Atelosteogenesis Type I

Mendelian MONDO:0007167 Pathograph 4 Skeletal Dysplasia Lethal Skeletal Dysplasia

Atelosteogenesis type I is a severe autosomal dominant FLNB-related skeletal dysplasia that is typically lethal in the perinatal period. It is characterized by marked skeletal maturation defects, hypoplastic long bones, vertebral abnormalities, joint dislocations, and frequent respiratory failure related to thoracic and pulmonary hypoplasia.

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1
Inheritance
3
Pathophys.
19
Phenotypes
4
Pathograph
1
Genes
2
Treatments
7
References
1
Deep Research
👪

Inheritance

1
Autosomal Dominant HP:0000006
Atelosteogenesis type I is inherited in an autosomal dominant pattern and is caused by heterozygous pathogenic FLNB variants.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:16752402 SUPPORT Human Clinical
"AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations."
This directly supports dominant inheritance and lethal disease severity in AOI.
⚙

Pathophysiology

3
FLNB Gain-of-Function Cytoskeletal Dysregulation
Dominant missense FLNB variants associated with AOI alter full-length filamin B, an actin-binding cytoskeletal scaffold in cartilage. The abnormal protein perturbs actin organization and cell signaling in skeletal lineage cells rather than causing simple FLNB haploinsufficiency.
Chondrocyte link
FLNB link
Actin filament organization link ⚠ ABNORMAL Cytoskeleton organization link ⚠ ABNORMAL PI3K-AKT signal transduction link ⚠ ABNORMAL TGF-beta receptor signaling link ⚠ ABNORMAL
actin filament binding link
Downstream
Disrupted Growth Plate Chondrocyte Maturation Cytoskeletal and signaling disruption in chondrocytes impairs cartilage maturation and endochondral ossification.
Show evidence (4 references)
PMID:16752402 SUPPORT Human Clinical
"The filamins are a family of cytoplasmic proteins that bind to and organize actin filaments, link membrane proteins to the cytoskeleton, and provide a scaffold for signaling molecules."
Establishes filamin B as an actin-cytoskeleton scaffold, the molecular context for dominant FLNB gain-of-function skeletal dysplasia.
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."
AOI/AOIII missense variants cluster in domains relevant to filamin B cytoskeletal function rather than representing loss-of-function alleles.
PMID:35832491 SUPPORT In Vitro
"And in vitro studies showed that both variants led to a lack of filopodia and accumulation of the mutants in the perinuclear region in HEK293 cells."
Functional studies of FLNB skeletal-dysplasia variants support disrupted cytoskeletal organization and mutant-protein localization as a mechanism.
+ 1 more reference
Disrupted Growth Plate Chondrocyte Maturation
AOI cartilage shows abnormal chondrocyte clustering, giant chondrocytes, and incomplete ossification of cartilage anlagen. This represents impaired growth-plate chondrocyte maturation and endochondral replacement of cartilage by mineralized bone.
Growth plate chondrocyte link
Cartilage development link ⚠ ABNORMAL Chondrocyte differentiation link ⚠ ABNORMAL Endochondral ossification link ↓ DECREASED Bone mineralization link ↓ DECREASED
Downstream
Thoracic Insufficiency and Upper Airway Failure Defective cartilage and ossification in the thorax and airway cartilage produce lethal respiratory compromise.
Show evidence (4 references)
PMID:16752402 SUPPORT Human Clinical
"Mutations in the gene encoding filamin B (FLNB) cause a spectrum of osteochondrodysplasias, including atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII)."
This supports FLNB as the causal molecular driver of AOI pathophysiology.
PMID:16752402 SUPPORT Human Clinical
"These results show that clustering of mutations in two regions of FLNB produce AOI/AOIII, and highlight the important role of this cytoskeletal protein in normal skeletogenesis."
This links FLNB mutation clustering to abnormal skeletal development.
PMID:9779808 SUPPORT Human Clinical
"Atelosteogenesis type 1 (AO1) is a rare lethal chondrodysplasia characterized by incomplete ossification of cartilage anlagen."
Directly supports incomplete endochondral ossification as a defining AOI pathophysiologic feature.
+ 1 more reference
Thoracic Insufficiency and Upper Airway Failure
Perinatal lethality reflects combined skeletal thoracic restriction, pulmonary hypoplasia, and primary upper-airway cartilage failure. In reported AOI neonates, severe subglottic hypoplasia and tracheomalacia allowed tracheal collapse and contributed to death independently of pulmonary hypoplasia.
Airway chondrocyte link Respiratory tract epithelial cell link
Trachea development link ⚠ ABNORMAL Lung development link ↓ DECREASED
Show evidence (3 references)
PMID:9779808 SUPPORT Human Clinical
"Although pulmonary hypoplasia was present, it was moderate and considered unlikely to be the sole cause of death."
Establishes that lethality is not explained by pulmonary hypoplasia alone.
PMID:9779808 SUPPORT Human Clinical
"The marked luminal narrowing, tracheomalacia, and temporal proximity of extubation to demise support tracheal collapse as a major contributor to the death in AO1."
Directly supports tracheomalacia and airway collapse as a primary lethal mechanism in AOI.
PMID:23401428 SUPPORT Human Clinical
"Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis, and pulmonary hypoplasia have all been described in patients with AO type I and we conclude that compromised pulmonary function is a major contributor to morbidity and mortality in this condition."
Confirms airway and pulmonary abnormalities as major contributors to AOI morbidity and mortality.
⬡

Pathograph

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

Phenotypes

19
Eye 2
Hypertelorism Hypertelorism (HP:0000316)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports hypertelorism as part of the AOI craniofacial phenotype.
Proptosis Proptosis (HP:0000520)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports proptosis as part of the AOI craniofacial phenotype.
Head and Neck 4
Prominent Forehead Prominent forehead (HP:0011220)
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK2534/ SUPPORT Human Clinical
"prominent forehead; hypertelorism; and proptosis."
GeneReviews includes prominent forehead in the perinatal-lethal FLNB-AOI craniofacial phenotype.
Downslanting Palpebral Fissures Downslanted palpebral fissures (HP:0000494)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports downslanting palpebral fissures as part of the AOI craniofacial phenotype.
Micrognathia Micrognathia (HP:0000347)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports retromicrognathia/micrognathia in AOI.
Cleft Palate Cleft palate (HP:0000175)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Facial features included proptosis, hypertelorism, downslanting palpebral fissures, cleft palate, and retromicrognathia."
This directly supports cleft palate in AOI.
Limbs 4
Fibular Aplasia Fibular aplasia (HP:0002990)
Show evidence (1 reference)
PMID:12454961 SUPPORT Human Clinical
"Fetal ultrasonography (US) revealed absent or deficient ossification of the posterior neural arches of the thoracic spine, humeri, radii, ulnae, fibulae, and short tubular bones other than the distal phalanges, in addition to extremely short, thick femora."
This prenatal AOI case directly documents absent/deficient fibular ossification.
Talipes Equinovarus Talipes equinovarus (HP:0001762)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports bilateral talipes equinovarus in AOI.
Brachydactyly Brachydactyly (HP:0001156)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports brachydactyly as part of the distal limb phenotype.
Broad Thumb Broad thumb (HP:0011304)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports broad thumbs in AOI.
Musculoskeletal 5
Joint Dislocation Joint dislocation (HP:0001373)
Show evidence (1 reference)
PMID:24624349 SUPPORT Human Clinical
"Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows."
This directly supports congenital large-joint dislocation in AOI.
Abnormality of the Vertebral Column Abnormality of the vertebral column (HP:0000925)
Show evidence (2 references)
PMID:16752402 SUPPORT Human Clinical
"AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations."
This multi-patient FLNB series supports vertebral abnormalities as a core AOI feature.
PMID:12454961 SUPPORT Human Clinical
"Fetal ultrasonography (US) revealed absent or deficient ossification of the posterior neural arches of the thoracic spine, humeri, radii, ulnae, fibulae, and short tubular bones other than the distal phalanges, in addition to extremely short, thick femora."
This directly documents deficient thoracic vertebral ossification in a prenatally diagnosed AOI fetus.
Platyspondyly Platyspondyly (HP:0000926)
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK2534/ SUPPORT Human Clinical
"Marked platyspondyly"
GeneReviews lists marked platyspondyly among the clinical and radiographic features that should raise suspicion for FLNB-related AOI.
Pectus Excavatum Pectus excavatum (HP:0000767)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports pectus excavatum in AOI.
Thoracic Hypoplasia Thoracic hypoplasia (HP:0005257)
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK2534/ SUPPORT Human Clinical
"On prenatal ultrasound examination, the findings of <i>FLNB</i>-AO1 consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements."
GeneReviews identifies thoracic hypoplasia as part of the prenatal AOI pattern.
Respiratory 2
Pulmonary Hypoplasia Pulmonary hypoplasia (HP:0002089)
Show evidence (2 references)
PMID:12454961 SUPPORT Human Clinical
"Fetal magnetic resonance imaging (MRI) using an ultrafast imaging sequence depicted dysmorphic features, pulmonary hypoplasia, and large cisterna magna."
This case provides direct evidence of pulmonary hypoplasia in AOI.
PMID:9779808 SUPPORT Human Clinical
"Pulmonary hypoplasia is a characteristic finding that has been presumed to be the cause of neonatal lethality."
This supports pulmonary hypoplasia as a characteristic and clinically important AOI complication.
Tracheomalacia Tracheomalacia (HP:0002779)
Show evidence (1 reference)
PMID:9779808 SUPPORT Human Clinical
"Detailed neonatal and postmortem examination showed severe subglottic hypoplasia and tracheomalacia."
This directly supports tracheomalacia as part of the lethal airway phenotype in AOI.
Growth 2
Disproportionate Short-Limb Short Stature Disproportionate short-limb short stature (HP:0008873)
Show evidence (1 reference)
PMID:24624349 SUPPORT Human Clinical
"Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows."
This directly supports severe disproportionate short-limb short stature in AOI.
Rhizomelia Rhizomelia (HP:0008905)
Show evidence (1 reference)
PMID:23401428 SUPPORT Human Clinical
"Both children had typical manifestations of AO type I, with severe rhizomelic shortening of the extremities, limited elbow and knee extension with mild webbing, pectus excavatum, broad thumbs with brachydactyly that was most marked for digits 3-5, dislocated hips and bilateral talipes equinovarus."
This directly supports proximal limb shortening as a characteristic AOI skeletal manifestation.
🧬

Genetic Associations

1
FLNB Pathogenic Variants (Causative)
Show evidence (1 reference)
PMID:16752402 SUPPORT Human Clinical
"In this study, 14 novel missense mutations in FLNB were found in 15 unrelated patients with AOI and AOIII."
This provides direct human genetic evidence for causative FLNB mutations in AOI-spectrum disease.
💊

Treatments

2
Perinatal Palliative and Respiratory Support Planning
Action: palliative care MAXO:0000021
There is no curative treatment for perinatal-lethal AOI. Management should focus on prenatal counseling, delivery planning, neonatal respiratory-support decisions, and comfort-centered care when airway and thoracic insufficiency make sustained ventilation non-beneficial.
Show evidence (2 references)
PMID:9779808 SUPPORT Human Clinical
"anticipation of the poor prognosis in AO1 is essential for appropriate genetic counseling of the parents and for determining postnatal treatment options."
Supports prenatal planning and postnatal treatment decisions around AOI's poor prognosis.
PMID:23401428 SUPPORT Human Clinical
"The clinical course of one child was influenced by airway instability and bronchopulmonary dysplasia that complicated intubation and prevented separation from ventilator support."
Demonstrates why neonatal respiratory support decisions in AOI require careful perinatal planning.
Genetic Counseling and Parental Mosaicism Assessment
Action: genetic counseling MAXO:0000079
Genetic counseling should explain dominant inheritance, the usual de novo origin of lethal AOI, and the residual recurrence risk from parental somatic or gonadal mosaicism. Parental FLNB testing is important when a parent has mild limb asymmetry or other subtle FLNB-spectrum findings.
Show evidence (2 references)
PMID:30231296 SUPPORT Human Clinical
"parents affected with a mild phenotype, probably with somatic mosaicism, can generate offspring with a much more severe phenotype of AOI."
Supports counseling families that a mildly affected mosaic parent can have a child with lethal AOI.
PMID:30231296 SUPPORT Human Clinical
"A missense mutation not previously described in the literature was detected in the FLNB gene, affecting ∼ 20% of the evaluated cells and, therefore, confirming the diagnosis of mosaic AOI in the father."
Directly supports parental molecular testing for suspected mosaicism.
{ }

Source YAML

click to show 
name: Atelosteogenesis Type I
creation_date: '2026-03-04T07:42:25Z'
updated_date: '2026-04-19T02:43:29Z'
category: Mendelian
description: >
  Atelosteogenesis type I is a severe autosomal dominant FLNB-related skeletal
  dysplasia that is typically lethal in the perinatal period. It is
  characterized by marked skeletal maturation defects, hypoplastic long bones,
  vertebral abnormalities, joint dislocations, and frequent respiratory failure
  related to thoracic and pulmonary hypoplasia.
disease_term:
  preferred_term: atelosteogenesis type I
  term:
    id: MONDO:0007167
    label: atelosteogenesis type I
parents:
- Skeletal Dysplasia
- Lethal Skeletal Dysplasia
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Atelosteogenesis type I is inherited in an autosomal dominant pattern and is
    caused by heterozygous pathogenic FLNB variants.
  evidence:
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AOI and AOIII are autosomal dominant lethal skeletal dysplasias
      characterized by overlapping clinical findings that include vertebral
      abnormalities, disharmonious skeletal maturation, hypoplastic long bones,
      and joint dislocations.
    explanation: >-
      This directly supports dominant inheritance and lethal disease severity in
      AOI.
prevalence:
- population: Global literature
  percentage: Unknown
  notes: >-
    No population-based prevalence estimate was identified for atelosteogenesis
    type I. Historical review literature summarized only 25 cases across
    atelosteogenesis and boomerang dysplasia, and AOI is consistently described
    as a rare lethal skeletal dysplasia.
  evidence:
  - reference: PMID:9133349
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical, radiographic, and morphological findings in 25 cases of atelosteogenesis and boomerang dysplasia have been reviewed."
    explanation: Historical review evidence shows that the entire atelosteogenesis/boomerang dysplasia literature consisted of only a small number of reported cases.
  - reference: PMID:24624349
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACKGROUND: Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows."
    explanation: A modern AOI report explicitly characterizes the disorder as rare and lethal, consistent with the absence of population-level prevalence estimates.
pathophysiology:
- name: FLNB Gain-of-Function Cytoskeletal Dysregulation
  description: >
    Dominant missense FLNB variants associated with AOI alter full-length
    filamin B, an actin-binding cytoskeletal scaffold in cartilage. The
    abnormal protein perturbs actin organization and cell signaling in skeletal
    lineage cells rather than causing simple FLNB haploinsufficiency.
  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
  - preferred_term: PI3K-AKT signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: ABNORMAL
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: ABNORMAL
  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: >-
      The filamins are a family of cytoplasmic proteins that bind to and organize
      actin filaments, link membrane proteins to the cytoskeleton, and provide a
      scaffold for signaling molecules.
    explanation: >-
      Establishes filamin B as an actin-cytoskeleton scaffold, the molecular
      context for dominant FLNB gain-of-function skeletal dysplasia.
  - 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.
    explanation: >-
      AOI/AOIII missense variants cluster in domains relevant to filamin B
      cytoskeletal function rather than representing loss-of-function alleles.
  - reference: PMID:35832491
    reference_title: "Cell-Dependent Pathogenic Roles of Filamin B in Different Skeletal Malformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      And in vitro studies showed that both variants led to a lack of filopodia
      and accumulation of the mutants in the perinuclear region in HEK293 cells.
    explanation: >-
      Functional studies of FLNB skeletal-dysplasia variants support disrupted
      cytoskeletal organization and mutant-protein localization as a mechanism.
  - reference: PMID:35832491
    reference_title: "Cell-Dependent Pathogenic Roles of Filamin B in Different Skeletal Malformations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      FLNB variants differentially affect skeletal development which contributes
      to clinical heterogeneity of FLNB-related disorders.
    explanation: >-
      Supports modeling AOI as part of a severity spectrum produced by
      variant-specific effects on skeletal development.
  downstream:
  - target: Disrupted Growth Plate Chondrocyte Maturation
    description: >
      Cytoskeletal and signaling disruption in chondrocytes impairs cartilage
      maturation and endochondral ossification.
    causal_link_type: DIRECT
- name: Disrupted Growth Plate Chondrocyte Maturation
  description: >
    AOI cartilage shows abnormal chondrocyte clustering, giant chondrocytes, and
    incomplete ossification of cartilage anlagen. This represents impaired
    growth-plate chondrocyte maturation and endochondral replacement of cartilage
    by mineralized bone.
  cell_types:
  - preferred_term: Growth plate chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: Cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  - preferred_term: Chondrocyte differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: ABNORMAL
  - preferred_term: Endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  - preferred_term: Bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  evidence:
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the gene encoding filamin B (FLNB) cause a spectrum of
      osteochondrodysplasias, including atelosteogenesis type I (AOI) and
      atelosteogenesis type III (AOIII).
    explanation: >-
      This supports FLNB as the causal molecular driver of AOI pathophysiology.
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results show that clustering of mutations in two regions of FLNB
      produce AOI/AOIII, and highlight the important role of this cytoskeletal
      protein in normal skeletogenesis.
    explanation: >-
      This links FLNB mutation clustering to abnormal skeletal development.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type 1 (AO1) is a rare lethal chondrodysplasia
      characterized by incomplete ossification of cartilage anlagen.
    explanation: >-
      Directly supports incomplete endochondral ossification as a defining AOI
      pathophysiologic feature.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologically, the cartilage contains irregular clusters that occasionally
      include giant chondrocytes.
    explanation: >-
      Postnatal pathology links AOI to abnormal chondrocyte organization and
      maturation.
  downstream:
  - target: Thoracic Insufficiency and Upper Airway Failure
    description: >
      Defective cartilage and ossification in the thorax and airway cartilage
      produce lethal respiratory compromise.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Thoracic Insufficiency and Upper Airway Failure
  description: >
    Perinatal lethality reflects combined skeletal thoracic restriction,
    pulmonary hypoplasia, and primary upper-airway cartilage failure. In
    reported AOI neonates, severe subglottic hypoplasia and tracheomalacia
    allowed tracheal collapse and contributed to death independently of
    pulmonary hypoplasia.
  cell_types:
  - preferred_term: Airway chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Respiratory tract epithelial cell
    term:
      id: CL:0002368
      label: respiratory tract epithelial cell
  biological_processes:
  - preferred_term: Trachea development
    term:
      id: GO:0060438
      label: trachea development
    modifier: ABNORMAL
  - preferred_term: Lung development
    term:
      id: GO:0030324
      label: lung development
    modifier: DECREASED
  evidence:
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although pulmonary hypoplasia was present, it was moderate and considered
      unlikely to be the sole cause of death.
    explanation: >-
      Establishes that lethality is not explained by pulmonary hypoplasia alone.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The marked luminal narrowing, tracheomalacia, and temporal proximity of
      extubation to demise support tracheal collapse as a major contributor to
      the death in AO1.
    explanation: >-
      Directly supports tracheomalacia and airway collapse as a primary lethal
      mechanism in AOI.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory insufficiency with tracheal hypoplasia, laryngeal stenosis,
      and pulmonary hypoplasia have all been described in patients with AO type
      I and we conclude that compromised pulmonary function is a major
      contributor to morbidity and mortality in this condition.
    explanation: >-
      Confirms airway and pulmonary abnormalities as major contributors to AOI
      morbidity and mortality.
genetic:
- name: FLNB Pathogenic Variants
  gene_term:
    preferred_term: FLNB
    term:
      id: hgnc:3755
      label: FLNB
  association: Causative
  notes: >
    Heterozygous pathogenic FLNB variants are causative for Atelosteogenesis
    Type I.
  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: >-
      In this study, 14 novel missense mutations in FLNB were found in 15
      unrelated patients with AOI and AOIII.
    explanation: >-
      This provides direct human genetic evidence for causative FLNB mutations in
      AOI-spectrum disease.
phenotypes:
- name: Disproportionate Short-Limb Short Stature
  description: >
    Affected neonates have severe short-limbed dwarfism.
  phenotype_term:
    preferred_term: Disproportionate short-limb short stature
    term:
      id: HP:0008873
      label: Disproportionate short-limb short stature
  evidence:
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic
      disorder characterized by severe short-limbed dwarfism and dislocated
      hips, knees, and elbows.
    explanation: >-
      This directly supports severe disproportionate short-limb short stature in
      AOI.
- name: Rhizomelia
  description: >
    Molecularly confirmed cases show marked shortening of the proximal limb
    segments.
  phenotype_term:
    preferred_term: Rhizomelic limb shortening
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports proximal limb shortening as a characteristic AOI
      skeletal manifestation.
- name: Joint Dislocation
  description: >
    Congenital large-joint dislocations prominently affect the hips, knees, and
    elbows.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic
      disorder characterized by severe short-limbed dwarfism and dislocated
      hips, knees, and elbows.
    explanation: >-
      This directly supports congenital large-joint dislocation in AOI.
- name: Abnormality of the Vertebral Column
  description: >
    Vertebral developmental and ossification defects are recurrent radiographic
    findings in AOI.
  phenotype_term:
    preferred_term: Abnormality of the vertebral column
    term:
      id: HP:0000925
      label: Abnormality of the vertebral column
  evidence:
  - reference: PMID:16752402
    reference_title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AOI and AOIII are autosomal dominant lethal skeletal dysplasias
      characterized by overlapping clinical findings that include vertebral
      abnormalities, disharmonious skeletal maturation, hypoplastic long bones,
      and joint dislocations.
    explanation: >-
      This multi-patient FLNB series supports vertebral abnormalities as a core
      AOI feature.
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal ultrasonography (US) revealed absent or deficient ossification of the
      posterior neural arches of the thoracic spine, humeri, radii, ulnae,
      fibulae, and short tubular bones other than the distal phalanges, in
      addition to extremely short, thick femora.
    explanation: >-
      This directly documents deficient thoracic vertebral ossification in a
      prenatally diagnosed AOI fetus.
- name: Platyspondyly
  description: >
    Marked flattening of vertebral bodies is a key radiographic feature
    supporting AOI within the FLNB-related lethal skeletal dysplasia spectrum.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
    reference_title: "FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked platyspondyly"
    explanation: >-
      GeneReviews lists marked platyspondyly among the clinical and radiographic
      features that should raise suspicion for FLNB-related AOI.
- name: Fibular Aplasia
  description: >
    Absent or severely deficient fibular ossification is a recurrent severe limb
    abnormality in AOI.
  phenotype_term:
    preferred_term: Fibular aplasia
    term:
      id: HP:0002990
      label: Fibular aplasia
  evidence:
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal ultrasonography (US) revealed absent or deficient ossification of the
      posterior neural arches of the thoracic spine, humeri, radii, ulnae,
      fibulae, and short tubular bones other than the distal phalanges, in
      addition to extremely short, thick femora.
    explanation: >-
      This prenatal AOI case directly documents absent/deficient fibular
      ossification.
- name: Talipes Equinovarus
  description: >
    Bilateral clubfoot is reported in molecularly confirmed AOI.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports bilateral talipes equinovarus in AOI.
- name: Brachydactyly
  description: >
    Distal digit shortening, especially involving digits 3-5, is reported in
    molecularly confirmed AOI.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports brachydactyly as part of the distal limb phenotype.
- name: Broad Thumb
  description: >
    Broad thumbs are part of the distal limb malformation pattern in some
    molecularly confirmed cases.
  phenotype_term:
    preferred_term: Broad thumb
    term:
      id: HP:0011304
      label: Broad thumb
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports broad thumbs in AOI.
- name: Pectus Excavatum
  description: >
    Pectus excavatum is reported in molecularly confirmed AOI.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both children had typical manifestations of AO type I, with severe
      rhizomelic shortening of the extremities, limited elbow and knee
      extension with mild webbing, pectus excavatum, broad thumbs with
      brachydactyly that was most marked for digits 3-5, dislocated hips and
      bilateral talipes equinovarus.
    explanation: >-
      This directly supports pectus excavatum in AOI.
- name: Thoracic Hypoplasia
  description: >
    Small, hypoplastic thorax contributes to the lethal respiratory phenotype
    and helps distinguish AOI from milder FLNB-related skeletal dysplasias.
  phenotype_term:
    preferred_term: Thoracic hypoplasia
    term:
      id: HP:0005257
      label: Thoracic hypoplasia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
    reference_title: "FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On prenatal ultrasound examination, the findings of <i>FLNB</i>-AO1
      consist of thoracic hypoplasia and limb shortening with delayed or absent
      ossification of vertebral and appendicular elements.
    explanation: >-
      GeneReviews identifies thoracic hypoplasia as part of the prenatal AOI
      pattern.
- name: Prominent Forehead
  description: >
    A prominent forehead is part of the craniofacial pattern in the severe
    FLNB-AOI spectrum.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
    reference_title: "FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent forehead; hypertelorism; and proptosis."
    explanation: >-
      GeneReviews includes prominent forehead in the perinatal-lethal FLNB-AOI
      craniofacial phenotype.
- name: Hypertelorism
  description: >
    Hypertelorism contributes to the recognizable craniofacial phenotype in some
    molecularly confirmed cases.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports hypertelorism as part of the AOI craniofacial
      phenotype.
- name: Proptosis
  description: >
    Proptosis is part of the craniofacial phenotype in some molecularly
    confirmed cases.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports proptosis as part of the AOI craniofacial
      phenotype.
- name: Downslanting Palpebral Fissures
  description: >
    Downslanting palpebral fissures are part of the craniofacial phenotype in
    some molecularly confirmed cases.
  phenotype_term:
    preferred_term: Downslanting palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports downslanting palpebral fissures as part of the AOI
      craniofacial phenotype.
- name: Micrognathia
  description: >
    Mandibular hypoplasia is part of the craniofacial phenotype in some
    molecularly confirmed cases.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports retromicrognathia/micrognathia in AOI.
- name: Cleft Palate
  description: >
    Cleft palate is reported in molecularly confirmed AOI and expands the
    craniofacial phenotype beyond limb and vertebral findings.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features included proptosis, hypertelorism, downslanting palpebral
      fissures, cleft palate, and retromicrognathia.
    explanation: >-
      This directly supports cleft palate in AOI.
- name: Pulmonary Hypoplasia
  description: >
    Pulmonary hypoplasia is a major contributor to severe perinatal respiratory
    compromise in AOI.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal magnetic resonance imaging (MRI) using an ultrafast imaging sequence
      depicted dysmorphic features, pulmonary hypoplasia, and large cisterna
      magna.
    explanation: >-
      This case provides direct evidence of pulmonary hypoplasia in AOI.
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary hypoplasia is a characteristic finding that has been presumed to
      be the cause of neonatal lethality.
    explanation: >-
      This supports pulmonary hypoplasia as a characteristic and clinically
      important AOI complication.
- name: Tracheomalacia
  description: >
    Severe airway malacia is a documented contributor to respiratory failure and
    death in AOI.
  phenotype_term:
    preferred_term: Tracheomalacia
    term:
      id: HP:0002779
      label: Tracheomalacia
  evidence:
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detailed neonatal and postmortem examination showed severe subglottic
      hypoplasia and tracheomalacia.
    explanation: >-
      This directly supports tracheomalacia as part of the lethal airway
      phenotype in AOI.
diagnosis:
- name: Prenatal Ultrasound and MRI
  description: >
    Prenatal diagnosis is supported by detailed fetal ultrasound and MRI findings
    of characteristic AOI ossification and limb abnormalities.
  evidence:
  - reference: PMID:12454961
    reference_title: "Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Meticulous evaluation using fetal US and MRI permits a definitive prenatal
      diagnosis of AO I to be made.
    explanation: >-
      This directly supports prenatal imaging-based diagnostic workflow for AOI.
- name: Molecular FLNB Testing and Spectrum Diagnosis
  description: >
    Molecular diagnosis uses a skeletal-dysplasia gene panel, exome sequencing,
    or genome sequencing to identify a heterozygous gain-of-function FLNB
    variant in a fetus or neonate with AOI-like findings. Molecular results are
    important for distinguishing FLNB-AOI from AO-like lethal dysplasias caused
    by other genes, including SLC26A2-related atelosteogenesis type II, and from
    recessive FLNB loss-of-function disorders such as spondylocarpotarsal
    synostosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In order to screen all possible genes associated with AO-like lethal
      skeletal dysplasias simultaneously, we performed whole-exome sequencing in
      a female newborn having clinical features of AO-I.
    explanation: >-
      Demonstrates exome sequencing as a diagnostic approach for AOI-like lethal
      skeletal dysplasia with differential genetic causes.
  - reference: PMID:24624349
    reference_title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified a novel missense variant (c.517G>A;
      p.Ala173Thr) in exon 2 of the FLNB gene in the patient.
    explanation: >-
      Supports molecular confirmation of AOI by identifying a heterozygous FLNB
      variant in a clinically affected newborn.
treatments:
- name: Perinatal Palliative and Respiratory Support Planning
  description: >
    There is no curative treatment for perinatal-lethal AOI. Management should
    focus on prenatal counseling, delivery planning, neonatal respiratory-support
    decisions, and comfort-centered care when airway and thoracic insufficiency
    make sustained ventilation non-beneficial.
  treatment_term:
    preferred_term: palliative care
    term:
      id: MAXO:0000021
      label: palliative care
  evidence:
  - reference: PMID:9779808
    reference_title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anticipation of the poor prognosis in AO1 is essential for appropriate
      genetic counseling of the parents and for determining postnatal treatment
      options.
    explanation: >-
      Supports prenatal planning and postnatal treatment decisions around AOI's
      poor prognosis.
  - reference: PMID:23401428
    reference_title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course of one child was influenced by airway instability and
      bronchopulmonary dysplasia that complicated intubation and prevented
      separation from ventilator support.
    explanation: >-
      Demonstrates why neonatal respiratory support decisions in AOI require
      careful perinatal planning.
- name: Genetic Counseling and Parental Mosaicism Assessment
  description: >
    Genetic counseling should explain dominant inheritance, the usual de novo
    origin of lethal AOI, and the residual recurrence risk from parental somatic
    or gonadal mosaicism. Parental FLNB testing is important when a parent has
    mild limb asymmetry or other subtle FLNB-spectrum findings.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:30231296
    reference_title: "Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      parents affected with a mild phenotype, probably with somatic mosaicism,
      can generate offspring with a much more severe phenotype of AOI.
    explanation: >-
      Supports counseling families that a mildly affected mosaic parent can have
      a child with lethal AOI.
  - reference: PMID:30231296
    reference_title: "Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A missense mutation not previously described in the literature was detected
      in the FLNB gene, affecting ∼ 20% of the evaluated cells and, therefore,
      confirming the diagnosis of mosaic AOI in the father.
    explanation: >-
      Directly supports parental molecular testing for suspected mosaicism.
notes: >
  Atelosteogenesis type I is usually fatal in the perinatal period and belongs
  to the severe end of the monoallelic FLNB gain-of-function spectrum, with
  boomerang and Piepkorn dysplasia now best treated as part of the FLNB-AOI
  spectrum, AOIII as an overlapping but sometimes survivable disorder, and
  Larsen syndrome as a milder dominant FLNB disorder. This mechanism is distinct
  from SLC26A2-related atelosteogenesis type II and from autosomal recessive
  FLNB loss-of-function spondylocarpotarsal synostosis. Most lethal AOI cases
  are de novo, but parental somatic mosaicism can produce a mild parental
  phenotype and a severely affected child.
datasets: []
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
  title: "FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf"
  tags:
  - GeneReviews
  findings: []
- reference: PMID:16752402
  title: "Mutations in two regions of FLNB result in atelosteogenesis I and III."
  findings: []
- reference: PMID:9779808
  title: "Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1."
  findings: []
- reference: PMID:23401428
  title: "Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue."
  findings: []
- reference: PMID:24624349
  title: "Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing."
  findings: []
- reference: PMID:35832491
  title: "Cell-Dependent Pathogenic Roles of Filamin B in Different Skeletal Malformations."
  findings: []
- reference: PMID:30231296
  title: "Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism."
  findings: []
📚

References & Deep Research

References

7
url:https://www.ncbi.nlm.nih.gov/books/NBK2534/
FLNB-Related Disorders - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:16752402
Mutations in two regions of FLNB result in atelosteogenesis I and III.
No top-level findings curated for this source.
PMID:9779808
Prenatal ultrasonographic description and postnatal pathological findings in atelosteogenesis type 1.
No top-level findings curated for this source.
PMID:23401428
Clinical report: Two patients with atelosteogenesis type I caused by missense mutations affecting the same FLNB residue.
No top-level findings curated for this source.
PMID:24624349
Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing.
No top-level findings curated for this source.
PMID:35832491
Cell-Dependent Pathogenic Roles of Filamin B in Different Skeletal Malformations.
No top-level findings curated for this source.
PMID:30231296
Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism.
No top-level findings curated for this source.

Deep Research

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

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

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

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

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

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

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

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

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

References:

  1. Robertson SP & Meira J. FLNB-Related Disorders. GeneReviews. Last updated Sep 11, 2025 (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov).
  2. Farrington-Rock C et al. “Mutations in two regions of FLNB result in atelosteogenesis I and III.” Hum Mutat. 2006 Jul;27(7):705-10 (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).
  3. MedlinePlus Genetics. Atelosteogenesis Type 1. Reviewed Oct 2015 (updated) (medlineplus.gov) (medlineplus.gov).
  4. Jeon GW et al. “Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis I by exome sequencing.” Ann Lab Med. 2014;34(2):134-138 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  5. Wu H et al. “Cell-dependent pathogenic roles of filamin B in different skeletal malformations.” Biomed Res Int. 2022;2022:8956636 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
  6. Meira JGC et al. “Diagnosis of Atelosteogenesis I suggested by fetal ultrasonography and mosaic paternal phenotype.” Clinics (São Paulo). 2023;78:e4605 (PMC10316906) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).