hypoplasia as a characteristic and clinically important AOI complication.
Tracheomalacia HP:0002779 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tracheomalacia (HP:0002779). HP:0002779 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9779808 SUPPORT Human Clinical
"Detailed neonatal and postmortem examination showed severe subglottic hypoplasia and tracheomalacia."
This directly supports tracheomalacia as part of the lethal airway phenotype in AOI.
Growth 2
Disproportionate Short-Limb Short Stature HP:0008873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disproportionate short-limb short stature (HP:0008873). HP:0008873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24624349 SUPPORT Human Clinical
"Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows."
This directly supports severe disproportionate short-limb short stature in AOI.
Rhizomelia FREQUENT HP:0008905 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhizomelic limb shortening, annotated with Rhizomelia (HP:0008905). HP:0008905 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0008905", "HPOTerm": "Rhizomelia" }, "HPOFrequency": "Frequent (79-30%)""
Current Orphadata classifies rhizomelia as frequent (79-30%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports proximal limb shortening as a characteristic AOI skeletal manifestation.
Other 1
Laryngeal Stenosis OCCASIONAL HP:0001602 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngeal stenosis (HP:0001602). HP:0001602 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190 SUPPORT Other
""HPOId": "HP:0001602", "HPOTerm": "Laryngeal stenosis" }, "HPOFrequency": "Occasional (29-5%)""
Current Orphadata classifies laryngeal stenosis as occasional (29-5%) in Atelosteogenesis type I.
PMID:23401428 SUPPORT Human Clinical
"Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis, and pulmonary hypoplasia have all been described in patients with AO type I and we conclude that compromised pulmonary function is a major contributor to morbidity and mortality in this condition."
The clinical report directly identifies laryngeal stenosis within the AO1 respiratory phenotype.
🧬

Genetic Associations

1
Heterozygous gain-of-function FLNB pathogenic variants (CAUSATIVE)
Gene: FLNB hgnc:3755 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FLNB (hgnc:3755). hgnc:3755 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:20301736 SUPPORT Other
"The diagnosis of other FLNB-related disorders (LS, AO1, AO3) is established in a proband by identification of a heterozygous gain-of-function pathogenic variant in FLNB by molecular genetic testing."
The current GeneReviews definition identifies the disease-causing allele class for FLNB-AO1.
PMID:16752402 SUPPORT Human Clinical
"In this study, 14 novel missense mutations in FLNB were found in 15 unrelated patients with AOI and AOIII."
This provides direct human genetic evidence for causative FLNB mutations in AOI-spectrum disease.
🗃️

External Assertions

1
Orphadata Atelosteogenesis type I record
Orphanet structured disease record ORPHA:1190
The current Orphadata record identifies ORPHA:1190 as Atelosteogenesis type I and maps it exactly to MONDO:0007167 and OMIM:108720.
Show evidence (2 references)
url:https://api.orphadata.com/rd-cross-referencing/orphacodes/1190 SUPPORT Other
""Preferred term": "Atelosteogenesis type I""
The current Orphadata record supplies the preferred disease identity.
url:https://api.orphadata.com/rd-cross-referencing/orphacodes/1190 SUPPORT Other
""Reference": "0007167", "Source": "MONDO""
Orphadata records the exact MONDO cross-reference used by this entry.
💊

Medical Actions

2
Individualized Perinatal Respiratory and Palliative Planning
Action: palliative careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is palliative care, annotated with Palliative Therapy (NCIT:C15292). NCIT:C15292 is a clinical intervention from the NCI Thesaurus. Ontology label: Palliative Therapy NCIT:C15292
No disease-modifying treatment is established for perinatal-lethal AO1. Prenatal counseling and delivery planning should prepare families and the neonatal team for potentially severe thoracic, pulmonary, and upper-airway compromise. Decisions about respiratory intervention and comfort-focused care should be individualized to the infant's anatomy, response to support, prognosis, and family goals.
Show evidence (2 references)
PMID:9779808 SUPPORT Human Clinical
"anticipation of the poor prognosis in AO1 is essential for appropriate genetic counseling of the parents and for determining postnatal treatment options."
Supports prenatal planning and postnatal treatment decisions around AOI's poor prognosis.
PMID:23401428 SUPPORT Human Clinical
"The clinical course of one child was influenced by airway instability and bronchopulmonary dysplasia that complicated intubation and prevented separation from ventilator support."
Demonstrates why neonatal respiratory support decisions in AOI require careful perinatal planning.
Genetic Counseling and Parental Mosaicism Assessment
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. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling should explain dominant inheritance, the usual de novo origin of lethal AOI, and the residual recurrence risk from parental somatic or gonadal mosaicism. Parental FLNB testing is important when a parent has mild limb asymmetry or other subtle FLNB-spectrum findings.
Show evidence (2 references)
PMID:30231296 SUPPORT Human Clinical
"parents affected with a mild phenotype, probably with somatic mosaicism, can generate offspring with a much more severe phenotype of AOI."
Supports counseling families that a mildly affected mosaic parent can have a child with lethal AOI.
PMID:30231296 SUPPORT Human Clinical
"A missense mutation not previously described in the literature was detected in the FLNB gene, affecting ∼ 20% of the evaluated cells and, therefore, confirming the diagnosis of mosaic AOI in the father."
Directly supports parental molecular testing for suspected mosaicism.
🔬

Diagnosis

2
Prenatal Ultrasound and MRI
Detailed fetal ultrasound and, when useful, MRI can recognize an AO-like pattern of severe limb shortening, dislocations, thoracic hypoplasia, and delayed or absent ossification. Because several lethal skeletal dysplasias overlap radiographically, imaging establishes suspicion and guides testing; molecular confirmation defines FLNB-AO1.
Show evidence (1 reference)
PMID:12454961 SUPPORT Human Clinical
"Meticulous evaluation using fetal US and MRI permits a definitive prenatal diagnosis of AO I to be made."
This historical case supports imaging-based prenatal recognition; current spectrum knowledge and genetic heterogeneity argue against treating the imaging pattern alone as molecularly definitive.
Molecular FLNB Testing and Spectrum Diagnosis
Molecular diagnosis uses a skeletal-dysplasia gene panel, exome sequencing, or genome sequencing to identify a heterozygous gain-of-function FLNB variant in a fetus or neonate with AOI-like findings. Molecular results are important for distinguishing FLNB-AOI from AO-like lethal dysplasias caused by other genes, including SLC26A2-related atelosteogenesis type II, and from recessive FLNB loss-of-function disorders such as spondylocarpotarsal synostosis.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: A heterozygous gain-of-function pathogenic FLNB variant.
Show evidence (3 references)
PMID:20301736 SUPPORT Other
"The diagnosis of other FLNB-related disorders (LS, AO1, AO3) is established in a proband by identification of a heterozygous gain-of-function pathogenic variant in FLNB by molecular genetic testing."
GeneReviews defines heterozygous gain-of-function FLNB molecular confirmation as the diagnostic standard.
PMID:24624349 SUPPORT Human Clinical
"In order to screen all possible genes associated with AO-like lethal skeletal dysplasias simultaneously, we performed whole-exome sequencing in a female newborn having clinical features of AO-I."
Demonstrates exome sequencing as a diagnostic approach for AOI-like lethal skeletal dysplasia with differential genetic causes.
PMID:24624349 SUPPORT Human Clinical
"Exome sequencing identified a novel missense variant (c.517G>A; p.Ala173Thr) in exon 2 of the FLNB gene in the patient."
Supports molecular confirmation of AOI by identifying a heterozygous FLNB variant in a clinically affected newborn.
📈

Progression

1
Prenatal onset with perinatal lethality
Age: Prenatal to neonatal period
Skeletal abnormalities arise prenatally and are detectable by fetal imaging. FLNB-AO1 is generally lethal in the perinatal period; compromised pulmonary function, including thoracic restriction, pulmonary hypoplasia, and upper airway instability or stenosis, is a major contributor to mortality.
Show evidence (2 references)
PMID:20301736 SUPPORT Other
"FLNB-AO1 is lethal in the perinatal period."
The current GeneReviews update defines the usual outcome of FLNB-AO1.
PMID:23401428 SUPPORT Human Clinical
"Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis, and pulmonary hypoplasia have all been described in patients with AO type I and we conclude that compromised pulmonary function is a major contributor to morbidity and mortality in this condition."
The two-patient report identifies respiratory compromise as a major determinant of the severe clinical course.
📊

Prevalence

1
Worldwide
Point Prevalence <1 in 1,000,000
Current Orphadata provides an expert-validated class-only estimate below one per million, not a measured numeric point estimate; no rate is imputed.
Show evidence (1 reference)
url:https://api.orphadata.com/rd-epidemiology/orphacodes/1190 SUPPORT Other
""PrevalenceClass": "<1 / 1 000 000""
The current Orphadata epidemiology record supplies the worldwide point-prevalence class.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Atelosteogenesis Type I:

Atelosteogenesis type II MONDO:0009727
Overlapping Features A clinically and radiographically overlapping perinatal-lethal skeletal dysplasia in the SLC26A2 sulfate-transporter spectrum, with autosomal recessive inheritance and distinctive cartilage-matrix pathology rather than monoallelic FLNB gain of function.
Distinguishing Features
  • Biallelic SLC26A2 disorder rather than a heterozygous FLNB disorder
  • Distinctive chondro-osseous histopathology with disturbed cartilage-matrix sulfation
Show evidence (1 reference)
PMID:9133349 SUPPORT Human Clinical
"Atelosteogenesis type II shows distinctive chondro-osseous histopathology with a major disturbance in cartilage matrix macromolecules."
The review identifies the cartilage-matrix pathology that separates AO2 from AO1.
Atelosteogenesis type III MONDO:0007168
Overlapping Features An allelic monoallelic FLNB gain-of-function skeletal dysplasia that overlaps AO1, but survival beyond the neonatal period can occur, especially with intensive respiratory support.
Distinguishing Features
  • Survival beyond the neonatal period is possible
  • Overlapping FLNB disorder requiring phenotype-spectrum interpretation
Show evidence (1 reference)
PMID:20301736 SUPPORT Other
"In individuals with FLNB-AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support."
GeneReviews distinguishes AO3 from perinatal-lethal AO1 by possible longer survival.
Larsen syndrome MONDO:0007875
Overlapping Features A generally milder monoallelic FLNB gain-of-function disorder with congenital large-joint dislocations, clubfeet, craniofacial findings, and vertebral anomalies that overlap AO1 but without the defining perinatal-lethal micromelic presentation.
Distinguishing Features
  • Usually milder than FLNB-AO1 and compatible with longer-term survival
  • Congenital dislocations and clubfeet overlap, so molecular and spectrum-level interpretation is needed
Show evidence (1 reference)
PMID:20301736 SUPPORT Other
"FLNB-LS is characterized by combinations of congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis (which can be associated with a cervical myelopathy); short, broad, spatulate distal phalanges; distinctive..."
GeneReviews describes the overlapping but generally milder FLNB-Larsen phenotype.
{ }

Source YAML

click to show 
name: Atelosteogenesis Type I
creation_date: '2026-03-04T07:42:25Z'
category: Mendelian
description: >
  Atelosteogenesis type I (FLNB-AO1) is the perinatal-lethal end of the
  monoallelic FLNB gain-of-function skeletal-dysplasia spectrum. It is
  characterized by severe short-limbed dwarfism, incomplete or regionally absent
  ossification, vertebral and long-bone abnormalities, congenital joint
  dislocations, clubfeet, distinctive craniofacial findings, and respiratory
  compromise from thoracic, pulmonary, and laryngotracheal abnormalities.
disease_term:
  preferred_term: atelosteogenesis type I
  term:
    id: MONDO:0007167
    label: atelosteogenesis type I
parents:
- Skeletal Dysplasia
- Lethal Skeletal Dysplasia
synonyms:
- FLNB-related atelosteogenesis type 1
- Atelosteogenesis type 1
- AO1
- AOI
- Giant cell chondrodysplasia
- Spondylo-humero-femoral dysplasia
- Atelosteogenesis type 1, FLNB-related
classifications:
  isds_skeletal_category:
  - classification_value: filamin_and_related
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 7 "Filamin group and
      related disorders"; listed as "Atelosteogenesis type 1 (AO1)".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007167
      label: atelosteogenesis type I
    mapping_predicate: skos:exactMatch
    mapping_source: Orphadata ORPHA:1190
    mapping_justification: >
      The current Orphadata cross-reference record lists MONDO:0007167 as a
      validated exact mapping for ORPHA:1190.
external_assertions:
- name: Orphadata Atelosteogenesis type I record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:1190
  url: https://api.orphadata.com/rd-cross-referencing/orphacodes/1190
  description: >
    The current Orphadata record identifies ORPHA:1190 as Atelosteogenesis type
    I and maps it exactly to MONDO:0007167 and OMIM:108720.
  evidence:
  - reference: url:https://api.orphadata.com/rd-cross-referencing/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-cross-referencing/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"Preferred term": "Atelosteogenesis type I"'
    explanation: The current Orphadata record supplies the preferred disease identity.
  - reference: url:https://api.orphadata.com/rd-cross-referencing/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-cross-referencing/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"Reference": "0007167", "Source": "MONDO"'
    explanation: Orphadata records the exact MONDO cross-reference used by this entry.
definitions:
- name: FLNB-AO1 spectrum definition
  definition_type: OTHER
  description: >
    A monoallelic FLNB gain-of-function disorder at the perinatal-lethal end of
    the FLNB skeletal-dysplasia spectrum; contemporary GeneReviews scope also
    subsumes the historically named boomerang and Piepkorn dysplasias under the
    FLNB-AO1 spectrum.
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum
      of phenotypic severity ranging from apparently isolated clubfoot to Larsen
      syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and
      atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal.
    explanation: The current GeneReviews update defines FLNB-AO1 within the monoallelic gain-of-function spectrum and states its perinatal lethality.
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For the purposes of this GeneReview, the previously described entities
      Piepkorn dysplasia and boomerang dysplasia are subsumed under the FLNB-AO1
      spectrum.
    explanation: The current GeneReviews scope supplies the historical-entity boundary used here.
inheritance:
- name: Autosomal dominant FLNB disorder
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    The disease model is autosomal dominant and is caused by a heterozygous
    gain-of-function FLNB pathogenic variant. Most lethal FLNB conditions arise
    de novo, but transmission from a heterozygous or mosaic parent is possible.
  de_novo_rate: The vast majority of lethal FLNB conditions result from de novo pathogenic variants.
  evidence:
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AOI and AOIII are autosomal dominant lethal skeletal dysplasias
      characterized by overlapping clinical findings that include vertebral
      abnormalities, disharmonious skeletal maturation, hypoplastic long bones,
      and joint dislocations.
    explanation: >-
      This directly supports dominant inheritance and lethal disease severity in
      AOI.
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some individuals have the disorder as the result of a de novo pathogenic
      variant (the vast majority of lethal FLNB conditions are the result of de
      novo pathogenic variants).
    explanation: GeneReviews supports the usual de novo origin while preserving the possibility of familial or mosaic transmission.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Current Orphadata provides an expert-validated class-only estimate below one
    per million, not a measured numeric point estimate; no rate is imputed.
  evidence:
  - reference: url:https://api.orphadata.com/rd-epidemiology/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-epidemiology/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"PrevalenceClass": "<1 / 1 000 000"'
    explanation: The current Orphadata epidemiology record supplies the worldwide point-prevalence class.
progression:
- phase: Prenatal onset with perinatal lethality
  age_range: Prenatal to neonatal period
  notes: >
    Skeletal abnormalities arise prenatally and are detectable by fetal imaging.
    FLNB-AO1 is generally lethal in the perinatal period; compromised pulmonary
    function, including thoracic restriction, pulmonary hypoplasia, and upper
    airway instability or stenosis, is a major contributor to mortality.
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "FLNB-AO1 is lethal in the perinatal period."
    explanation: The current GeneReviews update defines the usual outcome of FLNB-AO1.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis,
      and pulmonary hypoplasia have all been described in patients with AO type
      I and we conclude that compromised pulmonary function is a major
      contributor to morbidity and mortality in this condition.
    explanation: The two-patient report identifies respiratory compromise as a major determinant of the severe clinical course.
pathophysiology:
- name: Monoallelic FLNB gain-of-function and abnormal actin binding
  description: >
    FLNB-AO1 is caused by heterozygous gain-of-function FLNB variants, commonly
    clustered in the CH2 actin-binding domain or repeats 14-15. Biochemical work
    on the actin-binding-domain substitutions W148R and M202V showed increased
    F-actin affinity, and cellular work on W148R showed F-actin clustering,
    focal-adhesion rearrangement, and delayed directional migration. These
    experiments establish a plausible cytoskeletal mechanism for an important
    variant subset; they do not demonstrate that every AO1 variant has the same
    biochemical effect or fully resolve the bridge from altered FLNB to fetal
    cartilage pathology.
  genes:
  - preferred_term: FLNB
    term:
      id: hgnc:3755
      label: FLNB
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Actin filament organization
    term:
      id: GO:0007015
      label: actin filament organization
    modifier: ABNORMAL
  - preferred_term: Cytoskeleton organization
    term:
      id: GO:0007010
      label: cytoskeleton organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum
      of phenotypic severity ranging from apparently isolated clubfoot to Larsen
      syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and
      atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal.
    explanation: GeneReviews classifies FLNB-AO1 as a monoallelic gain-of-function disorder.
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of the mutations resided in exon 2 and exon 3, which encode
      the CH2 domain of the actin-binding region of filamin B. The remaining
      mutations were found in exon 28 and exon 29, which encode repeats 14 and
      15 of filamin B.
    explanation: >-
      The AOI/AOIII series identifies two recurrent variant clusters, including
      the actin-binding domain.
  - reference: PMID:19505475
    reference_title: "Disease-associated substitutions in the filamin B actin binding domain confer enhanced actin binding affinity in the absence of major structural disturbance: Insights from the crystal structures of filamin B actin binding domains."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Characterisation of the wild type and mutant ABD F-actin binding activities
      via co-sedimentation assays shows that the mutant FLNB ABDs have increased
      F-actin binding affinities, with dissociation constants of 2.0 microM
      (W148R) and 0.56 microM (M202V), compared to the wild type ABD K(d) of 7.0
      microM.
    explanation: >-
      Purified-protein assays demonstrate increased F-actin affinity for two
      disease-associated actin-binding-domain substitutions.
  - reference: PMID:26491051
    reference_title: F-actin clustering and cell dysmotility induced by the pathological W148R missense mutation of filamin B at the actin-binding domain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Ectopic expression of FLNB-W148R and, to a lesser extent, FLNB-E227K
      induced prominent F-actin accumulations and the consequent rearrangement
      of focal adhesions, myosin II, and septin filaments and results in a
      delayed directional migration of the cells.
    explanation: >-
      Cell experiments connect selected pathological FLNB substitutions to
      abnormal actin organization and migration.
  downstream:
  - target: Abnormal growth-plate cartilage and endochondral ossification
    description: >
      Altered FLNB-actin behavior is proposed to disturb chondrocyte organization
      and skeletal development, but the intervening in-vivo steps are not fully
      established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26491051
      reference_title: F-actin clustering and cell dysmotility induced by the pathological W148R missense mutation of filamin B at the actin-binding domain.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The F-actin clustering through the interaction with the mutant FLNB ABD
        may limit the cytoskeletal reorganization, preventing normal skeletal
        development.
      explanation: >-
        The study proposes the cytoskeletal-to-skeletal link for selected
        variants but does not resolve it in fetal growth-plate tissue.
- name: Abnormal growth-plate cartilage and endochondral ossification
  description: >
    AO1 cartilage shows irregular clusters that can include giant chondrocytes,
    while cartilage anlagen undergo incomplete ossification. The pathological
    observations support abnormal cartilage organization and endochondral bone
    formation, although they do not identify a single universal cellular step.
  cell_types:
  - preferred_term: Growth plate chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: Cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  - preferred_term: Chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: ABNORMAL
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  - preferred_term: Bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  evidence:
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results show that clustering of mutations in two regions of FLNB
      produce AOI/AOIII, and highlight the important role of this cytoskeletal
      protein in normal skeletogenesis.
    explanation: Human genetic data connect clustered FLNB variants to abnormal skeletogenesis.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type 1 (AO1) is a rare lethal chondrodysplasia
      characterized by incomplete ossification of cartilage anlagen.
    explanation: >-
      Directly supports incomplete endochondral ossification as a defining AOI
      pathophysiologic feature.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologically, the cartilage contains irregular clusters that occasionally
      include giant chondrocytes.
    explanation: >-
      Postnatal pathology links AOI to abnormal chondrocyte organization and
      maturation.
  downstream:
  - target: Thoracic and upper-airway cartilage insufficiency
    description: >
      Thoracic restriction, pulmonary hypoplasia, and malformed upper-airway
      cartilage combine to produce severe respiratory compromise.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis,
        and pulmonary hypoplasia have all been described in patients with AO
        type I and we conclude that compromised pulmonary function is a major
        contributor to morbidity and mortality in this condition.
      explanation: Clinical cases support the downstream respiratory mechanism and its importance.
  - target: Disproportionate Short-Limb Short Stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24624349
      reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic
        disorder characterized by severe short-limbed dwarfism and dislocated
        hips, knees, and elbows.
      explanation: Clinical occurrence supports placement downstream of skeletal dysplasia but does not establish edge directness.
  - target: Rhizomelia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both children had typical manifestations of AO type I, with severe
        rhizomelic shortening of the extremities, limited elbow and knee
        extension with mild webbing, pectus excavatum, broad thumbs with
        brachydactyly that was most marked for digits 3-5, dislocated hips and
        bilateral talipes equinovarus.
      explanation: Clinical occurrence supports the endpoint placement; developmental intermediates are inferred.
  - target: Joint Dislocation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24624349
      reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic
        disorder characterized by severe short-limbed dwarfism and dislocated
        hips, knees, and elbows.
      explanation: Clinical occurrence supports the endpoint placement; developmental intermediates are inferred.
  - target: Abnormality of the Vertebral Column
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16752402
      reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        AOI and AOIII are autosomal dominant lethal skeletal dysplasias
        characterized by overlapping clinical findings that include vertebral
        abnormalities, disharmonious skeletal maturation, hypoplastic long
        bones, and joint dislocations.
      explanation: The series supports the skeletal endpoint but not a direct cell-to-phenotype edge.
  - target: Platyspondyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"HPOId": "HP:0000926", "HPOTerm": "Platyspondyly"'
      explanation: Structured phenotype data support the endpoint, not the causal edge's directness.
  - target: Fibular Aplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12454961
      reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Fetal ultrasonography (US) revealed absent or deficient ossification of
        the posterior neural arches of the thoracic spine, humeri, radii, ulnae,
        fibulae, and short tubular bones other than the distal phalanges, in
        addition to extremely short, thick femora.
      explanation: The fetal observation supports the endpoint, with developmental intermediates inferred.
  - target: Talipes Equinovarus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both children had typical manifestations of AO type I, with severe
        rhizomelic shortening of the extremities, limited elbow and knee
        extension with mild webbing, pectus excavatum, broad thumbs with
        brachydactyly that was most marked for digits 3-5, dislocated hips and
        bilateral talipes equinovarus.
      explanation: Clinical occurrence supports the endpoint placement; developmental intermediates are inferred.
  - target: Brachydactyly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both children had typical manifestations of AO type I, with severe
        rhizomelic shortening of the extremities, limited elbow and knee
        extension with mild webbing, pectus excavatum, broad thumbs with
        brachydactyly that was most marked for digits 3-5, dislocated hips and
        bilateral talipes equinovarus.
      explanation: Clinical occurrence supports the endpoint placement; developmental intermediates are inferred.
  - target: Broad Thumb
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both children had typical manifestations of AO type I, with severe
        rhizomelic shortening of the extremities, limited elbow and knee
        extension with mild webbing, pectus excavatum, broad thumbs with
        brachydactyly that was most marked for digits 3-5, dislocated hips and
        bilateral talipes equinovarus.
      explanation: Clinical occurrence supports the endpoint placement; developmental intermediates are inferred.
  - target: Pectus Excavatum
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both children had typical manifestations of AO type I, with severe
        rhizomelic shortening of the extremities, limited elbow and knee
        extension with mild webbing, pectus excavatum, broad thumbs with
        brachydactyly that was most marked for digits 3-5, dislocated hips and
        bilateral talipes equinovarus.
      explanation: Clinical occurrence supports the endpoint placement; developmental intermediates are inferred.
  - target: Thoracic Hypoplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"HPOId": "HP:0005257", "HPOTerm": "Thoracic hypoplasia"'
      explanation: Structured phenotype data support the endpoint, not the causal edge's directness.
  - target: Prominent Forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301736
      reference_title: FLNB-Related Disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        At its most severe, the spectrum of phenotypes assigned FLNB-AO1 can
        present with perinatal-lethal micromelic dwarfism characterized by
        flipper-like limbs (polysyndactyly with complete syndactyly of all
        fingers and toes, hypoplastic or absent first digits, and duplicated
        intermediate and distal phalanges); macrobrachycephaly; prominent
        forehead; hypertelorism; and proptosis.
      explanation: GeneReviews supports the endpoint; its mechanistic connection remains unresolved.
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial features included proptosis, hypertelorism, downslanting
        palpebral fissures, cleft palate, and retromicrognathia.
      explanation: Clinical occurrence supports the endpoint while the intervening mechanism is unknown.
  - target: Proptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial features included proptosis, hypertelorism, downslanting
        palpebral fissures, cleft palate, and retromicrognathia.
      explanation: Clinical occurrence supports the endpoint while the intervening mechanism is unknown.
  - target: Downslanting Palpebral Fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial features included proptosis, hypertelorism, downslanting
        palpebral fissures, cleft palate, and retromicrognathia.
      explanation: Clinical occurrence supports the endpoint while the intervening mechanism is unknown.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial features included proptosis, hypertelorism, downslanting
        palpebral fissures, cleft palate, and retromicrognathia.
      explanation: Clinical occurrence supports the endpoint while the intervening mechanism is unknown.
  - target: Cleft Palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Facial features included proptosis, hypertelorism, downslanting
        palpebral fissures, cleft palate, and retromicrognathia.
      explanation: Clinical occurrence supports the endpoint while the intervening mechanism is unknown.
- name: Thoracic and upper-airway cartilage insufficiency
  description: >
    Perinatal lethality reflects combined skeletal thoracic restriction,
    pulmonary hypoplasia, and primary upper-airway cartilage failure. In
    reported AOI neonates, severe subglottic hypoplasia and tracheomalacia
    allowed tracheal collapse and contributed to death independently of
    pulmonary hypoplasia.
  cell_types:
  - preferred_term: Airway chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Respiratory tract epithelial cell
    term:
      id: CL:0002368
      label: respiratory tract epithelial cell
  biological_processes:
  - preferred_term: Trachea development
    term:
      id: GO:0060438
      label: trachea development
    modifier: ABNORMAL
  - preferred_term: Lung development
    term:
      id: GO:0030324
      label: lung development
    modifier: DECREASED
  evidence:
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although pulmonary hypoplasia was present, it was moderate and considered
      unlikely to be the sole cause of death.
    explanation: >-
      Establishes that lethality is not explained by pulmonary hypoplasia alone.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The marked luminal narrowing, tracheomalacia, and temporal proximity of
      extubation to demise support tracheal collapse as a major contributor to
      the death in AO1.
    explanation: >-
      Directly supports tracheomalacia and airway collapse as a primary lethal
      mechanism in AOI.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis,
      and pulmonary hypoplasia have all been described in patients with AO type
      I and we conclude that compromised pulmonary function is a major
      contributor to morbidity and mortality in this condition.
    explanation: >-
      Confirms airway and pulmonary abnormalities as major contributors to AOI
      morbidity and mortality.
  downstream:
  - target: Thoracic Hypoplasia
    causal_link_type: UNKNOWN
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"HPOId": "HP:0005257", "HPOTerm": "Thoracic hypoplasia"'
      explanation: Structured data support co-occurrence, while the direction and directness of this modeled edge are not established.
  - target: Pulmonary Hypoplasia
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis,
        and pulmonary hypoplasia have all been described in patients with AO
        type I and we conclude that compromised pulmonary function is a major
        contributor to morbidity and mortality in this condition.
      explanation: Clinical observations support pulmonary hypoplasia within the respiratory mechanism, not a directional causal edge.
  - target: Tracheomalacia
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:9779808
      reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Detailed neonatal and postmortem examination showed severe subglottic
        hypoplasia and tracheomalacia.
      explanation: Pathology supports the airway endpoint, while the modeled edge direction is interpretive.
  - target: Laryngeal Stenosis
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:23401428
      reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis,
        and pulmonary hypoplasia have all been described in patients with AO
        type I and we conclude that compromised pulmonary function is a major
        contributor to morbidity and mortality in this condition.
      explanation: Clinical observations support the endpoint, not a directional causal edge.
genetic:
- name: Heterozygous gain-of-function FLNB pathogenic variants
  gene_term:
    preferred_term: FLNB
    term:
      id: hgnc:3755
      label: FLNB
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >
    Heterozygous pathogenic FLNB variants are causative for Atelosteogenesis
    Type I.
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of other FLNB-related disorders (LS, AO1, AO3) is
      established in a proband by identification of a heterozygous
      gain-of-function pathogenic variant in FLNB by molecular genetic testing.
    explanation: The current GeneReviews definition identifies the disease-causing allele class for FLNB-AO1.
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, 14 novel missense mutations in FLNB were found in 15
      unrelated patients with AOI and AOIII.
    explanation: >-
      This provides direct human genetic evidence for causative FLNB mutations in
      AOI-spectrum disease.
phenotypes:
- name: Disproportionate Short-Limb Short Stature
  description: >
    Affected neonates have severe short-limbed dwarfism.
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
  evidence:
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic
      disorder characterized by severe short-limbed dwarfism and dislocated
      hips, knees, and elbows.
    explanation: >-
      This directly supports severe disproportionate short-limb short stature in
      AOI.
- name: Rhizomelia
  description: >
    Molecularly confirmed cases show marked shortening of the proximal limb
    segments.
  phenotype_term:
    preferred_term: Rhizomelic limb shortening
    term:
      id: HP:0008905
      label: Rhizomelia
  frequency: FREQUENT
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0008905", "HPOTerm": "Rhizomelia" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Current Orphadata classifies rhizomelia as frequent (79-30%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports proximal limb shortening as a characteristic AOI
      skeletal manifestation.
- name: Joint Dislocation
  description: >
    Congenital large-joint dislocations prominently affect the hips, knees, and
    elbows.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001373", "HPOTerm": "Joint dislocation" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies joint dislocation as occasional (29-5%) in Atelosteogenesis type I.
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic
      disorder characterized by severe short-limbed dwarfism and dislocated
      hips, knees, and elbows.
    explanation: >-
      This directly supports congenital large-joint dislocation in AOI.
- name: Abnormality of the Vertebral Column
  description: >
    Vertebral developmental and ossification defects are recurrent radiographic
    findings in AOI.
  phenotype_term:
    preferred_term: Abnormality of the vertebral column
    term:
      id: HP:0000925
      label: Abnormality of the vertebral column
  evidence:
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AOI and AOIII are autosomal dominant lethal skeletal dysplasias
      characterized by overlapping clinical findings that include vertebral
      abnormalities, disharmonious skeletal maturation, hypoplastic long bones,
      and joint dislocations.
    explanation: >-
      This multi-patient FLNB series supports vertebral abnormalities as a core
      AOI feature.
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal ultrasonography (US) revealed absent or deficient ossification of the
      posterior neural arches of the thoracic spine, humeri, radii, ulnae,
      fibulae, and short tubular bones other than the distal phalanges, in
      addition to extremely short, thick femora.
    explanation: >-
      This directly documents deficient thoracic vertebral ossification in a
      prenatally diagnosed AOI fetus.
- name: Platyspondyly
  description: >
    Marked flattening of vertebral bodies is a key radiographic feature
    supporting AOI within the FLNB-related lethal skeletal dysplasia spectrum.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0000926", "HPOTerm": "Platyspondyly" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies platyspondyly as occasional (29-5%) in Atelosteogenesis type I.
- name: Fibular Aplasia
  description: >
    Absent or severely deficient fibular ossification is a recurrent severe limb
    abnormality in AOI.
  phenotype_term:
    preferred_term: Fibular aplasia
    term:
      id: HP:0002990
      label: Fibular aplasia
  evidence:
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal ultrasonography (US) revealed absent or deficient ossification of the
      posterior neural arches of the thoracic spine, humeri, radii, ulnae,
      fibulae, and short tubular bones other than the distal phalanges, in
      addition to extremely short, thick femora.
    explanation: >-
      This prenatal AOI case directly documents absent/deficient fibular
      ossification.
- name: Talipes Equinovarus
  description: >
    Bilateral clubfoot is reported in molecularly confirmed AOI.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  frequency: FREQUENT
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001762", "HPOTerm": "Talipes equinovarus" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Current Orphadata classifies talipes equinovarus as frequent (79-30%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports bilateral talipes equinovarus in AOI.
- name: Brachydactyly
  description: >
    Distal digit shortening, especially involving digits 3-5, is reported in
    molecularly confirmed AOI.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  frequency: FREQUENT
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001156", "HPOTerm": "Brachydactyly" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Current Orphadata classifies brachydactyly as frequent (79-30%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports brachydactyly as part of the distal limb phenotype.
- name: Broad Thumb
  description: >
    Broad thumbs are part of the distal limb malformation pattern in some
    molecularly confirmed cases.
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports broad thumbs in AOI.
- name: Pectus Excavatum
  description: >
    Pectus excavatum is reported in molecularly confirmed AOI.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports pectus excavatum in AOI.
- name: Thoracic Hypoplasia
  description: >
    Small, hypoplastic thorax contributes to the lethal respiratory phenotype
    and helps distinguish AOI from milder FLNB-related skeletal dysplasias.
  phenotype_term:
    preferred_term: Thoracic hypoplasia
    term:
      id: HP:0005257
      label: Thoracic hypoplasia
  frequency: FREQUENT
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0005257", "HPOTerm": "Thoracic hypoplasia" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Current Orphadata classifies thoracic hypoplasia as frequent (79-30%) in Atelosteogenesis type I.
- name: Prominent Forehead
  description: >
    A prominent forehead is part of the craniofacial pattern in the severe
    FLNB-AOI spectrum.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At its most severe, the spectrum of phenotypes assigned FLNB-AO1 can
      present with perinatal-lethal micromelic dwarfism characterized by
      flipper-like limbs (polysyndactyly with complete syndactyly of all fingers
      and toes, hypoplastic or absent first digits, and duplicated intermediate
      and distal phalanges); macrobrachycephaly; prominent forehead;
      hypertelorism; and proptosis.
    explanation: >-
      The current GeneReviews update includes prominent forehead in the severe
      FLNB-AO1 spectrum.
- name: Hypertelorism
  description: >
    Hypertelorism contributes to the recognizable craniofacial phenotype in some
    molecularly confirmed cases.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0000316", "HPOTerm": "Hypertelorism" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies hypertelorism as occasional (29-5%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports hypertelorism as part of the AOI craniofacial
      phenotype.
- name: Proptosis
  description: >
    Proptosis is part of the craniofacial phenotype in some molecularly
    confirmed cases.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0000520", "HPOTerm": "Proptosis" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies proptosis as occasional (29-5%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports proptosis as part of the AOI craniofacial
      phenotype.
- name: Downslanting Palpebral Fissures
  description: >
    Downslanting palpebral fissures are part of the craniofacial phenotype in
    some molecularly confirmed cases.
  phenotype_term:
    preferred_term: Downslanting palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports downslanting palpebral fissures as part of the AOI
      craniofacial phenotype.
- name: Micrognathia
  description: >
    Mandibular hypoplasia is part of the craniofacial phenotype in some
    molecularly confirmed cases.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0000347", "HPOTerm": "Micrognathia" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies micrognathia as occasional (29-5%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports retromicrognathia/micrognathia in AOI.
- name: Cleft Palate
  description: >
    Cleft palate is reported in molecularly confirmed AOI and expands the
    craniofacial phenotype beyond limb and vertebral findings.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0000175", "HPOTerm": "Cleft palate" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies cleft palate as occasional (29-5%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports cleft palate in AOI.
- name: Pulmonary Hypoplasia
  description: >
    Pulmonary hypoplasia is a major contributor to severe perinatal respiratory
    compromise in AOI.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  frequency: FREQUENT
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0002089", "HPOTerm": "Pulmonary hypoplasia" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Current Orphadata classifies pulmonary hypoplasia as frequent (79-30%) in Atelosteogenesis type I.
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal magnetic resonance imaging (MRI) using an ultrafast imaging sequence
      depicted dysmorphic features, pulmonary hypoplasia, and large cisterna
      magna.
    explanation: >-
      This case provides direct evidence of pulmonary hypoplasia in AOI.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary hypoplasia is a characteristic finding that has been presumed to
      be the cause of neonatal lethality.
    explanation: >-
      This supports pulmonary hypoplasia as a characteristic and clinically
      important AOI complication.
- name: Tracheomalacia
  description: >
    Severe airway malacia is a documented contributor to respiratory failure and
    death in AOI.
  phenotype_term:
    preferred_term: Tracheomalacia
    term:
      id: HP:0002779
      label: Tracheomalacia
  evidence:
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detailed neonatal and postmortem examination showed severe subglottic
      hypoplasia and tracheomalacia.
    explanation: >-
      This directly supports tracheomalacia as part of the lethal airway
      phenotype in AOI.
- name: Laryngeal Stenosis
  description: >
    Laryngeal narrowing is an occasional upper-airway manifestation and can add
    to the severe neonatal respiratory burden.
  phenotype_term:
    preferred_term: Laryngeal stenosis
    term:
      id: HP:0001602
      label: Laryngeal stenosis
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/1190
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/1190"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0001602", "HPOTerm": "Laryngeal stenosis" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies laryngeal stenosis as occasional (29-5%) in Atelosteogenesis type I.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis,
      and pulmonary hypoplasia have all been described in patients with AO type
      I and we conclude that compromised pulmonary function is a major
      contributor to morbidity and mortality in this condition.
    explanation: The clinical report directly identifies laryngeal stenosis within the AO1 respiratory phenotype.
diagnosis:
- name: Prenatal Ultrasound and MRI
  description: >
    Detailed fetal ultrasound and, when useful, MRI can recognize an AO-like
    pattern of severe limb shortening, dislocations, thoracic hypoplasia, and
    delayed or absent ossification. Because several lethal skeletal dysplasias
    overlap radiographically, imaging establishes suspicion and guides testing;
    molecular confirmation defines FLNB-AO1.
  evidence:
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Meticulous evaluation using fetal US and MRI permits a definitive prenatal
      diagnosis of AO I to be made.
    explanation: >-
      This historical case supports imaging-based prenatal recognition; current
      spectrum knowledge and genetic heterogeneity argue against treating the
      imaging pattern alone as molecularly definitive.
- name: Molecular FLNB Testing and Spectrum Diagnosis
  description: >
    Molecular diagnosis uses a skeletal-dysplasia gene panel, exome sequencing,
    or genome sequencing to identify a heterozygous gain-of-function FLNB
    variant in a fetus or neonate with AOI-like findings. Molecular results are
    important for distinguishing FLNB-AOI from AO-like lethal dysplasias caused
    by other genes, including SLC26A2-related atelosteogenesis type II, and from
    recessive FLNB loss-of-function disorders such as spondylocarpotarsal
    synostosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: FLNB
        term:
          id: hgnc:3755
          label: FLNB
  results: A heterozygous gain-of-function pathogenic FLNB variant.
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of other FLNB-related disorders (LS, AO1, AO3) is
      established in a proband by identification of a heterozygous
      gain-of-function pathogenic variant in FLNB by molecular genetic testing.
    explanation: GeneReviews defines heterozygous gain-of-function FLNB molecular confirmation as the diagnostic standard.
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In order to screen all possible genes associated with AO-like lethal
      skeletal dysplasias simultaneously, we performed whole-exome sequencing in
      a female newborn having clinical features of AO-I.
    explanation: >-
      Demonstrates exome sequencing as a diagnostic approach for AOI-like lethal
      skeletal dysplasia with differential genetic causes.
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified a novel missense variant (c.517G>A;
      p.Ala173Thr) in exon 2 of the FLNB gene in the patient.
    explanation: >-
      Supports molecular confirmation of AOI by identifying a heterozygous FLNB
      variant in a clinically affected newborn.
treatments:
- name: Individualized Perinatal Respiratory and Palliative Planning
  description: >
    No disease-modifying treatment is established for perinatal-lethal AO1.
    Prenatal counseling and delivery planning should prepare families and the
    neonatal team for potentially severe thoracic, pulmonary, and upper-airway
    compromise. Decisions about respiratory intervention and comfort-focused
    care should be individualized to the infant's anatomy, response to support,
    prognosis, and family goals.
  treatment_term:
    preferred_term: palliative care
    term:
      id: NCIT:C15292
      label: Palliative Therapy
  evidence:
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anticipation of the poor prognosis in AO1 is essential for appropriate
      genetic counseling of the parents and for determining postnatal treatment
      options.
    explanation: >-
      Supports prenatal planning and postnatal treatment decisions around AOI's
      poor prognosis.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course of one child was influenced by airway instability and
      bronchopulmonary dysplasia that complicated intubation and prevented
      separation from ventilator support.
    explanation: >-
      Demonstrates why neonatal respiratory support decisions in AOI require
      careful perinatal planning.
- name: Genetic Counseling and Parental Mosaicism Assessment
  description: >
    Genetic counseling should explain dominant inheritance, the usual de novo
    origin of lethal AOI, and the residual recurrence risk from parental somatic
    or gonadal mosaicism. Parental FLNB testing is important when a parent has
    mild limb asymmetry or other subtle FLNB-spectrum findings.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30231296
    reference_title: "Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      parents affected with a mild phenotype, probably with somatic mosaicism,
      can generate offspring with a much more severe phenotype of AOI.
    explanation: >-
      Supports counseling families that a mildly affected mosaic parent can have
      a child with lethal AOI.
  - reference: PMID:30231296
    reference_title: "Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A missense mutation not previously described in the literature was detected
      in the FLNB gene, affecting ∼ 20% of the evaluated cells and, therefore,
      confirming the diagnosis of mosaic AOI in the father.
    explanation: >-
      Directly supports parental molecular testing for suspected mosaicism.
differential_diagnoses:
- name: Atelosteogenesis type II
  description: >
    A clinically and radiographically overlapping perinatal-lethal skeletal
    dysplasia in the SLC26A2 sulfate-transporter spectrum, with autosomal
    recessive inheritance and distinctive cartilage-matrix pathology rather
    than monoallelic FLNB gain of function.
  disease_term:
    preferred_term: atelosteogenesis type II
    term:
      id: MONDO:0009727
      label: atelosteogenesis type II
  distinguishing_features:
  - Biallelic SLC26A2 disorder rather than a heterozygous FLNB disorder
  - Distinctive chondro-osseous histopathology with disturbed cartilage-matrix sulfation
  evidence:
  - reference: PMID:9133349
    reference_title: "Atelosteogenesis syndromes: a review, with comments on their pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type II shows distinctive chondro-osseous histopathology
      with a major disturbance in cartilage matrix macromolecules.
    explanation: The review identifies the cartilage-matrix pathology that separates AO2 from AO1.
- name: Atelosteogenesis type III
  description: >
    An allelic monoallelic FLNB gain-of-function skeletal dysplasia that overlaps
    AO1, but survival beyond the neonatal period can occur, especially with
    intensive respiratory support.
  disease_term:
    preferred_term: atelosteogenesis type III
    term:
      id: MONDO:0007168
      label: atelosteogenesis type III
  distinguishing_features:
  - Survival beyond the neonatal period is possible
  - Overlapping FLNB disorder requiring phenotype-spectrum interpretation
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In individuals with FLNB-AO3, survival beyond the neonatal period is
      possible with intensive and invasive respiratory support.
    explanation: GeneReviews distinguishes AO3 from perinatal-lethal AO1 by possible longer survival.
- name: Larsen syndrome
  description: >
    A generally milder monoallelic FLNB gain-of-function disorder with congenital
    large-joint dislocations, clubfeet, craniofacial findings, and vertebral
    anomalies that overlap AO1 but without the defining perinatal-lethal
    micromelic presentation.
  disease_term:
    preferred_term: Larsen syndrome
    term:
      id: MONDO:0007875
      label: Larsen syndrome
  distinguishing_features:
  - Usually milder than FLNB-AO1 and compatible with longer-term survival
  - Congenital dislocations and clubfeet overlap, so molecular and spectrum-level interpretation is needed
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNB-LS is characterized by combinations of congenital dislocations of
      the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot
      deformities); scoliosis and cervical kyphosis (which can be associated
      with a cervical myelopathy); short, broad, spatulate distal phalanges;
      distinctive craniofacial features (prominent forehead, depressed nasal
      bridge, malar flattening, and widely spaced eyes); vertebral anomalies;
      and supernumerary carpal and tarsal ossification centers.
    explanation: GeneReviews describes the overlapping but generally milder FLNB-Larsen phenotype.
notes: >
  Atelosteogenesis type I is usually fatal in the perinatal period and belongs
  to the severe end of the monoallelic FLNB gain-of-function spectrum, with
  boomerang and Piepkorn dysplasia now best treated as part of the FLNB-AOI
  spectrum, AOIII as an overlapping but sometimes survivable disorder, and
  Larsen syndrome as a milder dominant FLNB disorder. This mechanism is distinct
  from SLC26A2-related atelosteogenesis type II and from autosomal recessive
  FLNB loss-of-function spondylocarpotarsal synostosis. Most lethal AOI cases
  are de novo, but parental somatic mosaicism can produce a mild parental
  phenotype and a severely affected child. Increased F-actin affinity and
  cellular F-actin clustering are demonstrated for selected actin-binding-domain
  substitutions, but the in-vivo steps linking different FLNB variants to fetal
  cartilage disorganization and the full AO1 phenotype remain incompletely
  resolved; variant-specific experimental results should not be generalized to
  every AO1 allele.
datasets: []
📚

References & Deep Research

Deep Research

1
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**References:**
o3-deep-research-2025-06-26 69 citations 2026-03-03T23:47:13.422381

Overview: Atelosteogenesis type I (AOI) is a rare, perinatally lethal skeletal dysplasia characterized by incomplete bone formation (the term “atelosteogenesis” literally means “imperfect osteogenesis”) and severe disproportionate short stature (pmc.ncbi.nlm.nih.gov) (medlineplus.gov). It belongs to a spectrum of filamin B (FLNB)–related osteochondrodysplasias that also includes atelosteogenesis type III, Larsen syndrome, and boomerang dysplasia (pubmed.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). AOI is caused by heterozygous gain-of-function mutations in the FLNB gene, which encodes the cytoskeletal protein filamin B (pubmed.ncbi.nlm.nih.gov) (medlineplus.gov). These mutations disrupt normal skeletal development and result in a distinctive set of bone abnormalities. Only a few dozen cases of AOI have been reported worldwide (medlineplus.gov), underscoring its extreme rarity.

Pathophysiology: Filamin B is an actin-binding protein that stabilizes the cytoskeleton and plays a crucial role in endochondral ossification – the process by which cartilage is converted to bone during fetal development (medlineplus.gov). It is highly expressed in chondrocytes (cartilage-forming cells) and is essential for their proliferation, differentiation, and the formation of a normal growth plate (medlineplus.gov). In AOI, mutant FLNB proteins have an abnormal (gain-of-function) activity that perturbs cytoskeletal and signaling functions in developing cartilage (medlineplus.gov). The abnormal filamin B appears to acquire a new deleterious function that interferes with chondrocyte maturation and ossification, leading to delayed/incomplete mineralization of cartilage models and profound skeletal dysplasia (medlineplus.gov) (pmc.ncbi.nlm.nih.gov). Proposed mechanisms include marked delays in long bone ossification, reduced bone mineral density, and disorganized chondrocyte proliferation and apoptosis, as well as impaired cell motility in the growth plate (pmc.ncbi.nlm.nih.gov). On a molecular level, different FLNB mutations may perturb cell signaling in variable ways; for example, one recent cell-based study showed distinct FLNB variants differentially affect pathways like AKT and TGF-β/Smad in cartilage cells, which contributes to the heterogeneous skeletal outcomes (pmc.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). The end result of FLNB gain-of-function mutations is a severe failure of normal bone formation, especially in the spine and long bones, which explains the hallmark features of AOI (short, under-ossified bones with multiple deformities).

Genetics and Inheritance: FLNB is the major gene implicated in Atelosteogenesis I. AOI arises from dominant missense or small in-frame deletions in one copy of the FLNB gene, typically clustered in the filamin B actin-binding domain or nearby regions (pubmed.ncbi.nlm.nih.gov). These mutations act in a dominant gain-of-function manner rather than causing haploinsufficiency (pmc.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). Atelosteogenesis type III is allelic to type I – it is caused by other missense mutations in FLNB and considered a slightly less severe phenotype on the same spectrum (pmc.ncbi.nlm.nih.gov). In contrast, atelosteogenesis type II is a genetically distinct disorder caused by biallelic loss-of-function mutations in the sulfate transporter gene SLC26A2 (formerly DTDST) (pmc.ncbi.nlm.nih.gov). AOII is inherited in an autosomal recessive pattern, whereas AOI is autosomal dominant (pubmed.ncbi.nlm.nih.gov). Because AOI is usually lethal in the perinatal period, most cases are sporadic due to new (de novo) mutations arising in the germline; indeed, the vast majority of FLNB mutations causing lethal AOI are not inherited from an affected parent (www.ncbi.nlm.nih.gov). Rarely, somatic mosaicism in a parent can lead to transmission of AOI – there are reports of a mildly affected mosaic parent (with subtle skeletal anomalies) having an offspring with full-blown lethal AOI (pmc.ncbi.nlm.nih.gov). In one 2023 case, for example, an asymmetrically affected father was found to be mosaic (~20% of cells) for an FLNB missense mutation and passed it to his newborn, who had classic lethal AOI (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This highlights that while AOI follows dominant inheritance, de novo mutations and mosaicism are the predominant real-world scenarios for this disorder.

Hallmark Skeletal Phenotypes: AOI has a recognizable constellation of skeletal abnormalities evident on prenatal ultrasound or at birth. Key features include:

  • Severe disproportionate short-limbed dwarfism: infants have markedly shortened arms and legs (rhizomelic shortening) with overall small stature (www.ncbi.nlm.nih.gov). Long bones (humeri and femora) are hypoplastic, often tapered or bowed, reflecting undermineralization. The term “disharmonious skeletal maturation” has been used to describe the uneven development of the skeleton in AOI (pubmed.ncbi.nlm.nih.gov).
  • Large joint dislocations and foot deformities: congenital dislocations of the hips, knees, and elbows are typically present, due to malformation of joint structures (www.ncbi.nlm.nih.gov). Affected newborns often have clubfeet (inward- and upward-turning feet) at birth (medlineplus.gov). These joint instabilities and contractures are similar to those seen in the milder FLNB-related Larsen syndrome, but in AOI they are more severe and universal.
  • Thoracic and spinal abnormalities: The rib cage is small and underdeveloped, leading to a narrow thorax (thoracic hypoplasia) and under-inflated lungs (medlineplus.gov). This causes respiratory insufficiency, the primary reason why AOI is typically lethal shortly after birth (medlineplus.gov). The vertebrae are flattened (platyspondyly) and may be malformed, contributing to a short trunk (www.ncbi.nlm.nih.gov). The pelvis is hypoplastic as well, with small iliac wings and poor ossification of pelvic bones (www.ncbi.nlm.nih.gov).
  • Limb bone malformations: Many long bones are incomplete or missing. Radiographs show absent or extremely short fibulae, and the radius can be absent or shortened with resultant bowing of the ulna; the femur and humerus are shortened and may be “distally tapered” (pointed) at the ends (www.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Ossification is incomplete in many skeletal elements – for example, the metacarpal bones and the proximal/middle phalanges of the fingers often remain unossified or only partially ossified at birth (www.ncbi.nlm.nih.gov). This lack of ossification in the hands and feet, along with the long bone changes, is a hallmark diagnostic clue for AOI on prenatal imaging or X-rays (pmc.ncbi.nlm.nih.gov).
  • Craniofacial features: Babies with AOI often have distinctive facial dysmorphism. Common findings include a prominent forehead (frontal bossing), wide-set, bulging eyes (ocular hypertelorism with proptosis), a depressed nasal bridge with upturned nose, and micrognathia (small jaw) (medlineplus.gov) (www.ncbi.nlm.nih.gov). Despite the large appearing skull (often termed macrocranium or macrobrachycephaly), many cranial bones may have poor ossification. A cleft palate is occasionally present (medlineplus.gov). These craniofacial signs, while not life-threatening, can aid in recognizing the syndrome.
  • “Flipper-like” extremities in extreme cases: In the most severe end of the AOI spectrum (overlapping with boomerang dysplasia), infants can exhibit polysyndactyly with complete syndactyly of all digits, giving the limbs a paddle-like appearance (www.ncbi.nlm.nih.gov). In such cases, all fingers and toes are fused and there may be duplicate distal bones (described as “distal octadactyly” in hands) with absent or rudimentary thumbs (www.ncbi.nlm.nih.gov). This dramatic malformation reflects an even more profound disruption of skeletal patterning. While not present in every AOI case, this “flipper limb” presentation is considered part of the AOI spectrum and is pathognomonic when observed (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov).

Diagnosis and Current Research: Atelosteogenesis I can often be suspected prenatally by ultrasound findings of severe skeletal abnormalities (short limbs, small chest, joint dislocations). Genetic testing is then used to confirm the diagnosis. Modern Next-Generation Sequencing approaches – multi-gene panels or whole-exome sequencing (WES) – have greatly improved the ability to identify the causative mutation in cases of lethal skeletal dysplasia like AOI (pmc.ncbi.nlm.nih.gov). For example, exome sequencing in a 2014 case pinpointed a de novo FLNB missense mutation in an infant with AOI, demonstrating the efficacy of WES in reaching a definitive molecular diagnosis (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Likewise, a recent report highlighted that recognizing subtle signs in a mosaic parent and testing for an FLNB variant enabled prenatal diagnosis of AOI in the fetus (pmc.ncbi.nlm.nih.gov). These diagnostic advances are critical for genetic counseling and early intervention, even though no curative treatment exists for AOI.

On the research front, ongoing studies are probing the mechanistic basis of FLNB mutations. The Genetics of AOI has been refined by gene discovery – FLNB’s role was first identified in the mid-2000s (pubmed.ncbi.nlm.nih.gov) and GeneReviews (updated 2025) now consolidates FLNB-related disorders as a spectrum (www.ncbi.nlm.nih.gov). Recent functional studies (2022–2023) are examining how different FLNB mutant proteins impact cell behavior. For instance, Wu et al. (2022) demonstrated that two distinct FLNB missense mutations had cell-dependent effects on chondrocyte signaling and gene expression, suggesting that FLNB variants can differentially disrupt pathways like PI3K–AKT and TGF-β/Smad, leading to variability in skeletal phenotypes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This line of research is helping to explain the range from milder Larsen syndrome to lethal AOI within the FLNB spectrum, and may eventually identify targets to modulate the disease process.

Conclusion: Atelosteogenesis type I is a genetically defined osteochondrodysplasia with a well-characterized mutation in a cytoskeletal protein (filamin B) as its cause. It exhibits an autosomal dominant inheritance pattern, though typically through de novo mutations. Mechanistically, a gain-of-function in filamin B disrupts the formation and ossification of cartilage, which manifests as profound skeletal abnormalities – from short, under-ossified long bones and dislocated joints to characteristic craniofacial features. The disorder’s hallmark skeletal phenotypes (severe short-limb dwarfism, joint dislocations, thoracic hypoplasia, and incomplete ossification of bones) correlate with the underlying molecular pathology in growth plate cartilage (medlineplus.gov) (www.ncbi.nlm.nih.gov). Ongoing research and advanced genomic diagnostics continue to refine our understanding of AOI, but it remains a lethal condition with no definitive treatment, emphasizing the importance of prenatal diagnosis and family planning in its management (medlineplus.gov). As our insight into filamin B’s role in skeletal development deepens, it provides a mechanistic framework not only for AOI but also for related skeletal dysplasias caused by FLNB, guiding both clinical recognition and future therapeutic ideas (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

References:

  1. Robertson SP & Meira J. FLNB-Related Disorders. GeneReviews. Last updated Sep 11, 2025 (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov).
  2. Farrington-Rock C et al. “Mutations in two regions of FLNB result in atelosteogenesis I and III.” Hum Mutat. 2006 Jul;27(7):705-10 (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).
  3. MedlinePlus Genetics. Atelosteogenesis Type 1. Reviewed Oct 2015 (updated) (medlineplus.gov) (medlineplus.gov).
  4. Jeon GW et al. “Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis I by exome sequencing.” Ann Lab Med. 2014;34(2):134-138 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  5. Wu H et al. “Cell-dependent pathogenic roles of filamin B in different skeletal malformations.” Biomed Res Int. 2022;2022:8956636 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
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