🏷

Classifications

ISDS Skeletal Nosology

🔗

Mappings

MONDO

MONDO:0007168 atelosteogenesis type III

The current Orphadata cross-reference record lists MONDO:0007168 as a validated exact mapping for ORPHA:56305.

📘

Definitions

1

FLNB-AO3 spectrum definition

A severe monoallelic FLNB gain-of-function disorder within a continuous phenotypic spectrum that also includes FLNB-related Larsen syndrome and FLNB-AO1. AO3 shares severe short-limb dwarfism, large-joint dislocations, and clubfeet with AO1, while postneonatal and adult survival distinguishes the possible AO3 course from perinatal-lethal AO1.

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 AO3 within the monoallelic FLNB gain-of-function spectrum.

PMID:10076882 SUPPORT Human Clinical

"This is the first documentation of survival to adulthood of an individual with this disorder, of prenatal diagnostic assessment of an affected individual, and of vertical transmission suggestive of autosomal dominant inheritance."

The mother-son report establishes that AO3 can be compatible with adult survival and vertical transmission.

👪

Inheritance

1

Autosomal dominant FLNB disorder HP:0000006

FLNB-AO3 follows an autosomal dominant disease model and is caused by a heterozygous gain-of-function FLNB pathogenic variant. Both vertical transmission and occurrence in an apparently simplex family are possible; parental mosaicism and marked intrafamilial severity differences must be considered in recurrence counseling.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:14991055 SUPPORT Human Clinical

"We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and..."

This directly supports autosomal dominant inheritance for the AOIII FLNB phenotype.

PMID:10076882 SUPPORT Human Clinical

"We describe two additional instances of atelosteogenesis, type III, in a woman and her son."

A mother-son pair provides direct evidence that AO3 can be transmitted vertically.

PMID:20301736 SUPPORT Other

"Comparatively mild (e.g., FLNB-LS) and severe (e.g., FLNB-AO3) forms of the autosomal dominant FLNB-related disorders can occur in the same family."

GeneReviews documents dominant inheritance with substantial within-family phenotypic variability.

⚙

Pathophysiology

3

Monoallelic FLNB gain-of-function cytoskeletal disorder

FLNB-AO3 is caused by heterozygous gain-of-function FLNB variants. Filamin B cross-links actin, links membrane proteins to the cytoskeleton, and provides a scaffold for signaling and trafficking. AO1/AO3 variants cluster in the CH2 actin-binding domain and in repeats 14-15, but the precise protein interactions or novel interactions responsible for AO3 are not resolved; the entry therefore does not assign one variant-universal biochemical effect.

Chondrocyte CL:0000138

FLNB hgnc:3755

Actin filament organization GO:0007015 ⚠ ABNORMAL Cytoskeleton organization GO:0007010 ⚠ ABNORMAL

actin filament binding GO:0051015

Downstream

Abnormal joint formation, vertebral development, and endochondral ossification Human developmental-expression and disease-association data connect FLNB to growth-plate, joint, vertebral, and ossification phenotypes, but do not resolve the complete molecular-to-tissue chain for AO3.

Show evidence (3 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 establishes the monoallelic gain-of-function classification for FLNB-AO3.

PMID:14991055 SUPPORT Human Clinical

"The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are..."

The causal gene's established protein functions supply the cytoskeletal context without specifying an AO3-only downstream interaction.

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 AO1/AO3 patient series identifies two recurrent FLNB variant clusters.

Abnormal joint formation, vertebral development, and endochondral ossification

Filamin B has a developmental role in joint formation, vertebral segmentation, and endochondral ossification. In AO3, disruption of these processes provides a bounded tissue-level explanation for congenital joint dislocations, severe limb and long-bone abnormalities, and vertebral dysplasia. Clinical occurrence supports endpoint placement but generally does not prove directness of individual edges.

Growth plate chondrocyte CL:1000217

Embryonic skeletal joint development GO:0072498 ⚠ ABNORMAL Cartilage development GO:0051216 ⚠ ABNORMAL Endochondral ossification GO:0001958 ⚠ ABNORMAL

Downstream

Thoracic and laryngotracheal insufficiency Abnormal skeletal and cartilage development can involve the thorax and laryngotracheal structures, but the precise tissue bridge is not defined.

Disproportionate Short-Limb Short Stature

Rhizomelia

Large Joint Dislocations

Talipes Equinovarus

Aplasia/Hypoplasia of the Humerus

Coronal Cleft Vertebrae

Scoliosis

Hypertelorism

Depressed Nasal Bridge

Micrognathia

Cleft Palate

Broad Thumb

Show evidence (2 references)

PMID:14991055 SUPPORT Human Clinical

"These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein."

The discovery series directly identifies the relevant developmental processes.

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."

The AO1/AO3 series links FLNB variants to the principal skeletal-development endpoints, although later reports establish that AO3 is not uniformly lethal.

Thoracic and laryngotracheal insufficiency

AO3 can combine thoracic hypoplasia with laryngotracheomalacia and other respiratory insufficiency. The relative contribution of thoracic restriction, airway instability, and pulmonary factors varies among individuals and is not quantified by the sparse case literature.

Chondrocyte CL:0000138

Trachea development GO:0060438 ⚠ ABNORMAL

Downstream

Laryngotracheomalacia

Respiratory Insufficiency

Apnea

Thoracic Hypoplasia

Show evidence (2 references)

PMID:1442028 SUPPORT Human Clinical

"The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age."

This case directly documents severe airway instability and respiratory events in AO3.

url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305 SUPPORT Other

""HPOId": "HP:0002093", "HPOTerm": "Respiratory insufficiency""

Current Orphadata independently records respiratory insufficiency in the AO3 phenotype set.

⬡

Pathograph

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

●

Phenotypes

16

Eye 1

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate."

This directly supports hypertelorism.

Head and Neck 3

Depressed Nasal Bridge HP:0005280

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate."

This supports a depressed/flat nasal bridge phenotype.

Micrognathia OCCASIONAL HP:0000347

Show evidence (2 references)

url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305 SUPPORT Other

""HPOId": "HP:0000347", "HPOTerm": "Micrognathia" }, "HPOFrequency": "Occasional (29-5%)""

Current Orphadata classifies micrognathia as occasional (29-5%) in AO3.

PMID:1442028 SUPPORT Human Clinical

"The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate."

This directly supports micrognathia.

Cleft Palate HP:0000175

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate."

This directly supports cleft palate.

Limbs 3

Talipes Equinovarus FREQUENT HP:0001762

Show evidence (2 references)

url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305 SUPPORT Other

""HPOId": "HP:0001762", "HPOTerm": "Talipes equinovarus" }, "HPOFrequency": "Frequent (79-30%)""

Current Orphadata classifies talipes equinovarus as frequent (79-30%) in AO3.

PMID:1442028 SUPPORT Human Clinical

"There was rhizomelic shortness of the limbs and a club-foot."

This directly supports talipes equinovarus (club-foot).

Aplasia/Hypoplasia of the Humerus HP:0006507

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies."

This directly supports humeral hypoplasia.

Broad Thumb HP:0011304

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"The infant had short broad thumbs in the hands similar to those observed in the feet."

This directly supports broad thumbs.

Musculoskeletal 4

Large Joint Dislocations HP:0005008

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 primary AOI/AOIII mutation series directly identifies joint dislocations as part of the shared phenotype.

PMID:20301736 SUPPORT Other

"FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet."

GeneReviews localizes the dislocations to the large joints most often emphasized in AOIII.

Coronal Cleft Vertebrae FREQUENT HP:0003417

Show evidence (2 references)

url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305 SUPPORT Other

""HPOId": "HP:0003417", "HPOTerm": "Coronal cleft vertebrae" }, "HPOFrequency": "Frequent (79-30%)""

Current Orphadata classifies coronal cleft vertebrae as frequent (79-30%) in AO3.

PMID:1442028 SUPPORT Human Clinical

"Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies."

This directly supports coronal cleft vertebral abnormalities.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies."

This directly supports scoliosis.

Thoracic Hypoplasia OCCASIONAL HP:0005257

Show evidence (1 reference)

url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305 SUPPORT Other

""HPOId": "HP:0005257", "HPOTerm": "Thoracic hypoplasia" }, "HPOFrequency": "Occasional (29-5%)""

Current Orphadata classifies thoracic hypoplasia as occasional (29-5%) in AO3.

Respiratory 2

Apnea HP:0002104

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age."

This directly supports recurrent apnea as part of the respiratory phenotype.

Respiratory Insufficiency FREQUENT HP:0002093

Show evidence (2 references)

url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305 SUPPORT Other

""HPOId": "HP:0002093", "HPOTerm": "Respiratory insufficiency" }, "HPOFrequency": "Frequent (79-30%)""

Current Orphadata classifies respiratory insufficiency as frequent (79-30%) in AO3.

PMID:20301736 SUPPORT Other

"In individuals with FLNB-AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support."

The need for intensive respiratory support in some survivors supports clinically important respiratory insufficiency.

Growth 2

Disproportionate Short-Limb Short Stature HP:0008873

Show evidence (2 references)

PMID:2368807 SUPPORT Human Clinical

"We present 5 cases of a short-limb dwarfism syndrome whose manifestations overlap those of atelosteogenesis and oto-palato-digital syndrome Type II."

The original AOIII case series directly identifies the condition as a short-limb dwarfism syndrome.

PMID:20301736 SUPPORT Other

"FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet."

GeneReviews summarizes AOIII within the FLNB spectrum as severe short-limbed dwarfism.

Rhizomelia HP:0008905

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"There was rhizomelic shortness of the limbs and a club-foot."

This directly supports rhizomelic limb shortening.

Other 1

Laryngotracheomalacia OCCASIONAL HP:0008755

Show evidence (2 references)

url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305 SUPPORT Other

""HPOId": "HP:0008755", "HPOTerm": "Laryngotracheomalacia" }, "HPOFrequency": "Occasional (29-5%)""

Current Orphadata classifies laryngotracheomalacia as occasional (29-5%) in AO3.

PMID:1442028 SUPPORT Human Clinical

"The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age."

This directly supports the tracheal component of laryngotracheomalacia as a major AO3 complication.

🧬

Genetic Associations

1

Heterozygous gain-of-function FLNB pathogenic variants (CAUSATIVE)

Gene: FLNB hgnc:3755 relationship_type: CAUSATIVE variant_origin: GERMLINE

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 the causative allele class for FLNB-AO3.

PMID:14991055 SUPPORT Human Clinical

"We identified mutations in the gene encoding filamin B in four human skeletal disorders."

This provides direct genetic evidence linking FLNB mutations to severe human skeletal disorders including AOIII.

PMID:14991055 SUPPORT Human Clinical

"We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and..."

This explicitly names missense FLNB mutations in AOIII.

🗃️

External Assertions

1

Orphadata Atelosteogenesis type III record

Orphanet structured disease record ORPHA:56305

The current Orphadata record identifies ORPHA:56305 as Atelosteogenesis type III and maps it exactly to MONDO:0007168 and OMIM:108721.

Show evidence (2 references)

url:https://api.orphadata.com/rd-cross-referencing/orphacodes/56305 SUPPORT Other

""Preferred term": "Atelosteogenesis type III""

The current Orphadata record supplies the preferred disease identity.

url:https://api.orphadata.com/rd-cross-referencing/orphacodes/56305 SUPPORT Other

""Reference": "0007168", "Source": "MONDO""

Orphadata records the exact MONDO cross-reference used by this entry.

💊

Medical Actions

3

Individualized Respiratory and Airway Support

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

Respiratory assessment should distinguish thoracic restriction from upper- and central-airway instability. Support is individualized; some infants may require prolonged ventilation, tracheostomy, or other invasive airway care, while published survival and severity vary. A single case requiring tracheostomy demonstrates possibility, not a universal treatment rule.

Show evidence (2 references)

PMID:1442028 SUPPORT Human Clinical

"The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age."

The case demonstrates that severe AO3 airway disease can require tracheostomy.

PMID:20301736 SUPPORT Other

"In individuals with FLNB-AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support."

GeneReviews supports planning for intensive respiratory support in selected individuals while acknowledging survival variability.

Individualized Orthopedic Follow-up in Survivors

Action: orthopedic procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Long-term survivors require individualized orthopedic assessment of joint dislocations, spinal curvature, limb deformity, mobility, and function. The published AO3 management literature is case-based, so no single operation or schedule is generalized to all affected individuals.

Show evidence (1 reference)

PMID:27258362 SUPPORT Human Clinical

"In the literature, an orthopedic management for this disorder has not been well described. We report the case and orthopedic management of a 6-year-old female patient with atelosteogenesis type III after 3 years of follow-up."

The report demonstrates multiyear orthopedic management but also shows that the evidence base is limited to case experience.

Genetic Counseling and Parental Evaluation

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling should explain autosomal dominant inheritance, the possibility of de novo or inherited disease, parental somatic or gonadal mosaicism, marked phenotypic variability, and a 50% transmission risk from a constitutional heterozygous individual. Evaluation of parents for the familial variant and subtle FLNB-spectrum findings refines recurrence counseling.

Show evidence (2 references)

PMID:20301736 SUPPORT Other

"FLNB-LS, FLNB-AO1, FLNB-AO3, and FLNB-related apparently isolated clubfoot are inherited in an autosomal dominant manner."

GeneReviews establishes the inheritance model underlying counseling.

PMID:20301736 SUPPORT Other

"Each child of a proband who is heterozygous for an FLNB pathogenic variant has a 50% chance of inheriting the pathogenic variant."

GeneReviews provides the transmission risk for a constitutional heterozygous parent.

🔬

Diagnosis

2

Clinical and Skeletal Radiographic Evaluation

Prenatal or postnatal imaging can identify the AO3 pattern of severe short-limb dysplasia, congenital dislocations, humeral and other long-bone abnormalities, and vertebral clefting or curvature. Because AO3 overlaps AO1, Larsen syndrome, atelosteogenesis type II, and otopalatodigital type II, radiography establishes a pattern and differential rather than a gene-level diagnosis.

radiograph imaging procedure NCIT:C38101

Show evidence (1 reference)

PMID:1442028 SUPPORT Human Clinical

"Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies."

This supports the diagnostic importance of distinctive radiographic skeletal abnormalities.

Molecular FLNB Confirmation and Spectrum Assignment

Molecular diagnosis requires identification of a heterozygous gain-of-function pathogenic FLNB variant. The variant must be interpreted together with the clinical-radiographic phenotype because FLNB-AO3 overlaps a broader allelic spectrum and individual variants do not always predict a single severity category.

molecular genetic testing NCIT:C19770

Results: A heterozygous gain-of-function pathogenic FLNB variant.

Show evidence (1 reference)

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 molecular confirmation for AO3 and the overlapping dominant FLNB spectrum.

📈

Progression

1

Congenital presentation with variable postnatal survival

Age: Prenatal period to adulthood

Skeletal abnormalities are present prenatally or at birth. Severe respiratory compromise can cause early death or require invasive support, yet survival beyond infancy and into adulthood is documented. The sparse case literature does not support a single deterministic survival trajectory.

Show evidence (2 references)

PMID:20301736 SUPPORT Other

"In individuals with FLNB-AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support."

GeneReviews summarizes the severe respiratory course while explicitly recognizing postneonatal survival.

PMID:10076882 SUPPORT Human Clinical

"This is the first documentation of survival to adulthood of an individual with this disorder, of prenatal diagnostic assessment of an affected individual, and of vertical transmission suggestive of autosomal dominant inheritance."

The report demonstrates that the AO3 course can extend from prenatal recognition through adulthood.

📊

Prevalence

2

Worldwide literature

Cases In Literature Ultra Rare

Current Orphadata records 25 worldwide cases/families. This is a case count, not a denominator-based prevalence estimate.

Show evidence (1 reference)

url:https://api.orphadata.com/rd-epidemiology/orphacodes/56305 SUPPORT Other

""PrevalenceQualification": "Case(s)", "PrevalenceType": "Cases/families", "PrevalenceValidationStatus": "Validated", "Source": "ORPHANET", "ValMoy": "25.0""

Orphadata supplies the validated worldwide case/family count of 25.

Worldwide

Point Prevalence <1 in 1,000,000

Orphadata provides a class-only point-prevalence estimate below one per million; no numeric rate is imputed from the class.

Show evidence (1 reference)

url:https://api.orphadata.com/rd-epidemiology/orphacodes/56305 SUPPORT Other

""PrevalenceClass": "<1 / 1 000 000""

The current Orphadata epidemiology record supplies the worldwide point-prevalence class.

⚖️

Clinical Burden

High

AO3 imposes high typical burden through major congenital skeletal deformity, joint dislocations, impaired mobility, and potentially severe airway or respiratory disease. Burden is variable rather than uniformly lethal: some individuals require tracheostomy or other invasive respiratory support, while long-term survivors require continuing orthopedic care.

Show evidence (2 references)

PMID:1442028 SUPPORT Human Clinical

"The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age."

This survivor required invasive airway management, supporting high clinical burden.

PMID:27258362 SUPPORT Human Clinical

"We report the case and orthopedic management of a 6-year-old female patient with atelosteogenesis type III after 3 years of follow-up."

A long-term survivor required multiyear orthopedic follow-up and management.

🔀

Differential Diagnoses

4

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

Atelosteogenesis type I MONDO:0007167

Overlapping Features The perinatal-lethal FLNB-AO1 end of the same gain-of-function spectrum can overlap AO3 in skeletal and joint findings. Persistent postneonatal or adult survival supports AO3, whereas AO1 is defined as perinatal lethal in current GeneReviews scope; molecular results still require phenotype-level spectrum interpretation.

Distinguishing Features

FLNB-AO1 is defined as perinatal lethal in the current spectrum
Survival beyond the neonatal period is possible in FLNB-AO3

Show evidence (1 reference)

PMID:20301736 SUPPORT Other

"FLNB-AO1 is lethal in the perinatal period. 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..."

GeneReviews supplies the perinatal-lethal AO1 boundary used to distinguish it from survivable AO3.

Atelosteogenesis type II MONDO:0009727

Overlapping Features A clinically and radiographically overlapping perinatal-lethal dysplasia in the autosomal recessive SLC26A2 sulfate-transporter spectrum, with a cartilage-matrix sulfation disorder rather than monoallelic FLNB gain of function.

Distinguishing Features

Biallelic SLC26A2 disorder rather than a heterozygous FLNB disorder
Distinctive cartilage-matrix histopathology and sulfation pathogenesis

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 distinction between AO2 and FLNB-related AO3.

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 abnormalities. Larsen syndrome and AO3 are allelic and can overlap within families, so severity and full radiographic pattern guide assignment.

Distinguishing Features

Generally milder skeletal severity than AO3
Allelic FLNB overlap and within-family variability limit rigid variant-only classification

Show evidence (1 reference)

PMID:10076882 SUPPORT Human Clinical

"The clinical and radiologic phenotype of atelosteogenesis, type III overlaps with that of another skeletal dysplasia, autosomal dominant Larsen syndrome; these most likely represent allelic conditions."

The familial AO3 report explicitly identifies Larsen syndrome as an overlapping allelic differential.

Otopalatodigital syndrome type II

Overlapping Features A severe X-linked FLNA-related skeletal dysplasia with craniofacial, digital, long-bone, and thoracic abnormalities that can resemble AO3. Sex-linked inheritance, FLNA molecular findings, and the full radiographic pattern distinguish it from autosomal dominant FLNB-AO3.

Distinguishing Features

FLNA-related X-linked disorder rather than a heterozygous FLNB disorder
The founding AO3 series found a distinct clinical, radiographic, genetic, and histologic pattern despite overlap

Show evidence (1 reference)

PMID:2368807 SUPPORT Human Clinical

"Clinical, radiographic, genetic, and histologic data are presented which demonstrate differences between our patients and previously reported cases of these other conditions."

The founding series explicitly separates AO3 from phenotypically overlapping OPD2.

{ }

Source YAML

click to show

name: Atelosteogenesis Type III
creation_date: '2026-03-04T07:57:38Z'
category: Mendelian
description: >
  Atelosteogenesis type III (FLNB-AO3) is a severe but variably survivable
  monoallelic FLNB gain-of-function skeletal dysplasia. It is characterized by
  severe short-limb disproportion, congenital large-joint dislocations,
  clubfeet, vertebral and long-bone abnormalities, and variable craniofacial,
  thoracic, and laryngotracheal involvement. Respiratory compromise can be
  life-threatening and may require invasive support, but survival into childhood
  and adulthood is documented; it should not be modeled as uniformly perinatal
  lethal.
disease_term:
  preferred_term: atelosteogenesis type III
  term:
    id: MONDO:0007168
    label: atelosteogenesis type III
parents:
- Skeletal Dysplasia
synonyms:
- FLNB-related atelosteogenesis type 3
- Atelosteogenesis type 3
- AO3
- AOIII
- Atelosteogenesis type 3, 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 3 (AO3)".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0007168
      label: atelosteogenesis type III
    mapping_predicate: skos:exactMatch
    mapping_source: Orphadata ORPHA:56305
    mapping_justification: >
      The current Orphadata cross-reference record lists MONDO:0007168 as a
      validated exact mapping for ORPHA:56305.
references:
- reference: PMID:20301736
  title: FLNB-Related Disorders.
  tags:
  - GeneReviews
  findings: []
external_assertions:
- name: Orphadata Atelosteogenesis type III record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:56305
  url: https://api.orphadata.com/rd-cross-referencing/orphacodes/56305
  description: >
    The current Orphadata record identifies ORPHA:56305 as Atelosteogenesis type
    III and maps it exactly to MONDO:0007168 and OMIM:108721.
  evidence:
  - reference: url:https://api.orphadata.com/rd-cross-referencing/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-cross-referencing/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"Preferred term": "Atelosteogenesis type III"'
    explanation: The current Orphadata record supplies the preferred disease identity.
  - reference: url:https://api.orphadata.com/rd-cross-referencing/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-cross-referencing/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"Reference": "0007168", "Source": "MONDO"'
    explanation: Orphadata records the exact MONDO cross-reference used by this entry.
definitions:
- name: FLNB-AO3 spectrum definition
  definition_type: OTHER
  description: >
    A severe monoallelic FLNB gain-of-function disorder within a continuous
    phenotypic spectrum that also includes FLNB-related Larsen syndrome and
    FLNB-AO1. AO3 shares severe short-limb dwarfism, large-joint dislocations,
    and clubfeet with AO1, while postneonatal and adult survival distinguishes
    the possible AO3 course from perinatal-lethal AO1.
  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 AO3 within the monoallelic FLNB gain-of-function spectrum.
  - reference: PMID:10076882
    reference_title: "Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first documentation of survival to adulthood of an individual
      with this disorder, of prenatal diagnostic assessment of an affected
      individual, and of vertical transmission suggestive of autosomal dominant
      inheritance.
    explanation: The mother-son report establishes that AO3 can be compatible with adult survival and vertical transmission.
inheritance:
- name: Autosomal dominant FLNB disorder
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    FLNB-AO3 follows an autosomal dominant disease model and is caused by a
    heterozygous gain-of-function FLNB pathogenic variant. Both vertical
    transmission and occurrence in an apparently simplex family are possible;
    parental mosaicism and marked intrafamilial severity differences must be
    considered in recurrence counseling.
  evidence:
  - reference: PMID:14991055
    reference_title: "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721).
    explanation: >-
      This directly supports autosomal dominant inheritance for the AOIII FLNB phenotype.
  - reference: PMID:10076882
    reference_title: "Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two additional instances of atelosteogenesis, type III, in a
      woman and her son.
    explanation: A mother-son pair provides direct evidence that AO3 can be transmitted vertically.
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Comparatively mild (e.g., FLNB-LS) and severe (e.g., FLNB-AO3) forms of
      the autosomal dominant FLNB-related disorders can occur in the same
      family.
    explanation: GeneReviews documents dominant inheritance with substantial within-family phenotypic variability.
prevalence:
- population: Worldwide literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Current Orphadata records 25 worldwide cases/families. This is a case count,
    not a denominator-based prevalence estimate.
  evidence:
  - reference: url:https://api.orphadata.com/rd-epidemiology/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-epidemiology/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "PrevalenceQualification": "Case(s)", "PrevalenceType":
      "Cases/families", "PrevalenceValidationStatus": "Validated", "Source":
      "ORPHANET", "ValMoy": "25.0"
    explanation: Orphadata supplies the validated worldwide case/family count of 25.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphadata provides a class-only point-prevalence estimate below one per
    million; no numeric rate is imputed from the class.
  evidence:
  - reference: url:https://api.orphadata.com/rd-epidemiology/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-epidemiology/orphacodes/56305"
    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: Congenital presentation with variable postnatal survival
  age_range: Prenatal period to adulthood
  notes: >-
    Skeletal abnormalities are present prenatally or at birth. Severe respiratory
    compromise can cause early death or require invasive support, yet survival
    beyond infancy and into adulthood is documented. The sparse case literature
    does not support a single deterministic survival trajectory.
  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 summarizes the severe respiratory course while explicitly recognizing postneonatal survival.
  - reference: PMID:10076882
    reference_title: "Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first documentation of survival to adulthood of an individual
      with this disorder, of prenatal diagnostic assessment of an affected
      individual, and of vertical transmission suggestive of autosomal dominant
      inheritance.
    explanation: The report demonstrates that the AO3 course can extend from prenatal recognition through adulthood.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    AO3 imposes high typical burden through major congenital skeletal
    deformity, joint dislocations, impaired mobility, and potentially severe
    airway or respiratory disease. Burden is variable rather than uniformly
    lethal: some individuals require tracheostomy or other invasive respiratory
    support, while long-term survivors require continuing orthopedic care.
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant experienced recurrent apnea and persistent severe
      tracheomalacia, which necessitated tracheostomy at 5 months of age.
    explanation: This survivor required invasive airway management, supporting high clinical burden.
  - reference: PMID:27258362
    reference_title: "Atelosteogenesis type III: orthopedic management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the case and orthopedic management of a 6-year-old female
      patient with atelosteogenesis type III after 3 years of follow-up.
    explanation: A long-term survivor required multiyear orthopedic follow-up and management.
pathophysiology:
- name: Monoallelic FLNB gain-of-function cytoskeletal disorder
  description: >
    FLNB-AO3 is caused by heterozygous gain-of-function FLNB variants. Filamin B
    cross-links actin, links membrane proteins to the cytoskeleton, and provides
    a scaffold for signaling and trafficking. AO1/AO3 variants cluster in the
    CH2 actin-binding domain and in repeats 14-15, but the precise protein
    interactions or novel interactions responsible for AO3 are not resolved;
    the entry therefore does not assign one variant-universal biochemical
    effect.
  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 establishes the monoallelic gain-of-function classification for FLNB-AO3.
  - reference: PMID:14991055
    reference_title: "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The filamins are cytoplasmic proteins that regulate the structure and
      activity of the cytoskeleton by cross-linking actin into three-dimensional
      networks, linking the cell membrane to the cytoskeleton and serving as
      scaffolds on which intracellular signaling and protein trafficking
      pathways are organized (reviewed in refs. 1,2).
    explanation: >-
      The causal gene's established protein functions supply the cytoskeletal context without specifying an AO3-only downstream interaction.
  - 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 AO1/AO3 patient series identifies two recurrent FLNB variant clusters.
  downstream:
  - target: Abnormal joint formation, vertebral development, and endochondral ossification
    description: >
      Human developmental-expression and disease-association data connect FLNB
      to growth-plate, joint, vertebral, and ossification phenotypes, but do not
      resolve the complete molecular-to-tissue chain for AO3.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:14991055
      reference_title: "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found that filamin B is expressed in human growth plate chondrocytes
      explanation: Developmental expression supports the proposed tissue bridge, while the intermediate causal steps remain unresolved.
- name: Abnormal joint formation, vertebral development, and endochondral ossification
  description: >
    Filamin B has a developmental role in joint formation, vertebral
    segmentation, and endochondral ossification. In AO3, disruption of these
    processes provides a bounded tissue-level explanation for congenital joint
    dislocations, severe limb and long-bone abnormalities, and vertebral
    dysplasia. Clinical occurrence supports endpoint placement but generally
    does not prove directness of individual edges.
  cell_types:
  - preferred_term: Growth plate chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: Embryonic skeletal joint development
    term:
      id: GO:0072498
      label: embryonic skeletal joint development
    modifier: ABNORMAL
  - preferred_term: Cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:14991055
    reference_title: "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicate an unexpected role in vertebral segmentation, joint
      formation and endochondral ossification for this ubiquitously expressed
      cytoskeletal protein.
    explanation: The discovery series directly identifies the relevant developmental processes.
  - 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 AO1/AO3 series links FLNB variants to the principal skeletal-development endpoints, although later reports establish that AO3 is not uniformly lethal.
  downstream:
  - target: Thoracic and laryngotracheal insufficiency
    description: >
      Abnormal skeletal and cartilage development can involve the thorax and
      laryngotracheal structures, but the precise tissue bridge is not defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The infant experienced recurrent apnea and persistent severe
        tracheomalacia, which necessitated tracheostomy at 5 months of age.
      explanation: A clinical case supports respiratory involvement, not the direct molecular-to-airway route.
  - target: Disproportionate Short-Limb Short Stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:2368807
      reference_title: "Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We present 5 cases of a short-limb dwarfism syndrome whose manifestations
        overlap those of atelosteogenesis and oto-palato-digital syndrome Type
        II.
      explanation: The founding series supports the endpoint; developmental intermediates are modeled rather than directly tested.
  - target: Rhizomelia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: There was rhizomelic shortness of the limbs and a club-foot.
      explanation: Clinical occurrence supports endpoint placement; the intervening developmental chain is inferred.
  - target: Large Joint Dislocations
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301736
      reference_title: FLNB-Related Disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism;
        dislocated hips, knees, and elbows; and clubfeet.
      explanation: GeneReviews supports the endpoint, while the edge's developmental intermediates remain modeled.
  - target: Talipes Equinovarus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301736
      reference_title: FLNB-Related Disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism;
        dislocated hips, knees, and elbows; and clubfeet.
      explanation: GeneReviews supports the endpoint, while the edge's developmental intermediates remain modeled.
  - target: Aplasia/Hypoplasia of the Humerus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Radiological examination demonstrated striking hypoplasia of the humerus
        with proximal rounding and distal tapering giving a 'drumstick'
        appearance, 'S'-shape configuration of the cervical spine, scoliosis and
        coronal cleft in the thoracolumbar vertebral bodies.
      explanation: The radiograph supports the endpoint, while causal directness is not tested.
  - target: Coronal Cleft Vertebrae
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Radiological examination demonstrated striking hypoplasia of the humerus
        with proximal rounding and distal tapering giving a 'drumstick'
        appearance, 'S'-shape configuration of the cervical spine, scoliosis and
        coronal cleft in the thoracolumbar vertebral bodies.
      explanation: The radiograph supports the endpoint, while causal directness is not tested.
  - target: Scoliosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Radiological examination demonstrated striking hypoplasia of the humerus
        with proximal rounding and distal tapering giving a 'drumstick'
        appearance, 'S'-shape configuration of the cervical spine, scoliosis and
        coronal cleft in the thoracolumbar vertebral bodies.
      explanation: The radiograph supports the endpoint, while causal directness is not tested.
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient had multiple craniofacial abnormalities at birth, including
        ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft
        palate.
      explanation: Clinical occurrence supports the endpoint; the intervening craniofacial mechanism is unknown.
  - target: Depressed Nasal Bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient had multiple craniofacial abnormalities at birth, including
        ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft
        palate.
      explanation: Clinical occurrence supports the endpoint; the intervening craniofacial mechanism is unknown.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient had multiple craniofacial abnormalities at birth, including
        ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft
        palate.
      explanation: Clinical occurrence supports the endpoint; the intervening craniofacial mechanism is unknown.
  - target: Cleft Palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The patient had multiple craniofacial abnormalities at birth, including
        ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft
        palate.
      explanation: Clinical occurrence supports the endpoint; the intervening craniofacial mechanism is unknown.
  - target: Broad Thumb
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The infant had short broad thumbs in the hands similar to those observed
        in the feet.
      explanation: Clinical occurrence supports the endpoint; the precise developmental intermediates are unknown.
- name: Thoracic and laryngotracheal insufficiency
  description: >
    AO3 can combine thoracic hypoplasia with laryngotracheomalacia and other
    respiratory insufficiency. The relative contribution of thoracic restriction,
    airway instability, and pulmonary factors varies among individuals and is
    not quantified by the sparse case literature.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Trachea development
    term:
      id: GO:0060438
      label: trachea development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant experienced recurrent apnea and persistent severe
      tracheomalacia, which necessitated tracheostomy at 5 months of age.
    explanation: This case directly documents severe airway instability and respiratory events in AO3.
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: '"HPOId": "HP:0002093", "HPOTerm": "Respiratory insufficiency"'
    explanation: Current Orphadata independently records respiratory insufficiency in the AO3 phenotype set.
  downstream:
  - target: Laryngotracheomalacia
    causal_link_type: UNKNOWN
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"HPOId": "HP:0008755", "HPOTerm": "Laryngotracheomalacia"'
      explanation: Structured data support the endpoint, while this modeled edge is close to a part-whole relation rather than a proven directional mechanism.
  - target: Respiratory Insufficiency
    causal_link_type: UNKNOWN
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"HPOId": "HP:0002093", "HPOTerm": "Respiratory insufficiency"'
      explanation: Structured data support the endpoint, not the relative contribution of airway and thoracic mechanisms.
  - target: Apnea
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:1442028
      reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The infant experienced recurrent apnea and persistent severe
        tracheomalacia, which necessitated tracheostomy at 5 months of age.
      explanation: The case supports co-occurring apnea and tracheomalacia, but not a universal causal direction.
  - target: Thoracic Hypoplasia
    causal_link_type: UNKNOWN
    evidence:
    - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
      reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: '"HPOId": "HP:0005257", "HPOTerm": "Thoracic hypoplasia"'
      explanation: Structured data support thoracic hypoplasia as part of AO3, while edge direction is not established.
genetic:
- name: Heterozygous gain-of-function FLNB pathogenic variants
  association: CAUSATIVE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: FLNB
    term:
      id: hgnc:3755
      label: FLNB
  notes: >
    Heterozygous gain-of-function FLNB variants cause AO3. The same recurrent
    variant can span AO1/AO3 or broader FLNB phenotypes, so variant identity
    alone does not fully predict clinical severity.
  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 the causative allele class for FLNB-AO3.
  - reference: PMID:14991055
    reference_title: "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified mutations in the gene encoding filamin B in four human skeletal disorders.
    explanation: >-
      This provides direct genetic evidence linking FLNB mutations to severe human skeletal disorders including AOIII.
  - reference: PMID:14991055
    reference_title: "Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721).
    explanation: >-
      This explicitly names missense FLNB mutations in AOIII.
phenotypes:
- name: Disproportionate Short-Limb Short Stature
  description: >
    AOIII is a severe short-limbed skeletal dysplasia with disproportionate limb
    shortening.
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
  evidence:
  - reference: PMID:2368807
    reference_title: "Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present 5 cases of a short-limb dwarfism syndrome whose manifestations overlap those of atelosteogenesis and oto-palato-digital syndrome Type II.
    explanation: >-
      The original AOIII case series directly identifies the condition as a short-limb dwarfism syndrome.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet.
    explanation: >-
      GeneReviews summarizes AOIII within the FLNB spectrum as severe short-limbed dwarfism.
- name: Rhizomelia
  description: >
    Rhizomelic shortening of the limbs is a key skeletal feature.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was rhizomelic shortness of the limbs and a club-foot.
    explanation: >-
      This directly supports rhizomelic limb shortening.
- name: Large Joint Dislocations
  description: >
    Congenital dislocations involving the hips, knees, and elbows are part of
    the core appendicular phenotype.
  phenotype_term:
    preferred_term: Large joint dislocations
    term:
      id: HP:0005008
      label: Large joint dislocations
  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 primary AOI/AOIII mutation series directly identifies joint dislocations as part of the shared phenotype.
  - reference: PMID:20301736
    reference_title: "FLNB-Related Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet.
    explanation: >-
      GeneReviews localizes the dislocations to the large joints most often emphasized in AOIII.
- name: Talipes Equinovarus
  description: >
    Club-foot deformity is present at birth.
  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/56305
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
    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 AO3.
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was rhizomelic shortness of the limbs and a club-foot.
    explanation: >-
      This directly supports talipes equinovarus (club-foot).
- name: Aplasia/Hypoplasia of the Humerus
  description: >
    Severe humeral underdevelopment is a striking radiographic feature.
  phenotype_term:
    preferred_term: Aplasia/hypoplasia of the humerus
    term:
      id: HP:0006507
      label: Aplasia/hypoplasia of the humerus
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies.
    explanation: >-
      This directly supports humeral hypoplasia.
- name: Coronal Cleft Vertebrae
  description: >
    Coronal clefting of thoracolumbar vertebrae indicates severe vertebral dysplasia.
  phenotype_term:
    preferred_term: Coronal cleft vertebrae
    term:
      id: HP:0003417
      label: Coronal cleft vertebrae
  frequency: FREQUENT
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0003417", "HPOTerm": "Coronal cleft vertebrae" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Current Orphadata classifies coronal cleft vertebrae as frequent (79-30%) in AO3.
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies.
    explanation: >-
      This directly supports coronal cleft vertebral abnormalities.
- name: Scoliosis
  description: >
    Spinal curvature abnormality is part of the AOIII axial skeletal phenotype.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies.
    explanation: >-
      This directly supports scoliosis.
- name: Hypertelorism
  description: >
    Ocular hypertelorism contributes to the characteristic craniofacial pattern.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate.
    explanation: >-
      This directly supports hypertelorism.
- name: Depressed Nasal Bridge
  description: >
    Nasal bridge depression is part of AOIII facial dysmorphism.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate.
    explanation: >-
      This supports a depressed/flat nasal bridge phenotype.
- name: Micrognathia
  description: >
    Mandibular hypoplasia is a recurrent craniofacial abnormality.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
    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 AO3.
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate.
    explanation: >-
      This directly supports micrognathia.
- name: Cleft Palate
  description: >
    Cleft palate is part of the craniofacial spectrum in AOIII.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate.
    explanation: >-
      This directly supports cleft palate.
- name: Broad Thumb
  description: >
    Broad thumbs are part of the distal limb malformation pattern.
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant had short broad thumbs in the hands similar to those observed in the feet.
    explanation: >-
      This directly supports broad thumbs.
- name: Laryngotracheomalacia
  description: >
    Laryngeal and/or tracheal airway malacia can contribute to severe respiratory
    compromise and the need for invasive airway support.
  phenotype_term:
    preferred_term: Laryngotracheomalacia
    term:
      id: HP:0008755
      label: Laryngotracheomalacia
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0008755", "HPOTerm": "Laryngotracheomalacia" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies laryngotracheomalacia as occasional (29-5%) in AO3.
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age.
    explanation: >-
      This directly supports the tracheal component of laryngotracheomalacia as a major AO3 complication.
- name: Apnea
  description: >
    Recurrent apnea has been documented in surviving infants with severe airway
    involvement.
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age.
    explanation: >-
      This directly supports recurrent apnea as part of the respiratory phenotype.
- name: Respiratory Insufficiency
  description: >
    Respiratory insufficiency is a frequent component of AO3 and may reflect
    varying contributions from thoracic restriction and airway malacia.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  frequency: FREQUENT
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0002093", "HPOTerm": "Respiratory insufficiency" },
      "HPOFrequency": "Frequent (79-30%)"
    explanation: Current Orphadata classifies respiratory insufficiency as frequent (79-30%) in AO3.
  - 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: The need for intensive respiratory support in some survivors supports clinically important respiratory insufficiency.
- name: Thoracic Hypoplasia
  description: >
    A hypoplastic thorax can add a restrictive component to respiratory burden
    in a subset of individuals.
  phenotype_term:
    preferred_term: Thoracic hypoplasia
    term:
      id: HP:0005257
      label: Thoracic hypoplasia
  frequency: OCCASIONAL
  evidence:
  - reference: url:https://api.orphadata.com/rd-phenotypes/orphacodes/56305
    reference_title: "https://api.orphadata.com/rd-phenotypes/orphacodes/56305"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "HPOId": "HP:0005257", "HPOTerm": "Thoracic hypoplasia" },
      "HPOFrequency": "Occasional (29-5%)"
    explanation: Current Orphadata classifies thoracic hypoplasia as occasional (29-5%) in AO3.
diagnosis:
- name: Clinical and Skeletal Radiographic Evaluation
  description: >
    Prenatal or postnatal imaging can identify the AO3 pattern of severe
    short-limb dysplasia, congenital dislocations, humeral and other long-bone
    abnormalities, and vertebral clefting or curvature. Because AO3 overlaps
    AO1, Larsen syndrome, atelosteogenesis type II, and otopalatodigital type II,
    radiography establishes a pattern and differential rather than a gene-level
    diagnosis.
  diagnosis_term:
    preferred_term: radiograph imaging procedure
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies.
    explanation: >-
      This supports the diagnostic importance of distinctive radiographic skeletal abnormalities.
- name: Molecular FLNB Confirmation and Spectrum Assignment
  description: >
    Molecular diagnosis requires identification of a heterozygous
    gain-of-function pathogenic FLNB variant. The variant must be interpreted
    together with the clinical-radiographic phenotype because FLNB-AO3 overlaps
    a broader allelic spectrum and individual variants do not always predict a
    single severity category.
  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 molecular confirmation for AO3 and the overlapping dominant FLNB spectrum.
treatments:
- name: Individualized Respiratory and Airway Support
  description: >
    Respiratory assessment should distinguish thoracic restriction from upper-
    and central-airway instability. Support is individualized; some infants may
    require prolonged ventilation, tracheostomy, or other invasive airway care,
    while published survival and severity vary. A single case requiring
    tracheostomy demonstrates possibility, not a universal treatment rule.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:1442028
    reference_title: "Atelosteogenesis type 3: the first patient in Japan and a survivor for more than 1 year."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age.
    explanation: >-
      The case demonstrates that severe AO3 airway disease can require tracheostomy.
  - 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 supports planning for intensive respiratory support in selected individuals while acknowledging survival variability.
- name: Individualized Orthopedic Follow-up in Survivors
  description: >
    Long-term survivors require individualized orthopedic assessment of joint
    dislocations, spinal curvature, limb deformity, mobility, and function. The
    published AO3 management literature is case-based, so no single operation or
    schedule is generalized to all affected individuals.
  treatment_term:
    preferred_term: orthopedic procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:27258362
    reference_title: "Atelosteogenesis type III: orthopedic management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the literature, an orthopedic management for this disorder has not
      been well described. We report the case and orthopedic management of a
      6-year-old female patient with atelosteogenesis type III after 3 years of
      follow-up.
    explanation: The report demonstrates multiyear orthopedic management but also shows that the evidence base is limited to case experience.
- name: Genetic Counseling and Parental Evaluation
  description: >
    Counseling should explain autosomal dominant inheritance, the possibility of
    de novo or inherited disease, parental somatic or gonadal mosaicism, marked
    phenotypic variability, and a 50% transmission risk from a constitutional
    heterozygous individual. Evaluation of parents for the familial variant and
    subtle FLNB-spectrum findings refines recurrence counseling.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNB-LS, FLNB-AO1, FLNB-AO3, and FLNB-related apparently isolated clubfoot
      are inherited in an autosomal dominant manner.
    explanation: GeneReviews establishes the inheritance model underlying counseling.
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of a proband who is heterozygous for an FLNB pathogenic variant
      has a 50% chance of inheriting the pathogenic variant.
    explanation: GeneReviews provides the transmission risk for a constitutional heterozygous parent.
differential_diagnoses:
- name: Atelosteogenesis type I
  description: >
    The perinatal-lethal FLNB-AO1 end of the same gain-of-function spectrum can
    overlap AO3 in skeletal and joint findings. Persistent postneonatal or adult
    survival supports AO3, whereas AO1 is defined as perinatal lethal in current
    GeneReviews scope; molecular results still require phenotype-level spectrum
    interpretation.
  disease_term:
    preferred_term: atelosteogenesis type I
    term:
      id: MONDO:0007167
      label: atelosteogenesis type I
  distinguishing_features:
  - FLNB-AO1 is defined as perinatal lethal in the current spectrum
  - Survival beyond the neonatal period is possible in FLNB-AO3
  evidence:
  - reference: PMID:20301736
    reference_title: FLNB-Related Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FLNB-AO1 is lethal in the perinatal period. 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 supplies the perinatal-lethal AO1 boundary used to distinguish it from survivable AO3.
- name: Atelosteogenesis type II
  description: >
    A clinically and radiographically overlapping perinatal-lethal dysplasia in
    the autosomal recessive SLC26A2 sulfate-transporter spectrum, with a
    cartilage-matrix sulfation disorder 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 cartilage-matrix histopathology and sulfation pathogenesis
  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 distinction between AO2 and FLNB-related AO3.
- name: Larsen syndrome
  description: >
    A generally milder monoallelic FLNB gain-of-function disorder with
    congenital large-joint dislocations, clubfeet, craniofacial findings, and
    vertebral abnormalities. Larsen syndrome and AO3 are allelic and can overlap
    within families, so severity and full radiographic pattern guide assignment.
  disease_term:
    preferred_term: Larsen syndrome
    term:
      id: MONDO:0007875
      label: Larsen syndrome
  distinguishing_features:
  - Generally milder skeletal severity than AO3
  - Allelic FLNB overlap and within-family variability limit rigid variant-only classification
  evidence:
  - reference: PMID:10076882
    reference_title: "Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical and radiologic phenotype of atelosteogenesis, type III
      overlaps with that of another skeletal dysplasia, autosomal dominant
      Larsen syndrome; these most likely represent allelic conditions.
    explanation: The familial AO3 report explicitly identifies Larsen syndrome as an overlapping allelic differential.
- name: Otopalatodigital syndrome type II
  description: >
    A severe X-linked FLNA-related skeletal dysplasia with craniofacial, digital,
    long-bone, and thoracic abnormalities that can resemble AO3. Sex-linked
    inheritance, FLNA molecular findings, and the full radiographic pattern
    distinguish it from autosomal dominant FLNB-AO3.
  distinguishing_features:
  - FLNA-related X-linked disorder rather than a heterozygous FLNB disorder
  - The founding AO3 series found a distinct clinical, radiographic, genetic, and histologic pattern despite overlap
  evidence:
  - reference: PMID:2368807
    reference_title: "Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, radiographic, genetic, and histologic data are presented which
      demonstrate differences between our patients and previously reported
      cases of these other conditions.
    explanation: The founding series explicitly separates AO3 from phenotypically overlapping OPD2.
notes: >-
  AO3 is a severe but variably survivable member of the monoallelic FLNB
  gain-of-function spectrum. Historical publications sometimes called AO1 and
  AO3 lethal together, but documented childhood and adult survivors make a
  uniformly lethal AO3 model inaccurate. The proximal mechanism remains bounded:
  FLNB gain of function, variant clustering, and roles in actin scaffolding,
  joint formation, vertebral development, and endochondral ossification are
  established, whereas the precise altered protein interactions and complete
  variant-to-tissue chain are unresolved. A ClinicalTrials.gov search on
  2026-07-21 identified no AO3-specific interventional studies, and no
  disease-modifying treatment is established.

📚

References & Deep Research

References

1

PMID:20301736

FLNB-Related Disorders.

No top-level findings curated for this source.

Deep Research

2

Manual Pubmed Review ▸

Atelosteogenesis Type III phenotype curation note

n/a 6 citations 2026-04-19T02:15:00Z

Atelosteogenesis Type III phenotype curation note

Core phenotype additions supported

Disproportionate short-limb short stature is directly supportable from the original AOIII delineation as a "short-limb dwarfism syndrome" (PMID:2368807) and from the updated FLNB GeneReviews summary describing FLNB-AO3 as "severe short-limbed dwarfism" (PMID:20301736).
Large joint dislocations were missing from the file despite being a hallmark of the FLNB-AO3 phenotype. Primary mutation-series evidence supports joint dislocations in AOI/AOIII (PMID:16752402), and GeneReviews localizes these to the hips, knees, and elbows in AO3 (PMID:20301736).
Apnea is directly documented in the 1992 long-term survivor report together with severe tracheomalacia and tracheostomy requirement (PMID:1442028).
Motor delay is supportable only in a qualified way from the same survivor report, which states the infant survived more than one year "with motoneuronal developmental delay" (PMID:1442028). Because this may reflect secondary morbidity rather than a primary neurodevelopmental effect, the YAML description should stay cautious.

Existing phenotype claims retained

Rhizomelia, clubfoot, humeral hypoplasia, coronal cleft vertebrae, scoliosis, hypertelorism, flat/depressed nasal bridge, micrognathia, cleft palate, broad thumbs, and tracheomalacia are all directly supportable from the abstract of the Japanese survivor report (PMID:1442028).

Candidate claims not added or intentionally softened

Pelvic hypoplasia, rib hypoplasia, and generalized vertebral hypoplasia are mentioned in broader AOIII summaries (for example PMID:27258362), but the abstract language is too introductory and nonspecific to map confidently to narrower HPO terms without overclaiming.
Specific toe phenotypes were not added. PMID:1442028 notes that the feet had abnormalities similar to the short broad thumbs, but the abstract does not localize the finding clearly enough to justify Broad hallux or another toe-specific HPO term.
Intellectual disability / global developmental delay were not added. PMID:8008496 mentions prognosis for physical and intellectual disability only at a high level, without a clean disease-level assertion or count.
Frequency and onset qualifiers were omitted because none of the usable AOIII phenotype abstracts directly quantify occurrence or provide a cohort-based onset statement for the added entries.

PubMed set reviewed

PMID:1442028
PMID:2368807
PMID:8008496
PMID:10076882
PMID:16752402
PMID:20301736

OpenAI ▸

Atelosteogenesis Type III: Mechanistic Pathophysiology and Clinical Overview

o3-deep-research-2025-06-26 76 citations 2026-03-04T00:02:45.445081

Atelosteogenesis Type III: Mechanistic Pathophysiology and Clinical Overview

Definition and Background

Atelosteogenesis Type III (AO3) is a rare and severe skeletal dysplasia characterized by profound abnormalities in bone development. Fewer than 25 cases have been reported worldwide (medlineplus.gov), reflecting an extremely low prevalence (on the order of <1 in 1,000,000 (www.orpha.net)). Clinically, AO3 falls on the severe end of the filamin B (FLNB)–related skeletal disorder spectrum, which also includes Larsen syndrome (milder) and Atelosteogenesis Type I (more severe, typically perinatal lethal) (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). Affected infants present with disproportionate short-limb dwarfism, multiple joint dislocations, and distinctive craniofacial anomalies (www.ncbi.nlm.nih.gov). Most cases are diagnosed at birth or prenatally by ultrasound due to the striking skeletal abnormalities, and neonatal mortality is high because of chest wall hypoplasia and airway malformations leading to respiratory failure (medlineplus.gov). Rarely, with intensive medical support, infants have survived beyond the newborn period (medlineplus.gov).

Genetic Cause and Inheritance

AO3 is caused by mutations in the FLNB gene, which encodes the cytoskeletal protein filamin B (medlineplus.gov). Filamin B is an actin-binding protein that organizes the intracellular cytoskeleton and links it to the cell membrane, serving as a scaffold for signaling pathways (pubmed.ncbi.nlm.nih.gov). It is highly expressed in developing cartilage (growth plate chondrocytes) and bone structures during embryogenesis (pubmed.ncbi.nlm.nih.gov). Heterozygous missense mutations or small in-frame deletions in FLNB underlie AO3 (www.ncbi.nlm.nih.gov). These mutations produce an abnormal full-length filamin B protein that has a gain-of-function (neomorphic) effect, rather than a simple loss of function (www.ncbi.nlm.nih.gov) (medlineplus.gov). Mechanistically, the mutant filamin B interferes with normal chondrocyte proliferation and differentiation, disrupting endochondral ossification (the process by which cartilage is replaced by bone) (medlineplus.gov). This dominant-negative effect on cartilage development leads to impaired skeletal segmentation, joint formation, and bone mineralization (pubmed.ncbi.nlm.nih.gov). In a landmark 2004 study, researchers identified FLNB mutations in AO3 and related disorders, establishing that filamin B is crucial for vertebral segmentation and limb skeletogenesis (pubmed.ncbi.nlm.nih.gov). Recent experimental research (2024) in a mouse model further showed that an FLNB mutation can alter the number of ossification centers, implicating disrupted embryonic patterning (e.g. HOX gene–regulated segmentation) in AO3 pathogenesis (pmc.ncbi.nlm.nih.gov).

Inheritance Pattern: Atelosteogenesis III is inherited in an autosomal dominant manner (medlineplus.gov). In virtually all reported cases, the pathogenic FLNB variant arose de novo (a new mutation in the affected child), since individuals with AO3 rarely survive to reproduce (medlineplus.gov). Parents of affected infants typically have no family history of the disorder. However, there are rare instances of germline mosaicism – a mildly affected parent (often with a phenotype resembling a milder FLNB-related condition like Larsen syndrome) can carry the mutation in some cells and transmit a fully penetrant mutation to their child (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). Such cases demonstrate the variable expressivity of FLNB mutations within families. Genetic testing confirms FLNB mutations in AO3 patients, which is important for definitive diagnosis and prenatal counseling (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov).

Pathophysiology and Mechanistic Insights

At the cellular level, mutant filamin B disrupts the architecture and signaling of chondrocytes (cartilage cells). Normally, filamin B cross-links actin filaments into networks and connects them to membrane proteins, helping chondrocytes maintain shape and respond to mechanical signals (pubmed.ncbi.nlm.nih.gov). It also acts as a scaffold for proteins that regulate chondrocyte maturation and division (pubmed.ncbi.nlm.nih.gov). In AO3, the gain-of-function FLNB mutation produces an aberrant filamin B protein that is still present (not truncated) but functionally misbehaves (medlineplus.gov). This abnormal protein can oligomerize and incorporate into the cytoskeleton, where it likely sequesters or mislocalizes binding partners, ultimately interfering with normal cartilage development (medlineplus.gov). Chondrocytes with mutant filamin B show reduced proliferation and abnormal differentiation, which means the growth plates cannot properly form bone tissue (medlineplus.gov). As a result, endochondral ossification is profoundly impaired – many skeletal elements remain partially cartilaginous or undersized in the fetus (www.ncbi.nlm.nih.gov). The developmental timing of ossification is also disrupted (“disharmonious skeletal maturation”), so some bones ossify late or irregularly (www.ncbi.nlm.nih.gov). Moreover, filamin B’s role in joint and spine development is deranged: the formation of normal joint capsules and segmented vertebrae requires filamin-mediated signaling, so mutations lead to joint malformations (e.g. failed separations, causing dislocations) and vertebral fusions (pubmed.ncbi.nlm.nih.gov). In summary, the FLNB mutation creates a dominant pathogenic protein that acts in a dominant-negative fashion within cartilage and bone cells, causing multi-system skeletal malformations characteristic of AO3 (pubmed.ncbi.nlm.nih.gov). No other major genes are known to cause AO3 — it is specifically a filamin B–related disorder, distinct from Atelosteogenesis type II (which is caused by a different gene and inherited recessively) (www.ncbi.nlm.nih.gov) . Ongoing research continues to probe how mutant filamin B perturbs developmental pathways; for instance, recent studies suggest it may affect genetic regulators of skeletal patterning (such as HOX genes), further explaining the abnormal skeletal segmentation observed in these patients (pmc.ncbi.nlm.nih.gov).

Hallmark Skeletal Phenotypes

AO3 has distinctive and severe skeletal abnormalities apparent at birth. Key hallmark phenotypes include:

Severely shortened limbs: Affected infants have micromelic dwarfism, with extremely short arms and legs. Many limb bones are underdeveloped or even absent in severe cases, resulting in shortened upper and lower extremities (medlineplus.gov). The long bones that are present often appear poorly modeled (dysplastic) on X-rays, with flared metaphyses and tapered, thin diaphyses (www.ncbi.nlm.nih.gov).
Joint dislocations: There are multiple congenital joint dislocations, notably of the large joints. The hips, knees, and elbows are frequently dislocated or subluxed at birth (medlineplus.gov). This reflects the abnormal joint formation due to the FLNB mutation disrupting normal connective tissue and joint capsule development (pubmed.ncbi.nlm.nih.gov). Recurrent or fixed dislocations are a defining clinical feature, often requiring orthopedic management if the child survives (www.ncbi.nlm.nih.gov).
Clubfeet (foot deformities): Virtually all reported cases have bilateral clubfoot, where the feet are fixed in an inward- and upward-turning position (talipes equinovarus or similar deformity) (medlineplus.gov). This foot malposition is a common finding in filamin B disorders and is present at birth as part of the AO3 phenotype (www.ncbi.nlm.nih.gov).
Hand and finger anomalies: The hands and feet are unusually broad with short, thick fingers and toes (medlineplus.gov). Often the digits exhibit permanent flexion contractures (camptodactyly), and some may be partially fused (syndactyly) (medlineplus.gov). In severe cases (overlapping with AOI), there can be polysyndactyly or “flipper-like” appendages where digits are completely fused, although AO3 typically has distinct but broad digits (medlineplus.gov) (www.ncbi.nlm.nih.gov). These digital anomalies further reflect aberrant ossification in the hands and feet.
Spine and chest deformities: AO3 involves significant axial skeletal malformations. Many patients have vertebral anomalies – the spine may show segmentation defects (fused vertebrae or hemivertebrae) and abnormal curvature (scoliosis or lordosis) (www.ncbi.nlm.nih.gov). The rib cage is hypoplastic (underdeveloped) and narrow (medlineplus.gov), due to shortened ribs and abnormal costal cartilage development. This small thoracic cage severely compromises lung development and expansion, leading to respiratory insufficiency at birth (medlineplus.gov). The pelvis is also undersized and malformed, and some pelvic bones can be incompletely ossified or fused (medlineplus.gov). These axial skeletal defects contribute to the lethal respiratory complications and limited mobility associated with AO3.
Craniofacial features: Although primarily a bone disorder, AO3 has recognizable facial dysmorphism related to the underlying skeletal maldevelopment. Infants have a prominent, broad forehead and widely spaced eyes (hypertelorism) (medlineplus.gov). The midface is flattened with a depressed nasal bridge and small nose, due to midfacial hypoplasia (medlineplus.gov). Approximately half of patients have a cleft palate (an opening in the roof of the mouth) (medlineplus.gov), indicating incomplete fusion of the palatal bones. These craniofacial findings, while not life-threatening, are often noted in conjunction with the skeletal abnormalities and can aid in diagnosis.

Radiographic hallmarks of AO3 correlate with these phenotypes. X-rays typically show “punctate” or delayed ossification in many bones, distally tapering humeri, and vertebral fusion or coronal clefting, alongside the limb shortening and flared metaphyses (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). The combination of rhizomelic limb shortening, joint dislocations, and a narrow thorax on prenatal ultrasound or postnatal radiographs is highly indicative of AO3 (www.ncbi.nlm.nih.gov) (medlineplus.gov). Genetic testing for FLNB mutations confirms the diagnosis and distinguishes AO3 from other skeletal dysplasias with overlapping features (such as Atelosteogenesis type II, which has a different genetic cause) (www.ncbi.nlm.nih.gov) .

Prognosis and Current Insights

Prognosis for AO3 is poor, given the critical respiratory issues from thoracic insufficiency. Most affected fetuses are either stillborn or die in the neonatal period due to respiratory failure despite intensive intervention (medlineplus.gov). Cervical spine instability (from vertebral anomalies) can further complicate early life and contribute to mortality (www.ncbi.nlm.nih.gov). A small number of patients have survived beyond infancy with tracheostomies, ventilatory support, and multiple orthopedic surgeries; in these cases, developmental milestones are often delayed, partly due to prolonged hospitalization and limited mobility (medlineplus.gov). Long-term survivors may show mild neurodevelopmental impairment, likely secondary to chronic hypoxia in infancy rather than a direct effect of the mutation (medlineplus.gov). There is no curative treatment for AO3 – management is supportive and symptomatic. Orthopedic interventions (casting or surgical correction of clubfoot, stabilization of dislocated joints, spinal decompression) have been reported on a case-by-case basis (www.ncbi.nlm.nih.gov), but the severity of the skeletal malformations limits the effectiveness of such measures.

On the research front, Atelosteogenesis III continues to provide insights into skeletal development. The discovery of FLNB as the causative gene (first reported in 2004 (pubmed.ncbi.nlm.nih.gov)) revealed an unexpected role for the cytoskeleton in bone formation and joint morphogenesis. Ongoing studies are using animal models and cellular assays to unravel how mutant filamin B perturbs signaling pathways in chondrocytes (pmc.ncbi.nlm.nih.gov). This not only deepens the understanding of AO3 pathophysiology but also sheds light on fundamental processes like vertebral segmentation and endochondral ossification that are relevant to many skeletal conditions. While AO3 itself is exceedingly rare, these mechanistic insights may inform future therapies for more common orthopedic disorders and improve genetic counseling for skeletal dysplasias. Continued documentation of AO3 cases in medical literature (with only a few dozen known, each case report is valuable) will further refine knowledge of its clinical spectrum and management outcomes (medlineplus.gov) (pubmed.ncbi.nlm.nih.gov). Experts emphasize the importance of early diagnosis – often via prenatal imaging and molecular testing – to guide perinatal care and family planning in this devastating but illuminating genetic bone disorder (www.ncbi.nlm.nih.gov) (medlineplus.gov).

References:

MedlinePlus Genetics. Atelosteogenesis Type 3. (Review updated: Oct 2020) (medlineplus.gov) (medlineplus.gov)
Krakow D. et al. “Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis.” Nat. Genet. 36, 405–410 (2004) (pubmed.ncbi.nlm.nih.gov). PMID: 14991055.
Farrington-Rock C. et al. “Mutations in two regions of FLNB result in atelosteogenesis I and III.” Hum. Mutat. 27(7):705-10 (2006) (medlineplus.gov). PMID: 16752402.
Orphanet. Atelosteogenesis type III. Orpha Code 56305 (2023) (www.orpha.net) (www.orpha.net).
GeneReviews (NIH/NCBI). FLNB-Related Disorders – Atelosteogenesis III (Updated Sept 2025) (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov).
Sarikaya IA et al. “Atelosteogenesis type III: orthopedic management.” J. Pediatr. Orthop. B 26(6):546-551 (2017). PMID: 27258362 .

Atelosteogenesis Type III

Ask OpenScientist

OpenScientist Report

Classifications

Mappings

Definitions

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Atelosteogenesis Type III phenotype curation note

Core phenotype additions supported

Existing phenotype claims retained

Candidate claims not added or intentionally softened

PubMed set reviewed

Atelosteogenesis Type III: Mechanistic Pathophysiology and Clinical Overview

Definition and Background

Genetic Cause and Inheritance

Pathophysiology and Mechanistic Insights

Hallmark Skeletal Phenotypes

Prognosis and Current Insights