Atelosteogenesis Type II

Mendelian MONDO:0009727 Pathograph 2 Skeletal Dysplasia Lethal Skeletal Dysplasia

Atelosteogenesis Type II is a severe SLC26A2-related chondrodysplasia characterized by rhizomelic limb shortening, hitchhiker thumbs, and a narrow thorax, and is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia.

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1
Inheritance
2
Pathophys.
18
Phenotypes
2
Pathograph
1
Genes
1
Treatments
1
References
2
Deep Research
👪

Inheritance

1
Autosomal Recessive HP:0000007
Atelosteogenesis Type II is inherited in an autosomal recessive pattern with biallelic pathogenic variants in SLC26A2.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20301493 SUPPORT Human Clinical
"SLC26A2-related atelosteogenesis is inherited in an autosomal recessive manner."
This directly supports autosomal recessive inheritance for Atelosteogenesis Type II.
PMID:20301493 SUPPORT Human Clinical
"If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of a proband with SLC26A2-related atelosteogenesis has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
This supports the expected Mendelian recurrence risk for an autosomal recessive disorder.
⚙

Pathophysiology

2
Sulfate Transport Deficiency in Chondrocytes
SLC26A2/DTDST dysfunction impairs sulfate import into chondrocytes and causes insufficient sulfation of extracellular matrix macromolecules, a core biochemical defect in Atelosteogenesis Type II.
Chondrocyte link
SLC26A2 link
sulfate transmembrane transport link Extracellular Matrix Organization link
sulfate transmembrane transporter activity link
Show evidence (2 references)
PMID:11448940 SUPPORT In Vitro
"The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans."
This directly links DTDST/SLC26A2 function to sulfate transport and proteoglycan sulfation in chondrocytes.
PMID:8571951 SUPPORT In Vitro
"Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro."
This supports sulfate uptake failure and undersulfation as a disease mechanism in AOII.
Disrupted Endochondral Ossification
Defective cartilage matrix sulfation in AOII contributes to severe chondrodysplasia and disrupted endochondral ossification, driving profound skeletal malformation and perinatal lethality.
Chondrocyte link
Cartilage Development link Endochondral Ossification link
Show evidence (2 references)
PMID:8571951 SUPPORT Human Clinical
"Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD)."
This supports severe chondrodysplasia with pathological cartilage involvement in AOII.
PMID:8571951 SUPPORT Human Clinical
"The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein."
This supports a mechanism where reduced transporter activity drives severity of skeletal disease.
⬡

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 II 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

18
Head and Neck 5
Cleft Palate Cleft palate (HP:0000175)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This directly supports cleft palate as part of the AOII craniofacial phenotype.
Midface Retrusion Midface retrusion (HP:0011800)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This directly supports midface retrusion in AOII.
Depressed Nasal Bridge Depressed nasal bridge (HP:0005280)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This directly supports depressed nasal bridge.
Epicanthus Epicanthus (HP:0000286)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This directly supports epicanthus in AOII.
Micrognathia Micrognathia (HP:0000347)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This directly supports micrognathia in the AOII phenotype spectrum.
Limbs 6
Severe Micromelia Micromelia (HP:0002983)
⚠ ABNORMAL
Show evidence (1 reference)
PMID:1279661 SUPPORT Human Clinical
"Atelosteogenesis type II is a lethal chondrodysplasia characterized by severe micromelia, spinal abnormalities, talipes equinovarus, and abducted thumbs and toes."
This directly supports severe generalized limb shortening in AOII.
Hitchhiker Thumb Hitchhiker thumb (HP:0001234)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This directly reports hitchhiker thumbs in affected individuals.
Ulnar Deviation of Hands Ulnar deviation of the hand or of fingers of the hand (HP:0001193)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot."
This directly supports ulnar deviation of the hand/fingers in AOII.
Sandal Gap Sandal gap (HP:0001852)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot."
This directly supports a widened first interdigital space in AOII.
Talipes Equinovarus Talipes equinovarus (HP:0001762)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot."
This directly supports clubfoot (talipes equinovarus).
Bowed Long Bones Bowing of the long bones (HP:0006487)
Show evidence (1 reference)
PMID:3799721 SUPPORT Human Clinical
"Other long bones were short and bowed."
This directly supports bowing of the long bones in AOII.
Musculoskeletal 3
Narrow Chest Narrow chest (HP:0000774)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This supports a narrow/small thorax phenotype in AOII.
Coronal Cleft Vertebrae Coronal cleft vertebrae (HP:0003417)
Show evidence (1 reference)
PMID:1279661 SUPPORT Human Clinical
"The feasibility of diagnosing the following morphological features by prenatal ultrasonography is demonstrated: coronal clefts of the vertebral bodies, metaphyseal and epiphyseal abnormalities, spinal deviations such as cervical kyphosis and a horizontal sacrum, additional ossification centres..."
This directly supports coronal cleft vertebral abnormalities in AOII.
Cervical Kyphosis Cervical kyphosis (HP:0002947)
Show evidence (1 reference)
PMID:1279661 SUPPORT Human Clinical
"The feasibility of diagnosing the following morphological features by prenatal ultrasonography is demonstrated: coronal clefts of the vertebral bodies, metaphyseal and epiphyseal abnormalities, spinal deviations such as cervical kyphosis and a horizontal sacrum, additional ossification centres..."
This directly supports cervical kyphosis in AOII.
Respiratory 2
Pulmonary Hypoplasia Pulmonary hypoplasia (HP:0002089)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia."
This directly supports pulmonary hypoplasia as a critical AOII complication.
Tracheobronchomalacia Tracheobronchomalacia (HP:0002786)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia."
This directly supports tracheobronchomalacia in AOII.
Growth 1
Rhizomelia Rhizomelia (HP:0008905)
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia)."
This directly documents rhizomelic limb shortening.
Other 1
Laryngeal Stenosis Laryngeal stenosis (HP:0001602)
Show evidence (1 reference)
PMID:3799721 SUPPORT Human Clinical
"Neonatal death occurred in all cases and may be attributed to a consistent triad of respiratory tract malformations: laryngeal stenosis, tracheobronchomalacia, and pulmonary hypoplasia."
This directly supports laryngeal stenosis as a clinically important AOII airway manifestation.
🧬

Genetic Associations

1
SLC26A2 Pathogenic Variants (Causative)
Show evidence (2 references)
PMID:20301493 SUPPORT Human Clinical
"The diagnosis of SLC26A2-related atelosteogenesis is established in a proband with characteristic clinical, radiologic, and histopathologic features and biallelic pathogenic variants in SLC26A2 identified by molecular genetic testing."
This directly supports biallelic SLC26A2 variants as the molecular basis of disease.
PMID:8571951 SUPPORT In Vitro
"Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro."
This supports DTDST (SLC26A2) mutations as causative in AOII.
💊

Treatments

1
Supportive and Palliative Care
Action: supportive care MAXO:0000950
No disease-modifying therapy is established; care is individualized as supportive versus palliative according to respiratory status and overall prognosis.
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"There is no specific treatment currently available, and the aim of therapy (supportive versus palliative) will depend on clinical status and respiratory prognosis of the individual patient."
This supports supportive/palliative management as the current standard approach.
{ }

Source YAML

click to show 
name: Atelosteogenesis Type II
creation_date: '2026-03-04T07:56:34Z'
updated_date: '2026-04-19T02:18:29Z'
category: Mendelian
description: >
  Atelosteogenesis Type II is a severe SLC26A2-related chondrodysplasia characterized by
  rhizomelic limb shortening, hitchhiker thumbs, and a narrow thorax, and is usually
  lethal at birth or shortly thereafter due to pulmonary hypoplasia and
  tracheobronchomalacia.
disease_term:
  preferred_term: atelosteogenesis type II
  term:
    id: MONDO:0009727
    label: atelosteogenesis type II
parents:
- Skeletal Dysplasia
- Lethal Skeletal Dysplasia
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Atelosteogenesis Type II is inherited in an autosomal recessive pattern with
    biallelic pathogenic variants in SLC26A2.
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SLC26A2-related atelosteogenesis is inherited in an autosomal recessive manner.
    explanation: >-
      This directly supports autosomal recessive inheritance for Atelosteogenesis Type II.
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of a proband with SLC26A2-related atelosteogenesis has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: >-
      This supports the expected Mendelian recurrence risk for an autosomal recessive disorder.
prevalence:
- population: Global literature
  percentage: Unknown
  notes: >-
    No population-based prevalence estimate was identified for atelosteogenesis
    type II. Historical review literature summarized only 25 cases across
    atelosteogenesis and boomerang dysplasia, and published AOII literature
    remains dominated by isolated prenatal and perinatal case reports.
  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 indicates that reported atelosteogenesis-spectrum cases were very few, consistent with extreme rarity of AOII.
  - reference: PMID:1279661
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a case diagnosed at 21 weeks of gestation in which antenatal sonographic and post-mortem radiological findings were correlated."
    explanation: AOII publications are still typically isolated case reports, reinforcing that subtype-specific prevalence has not been quantified in population studies.
pathophysiology:
- name: Sulfate Transport Deficiency in Chondrocytes
  description: >
    SLC26A2/DTDST dysfunction impairs sulfate import into chondrocytes and causes
    insufficient sulfation of extracellular matrix macromolecules, a core biochemical
    defect in Atelosteogenesis Type II.
  genes:
  - preferred_term: SLC26A2
    term:
      id: hgnc:10994
      label: SLC26A2
  molecular_functions:
  - preferred_term: sulfate transmembrane transporter activity
    term:
      id: GO:0015116
      label: sulfate transmembrane transporter activity
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: sulfate transmembrane transport
    term:
      id: GO:1902358
      label: sulfate transmembrane transport
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:11448940
    reference_title: "Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans.
    explanation: >-
      This directly links DTDST/SLC26A2 function to sulfate transport and proteoglycan sulfation in chondrocytes.
  - reference: PMID:8571951
    reference_title: "Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro.
    explanation: >-
      This supports sulfate uptake failure and undersulfation as a disease mechanism in AOII.
- name: Disrupted Endochondral Ossification
  description: >
    Defective cartilage matrix sulfation in AOII contributes to severe chondrodysplasia
    and disrupted endochondral ossification, driving profound skeletal malformation and
    perinatal lethality.
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: Cartilage Development
    term:
      id: GO:0051216
      label: cartilage development
  - preferred_term: Endochondral Ossification
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:8571951
    reference_title: "Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD).
    explanation: >-
      This supports severe chondrodysplasia with pathological cartilage involvement in AOII.
  - reference: PMID:8571951
    reference_title: "Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein.
    explanation: >-
      This supports a mechanism where reduced transporter activity drives severity of skeletal disease.
genetic:
- name: SLC26A2 Pathogenic Variants
  association: Causative
  gene_term:
    preferred_term: SLC26A2
    term:
      id: hgnc:10994
      label: SLC26A2
  notes: >
    Biallelic SLC26A2 pathogenic variants are causative and place AOII on the SLC26A2
    chondrodysplasia severity spectrum.
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SLC26A2-related atelosteogenesis is established in a proband with characteristic clinical, radiologic, and histopathologic features and biallelic pathogenic variants in SLC26A2 identified by molecular genetic testing.
    explanation: >-
      This directly supports biallelic SLC26A2 variants as the molecular basis of disease.
  - reference: PMID:8571951
    reference_title: "Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro.
    explanation: >-
      This supports DTDST (SLC26A2) mutations as causative in AOII.
phenotypes:
- name: Rhizomelia
  description: >
    Rhizomelic shortening of the proximal limbs is a characteristic AOII skeletal phenotype.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This directly documents rhizomelic limb shortening.
- name: Severe Micromelia
  description: >
    Generalized marked limb shortening is part of the reported AOII skeletal phenotype.
  phenotype_term:
    preferred_term: Severe Micromelia
    term:
      id: HP:0002983
      label: Micromelia
    modifier: ABNORMAL
  evidence:
  - reference: PMID:1279661
    reference_title: "Atelosteogenesis type II: sonographic and radiological correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type II is a lethal chondrodysplasia characterized by severe micromelia, spinal abnormalities, talipes equinovarus, and abducted thumbs and toes.
    explanation: >-
      This directly supports severe generalized limb shortening in AOII.
- name: Hitchhiker Thumb
  description: >
    Medially deviated abducted thumbs are characteristic of AOII.
  phenotype_term:
    preferred_term: Hitchhiker thumb
    term:
      id: HP:0001234
      label: Hitchhiker thumb
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This directly reports hitchhiker thumbs in affected individuals.
- name: Ulnar Deviation of Hands
  description: >
    Ulnar deviation of the fingers is part of the characteristic hand phenotype.
  phenotype_term:
    preferred_term: Ulnar deviation of the hand
    term:
      id: HP:0001193
      label: Ulnar deviation of the hand or of fingers of the hand
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot.
    explanation: >-
      This directly supports ulnar deviation of the hand/fingers in AOII.
- name: Sandal Gap
  description: >
    A widened gap between the first and second toes is part of the typical pedal phenotype.
  phenotype_term:
    preferred_term: Sandal gap
    term:
      id: HP:0001852
      label: Sandal gap
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot.
    explanation: >-
      This directly supports a widened first interdigital space in AOII.
- name: Narrow Chest
  description: >
    Thoracic narrowing is part of the described neonatal skeletal phenotype.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This supports a narrow/small thorax phenotype in AOII.
- name: Cleft Palate
  description: >
    Orofacial clefting is a recurrent craniofacial feature in AOII.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This directly supports cleft palate as part of the AOII craniofacial phenotype.
- name: Midface Retrusion
  description: >
    Midface retrusion contributes to the characteristic facial appearance.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This directly supports midface retrusion in AOII.
- name: Depressed Nasal Bridge
  description: >
    Depressed nasal bridge is part of the characteristic facial dysmorphism.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This directly supports depressed nasal bridge.
- name: Epicanthus
  description: >
    Epicanthal folds are part of the reported craniofacial phenotype.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This directly supports epicanthus in AOII.
- name: Micrognathia
  description: >
    Mandibular hypoplasia is part of the reported craniofacial phenotype.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia).
    explanation: >-
      This directly supports micrognathia in the AOII phenotype spectrum.
- name: Talipes Equinovarus
  description: >
    Clubfoot is part of the typical lower-limb phenotype.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot.
    explanation: >-
      This directly supports clubfoot (talipes equinovarus).
- name: Coronal Cleft Vertebrae
  description: >
    Coronal clefting of the vertebral bodies is a reported prenatal imaging finding.
  phenotype_term:
    preferred_term: Coronal cleft vertebrae
    term:
      id: HP:0003417
      label: Coronal cleft vertebrae
  evidence:
  - reference: PMID:1279661
    reference_title: "Atelosteogenesis type II: sonographic and radiological correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The feasibility of diagnosing the following morphological features by prenatal ultrasonography is demonstrated: coronal clefts of the vertebral bodies, metaphyseal and epiphyseal abnormalities, spinal deviations such as cervical kyphosis and a horizontal sacrum, additional ossification centres in the pelvis, and preaxial deviation of the thumbs and toes.
    explanation: >-
      This directly supports coronal cleft vertebral abnormalities in AOII.
- name: Cervical Kyphosis
  description: >
    Cervical kyphosis is part of the reported spinal phenotype.
  phenotype_term:
    preferred_term: Cervical kyphosis
    term:
      id: HP:0002947
      label: Cervical kyphosis
  evidence:
  - reference: PMID:1279661
    reference_title: "Atelosteogenesis type II: sonographic and radiological correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The feasibility of diagnosing the following morphological features by prenatal ultrasonography is demonstrated: coronal clefts of the vertebral bodies, metaphyseal and epiphyseal abnormalities, spinal deviations such as cervical kyphosis and a horizontal sacrum, additional ossification centres in the pelvis, and preaxial deviation of the thumbs and toes.
    explanation: >-
      This directly supports cervical kyphosis in AOII.
- name: Bowed Long Bones
  description: >
    Long bones are reported as shortened and bowed on radiographs.
  phenotype_term:
    preferred_term: Bowed long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:3799721
    reference_title: "de la Chapelle dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other long bones were short and bowed.
    explanation: >-
      This directly supports bowing of the long bones in AOII.
- name: Pulmonary Hypoplasia
  description: >
    Pulmonary hypoplasia is a major contributor to neonatal lethality.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia.
    explanation: >-
      This directly supports pulmonary hypoplasia as a critical AOII complication.
- name: Tracheobronchomalacia
  description: >
    Airway malacia is part of the severe respiratory phenotype.
  phenotype_term:
    preferred_term: Tracheobronchomalacia
    term:
      id: HP:0002786
      label: Tracheobronchomalacia
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia.
    explanation: >-
      This directly supports tracheobronchomalacia in AOII.
- name: Laryngeal Stenosis
  description: >
    Laryngeal stenosis is part of the reported respiratory tract malformation triad.
  phenotype_term:
    preferred_term: Laryngeal stenosis
    term:
      id: HP:0001602
      label: Laryngeal stenosis
  evidence:
  - reference: PMID:3799721
    reference_title: "de la Chapelle dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neonatal death occurred in all cases and may be attributed to a consistent triad of respiratory tract malformations: laryngeal stenosis, tracheobronchomalacia, and pulmonary hypoplasia.
    explanation: >-
      This directly supports laryngeal stenosis as a clinically important AOII airway manifestation.
diagnosis:
- name: Clinical, Radiologic, and Molecular Diagnosis
  description: >
    Diagnosis is established by characteristic skeletal findings and confirmation of
    biallelic pathogenic variants in SLC26A2; prenatal ultrasound can complement or
    guide prenatal molecular testing.
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SLC26A2-related atelosteogenesis is established in a proband with characteristic clinical, radiologic, and histopathologic features and biallelic pathogenic variants in SLC26A2 identified by molecular genetic testing.
    explanation: >-
      This supports the combined clinical-radiologic-genetic diagnostic framework.
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrasound examination early in pregnancy is a reasonable complement or alternative to molecular genetic prenatal testing.
    explanation: >-
      This supports prenatal ultrasound and prenatal genetic testing in at-risk pregnancies.
treatments:
- name: Supportive and Palliative Care
  description: >
    No disease-modifying therapy is established; care is individualized as supportive
    versus palliative according to respiratory status and overall prognosis.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is no specific treatment currently available, and the aim of therapy (supportive versus palliative) will depend on clinical status and respiratory prognosis of the individual patient.
    explanation: >-
      This supports supportive/palliative management as the current standard approach.
notes: >-
  AOII is part of a DTDST/SLC26A2 phenotypic series that includes diastrophic dysplasia
  and achondrogenesis type IB, with severity linked to residual transporter activity.
references:
- reference: PMID:20301493
  title: "SLC26A2-Related Atelosteogenesis."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301493
SLC26A2-Related Atelosteogenesis.
No top-level findings curated for this source.

Deep Research

2
Atelosteogenesis Type II phenotype curation notes ▸

Atelosteogenesis Type II phenotype curation notes

Date: 2026-04-19 Curator: Codex Scope: phenotype section only for kb/disorders/Atelosteogenesis_Type_II.yaml

Sources used

  • PMID:20301493, SLC26A2-Related Atelosteogenesis.
  • PMID:1279661, Atelosteogenesis type II: sonographic and radiological correlation.
  • PMID:3799721, de la Chapelle dysplasia.
  • PMID:7632220, De la Chapelle dysplasia (atelosteogenesis type II): case report and review of the literature [corrected].

Phenotypes added or tightened

  • Added Micromelia from PMID:1279661.
  • Added Midface retrusion, Epicanthus, Ulnar deviation of the hand or of fingers of the hand, and Sandal gap from PMID:20301493.
  • Added Coronal cleft vertebrae and Cervical kyphosis from PMID:1279661.
  • Added Bowing of the long bones and Laryngeal stenosis from PMID:3799721.
  • Softened unsupported wording such as hallmark, commonly, and frequent in free-text descriptions where the cited abstracts did not make a frequency claim.

Claims considered but not added

  • Protuberant abdomen is present in the GeneReviews text, but I did not add it because I did not confirm a clean, repo-validated HPO mapping during this pass.
  • Metaphyseal and epiphyseal abnormalities, horizontal sacrum, and additional ossification centres in the pelvis are clearly described in PMID:1279661, but I did not add them without a more confident term choice.
  • Ulna/fibula hypoplasia is described in PMID:3799721, but the abstract wording supports severe reduction rather than a clean absent-versus-hypoplastic distinction, so I left it out rather than overstate the ontology mapping.

Frequency and onset

  • No new frequency values were added.
  • No onset values were added.
  • Although prenatal detection is reported in PMID:1279661, I left onset unset because the abstracts here more clearly support prenatal detectability than a disease-wide onset annotation policy for individual phenotypes.
OpenAI ▸
Atelosteogenesis Type II: Pathophysiology, Genetics, and Skeletal Phenotypes
o3-deep-research-2025-06-26 36 citations 2026-03-03T23:56:36.797326

Atelosteogenesis Type II: Pathophysiology, Genetics, and Skeletal Phenotypes

Overview

Atelosteogenesis Type II (AO2) is a rare, perinatal-lethal skeletal dysplasia characterized by severe short-limb dwarfism with a normal-sized skull, cleft palate, distinctive facial dysmorphism, and the classic “hitchhiker” thumbs (abducted, medially deviated great thumbs) (www.orpha.net). It is caused by biallelic mutations in the diastrophic dysplasia sulfate transporter gene (DTDST), now known as SLC26A2, which disrupt normal cartilage and bone development (www.orpha.net). The disorder is exceedingly rare (prevalence <1 in 1,000,000) (www.orpha.net), with only a handful of cases reported in the medical literature (www.ncbi.nlm.nih.gov). Autosomal recessive inheritance is observed – heterozygous carrier parents (usually asymptomatic) have a 25% chance of an affected child in each pregnancy (pubmed.ncbi.nlm.nih.gov). AO2 is usually perinatally lethal due to respiratory failure from a severely narrow thoracic cage and pulmonary hypoplasia (pubmed.ncbi.nlm.nih.gov). Notably, AO2 lies on a phenotypic continuum with other SLC26A2-related chondrodysplasias: it is intermediate in severity between the milder diastrophic dysplasia (non-lethal) and the more severe achondrogenesis type 1B (most extreme, perinatal lethal) (pubmed.ncbi.nlm.nih.gov). A few long-term survivors of AO2 have been documented, underscoring this spectrum of disease (pubmed.ncbi.nlm.nih.gov).

Molecular Pathophysiology

SLC26A2 encodes a sulfate transporter protein that is predominantly expressed in developing cartilage, responsible for importing sulfate ions into chondrocytes (www.ncbi.nlm.nih.gov). These sulfate ions are required for the sulfation of proteoglycans – key molecules in the cartilage extracellular matrix that give cartilage its structural integrity (www.ncbi.nlm.nih.gov). Loss-of-function mutations in SLC26A2 impair sulfate transport, leading to intracellular sulfate depletion and the synthesis of proteoglycans that are undersulfated (or not sulfated at all) (www.ncbi.nlm.nih.gov). The resultant defective cartilage matrix appears coarse and abnormally sparse in sulfated components, with disorganized fibrillar material and poor cell column formation in growth plates (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). This disrupted cartilage architecture cannot support normal endochondral ossification, causing the severe chondrodysplasia seen in AO2 (marked shortening of bones and delayed/incomplete ossification of skeletal elements) (www.ncbi.nlm.nih.gov). On a biochemical spectrum, residual transporter activity correlates inversely with disease severity – milder SLC26A2 mutations that retain partial function cause milder phenotypes (e.g. multiple epiphyseal dysplasia or diastrophic dysplasia), whereas combinations of severe/null mutations result in the lethal AO2 or achondrogenesis IB phenotypes (www.ncbi.nlm.nih.gov). For example, a recurrent missense mutation p.Arg279Trp (R279W) in SLC26A2 is commonly associated with the atelosteogenesis type II phenotype, especially when present alongside a second, null variant (www.ncbi.nlm.nih.gov). In the Finnish population, a founder splice-site mutation (c.-26+2T>C in SLC26A2) is frequently observed in severe SLC26A2-related dysplasias (including AO2) (medlineplus.gov). Overall, the pathophysiology of AO2 is a failure of proper cartilage extracellular matrix sulfation, leading to structurally weak cartilage in the trachea, ribs, and long bones, which in turn causes skeletal malformations and fatal respiratory compromise (www.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov).

Hallmark Skeletal Phenotypes

Clinically, AO2 presents with striking skeletal abnormalities evident at birth. There is proportionately short stature with severe rhizomelic limb shortening (marked shortening of the upper arms and thighs) while the skull is relatively normal-sized (pubmed.ncbi.nlm.nih.gov). The hands show the characteristic “hitchhiker thumb,” in which the thumbs are abducted and flexed (often accompanied by ulnar deviation of the other fingers) (pubmed.ncbi.nlm.nih.gov). The feet often have a wide gap between the first and second toes (sandal gap) and clubfoot (talipes equinovarus) deformities (pubmed.ncbi.nlm.nih.gov). Craniofacial and axial features include a cleft palate, a depressed nasal bridge with midface retrusion, hypertelorism or epicanthal folds, and micrognathia (small jaw) (pubmed.ncbi.nlm.nih.gov). The chest is very narrow (thoracic hypoplasia) with short, horizontal ribs, leading to a small lung volume, and the abdomen is protuberant (pubmed.ncbi.nlm.nih.gov). Radiographically, there is generalized platyspondyly (flattened vertebral bodies) and deficient ossification of many bones – for instance, iliac bones can be hypoplastic, long bones are short with flared or irregular metaphyses, and the distal humerus may appear bifid or ribbon-like (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). These skeletal hallmarks, especially the combination of hitchhiker thumbs, clubfeet, and extreme limb shortening with a normal-calvarium, are diagnostic for AO2 (pmc.ncbi.nlm.nih.gov). The profound thoracic restriction caused by the skeletal anomalies typically results in pulmonary hypoplasia and tracheobronchomalacia, explaining the high neonatal mortality (pubmed.ncbi.nlm.nih.gov).

Diagnosis and Outlook

Diagnosis of atelosteogenesis II can be suspected prenatally via ultrasound if severe skeletal shortening and clubfeet are observed, and it is confirmed by identifying biallelic SLC26A2 mutations through molecular genetic testing (www.ncbi.nlm.nih.gov). Given the rarity of the condition, genetic testing panels for lethal skeletal dysplasias or targeted SLC26A2 sequencing are employed when AO2 is suspected (www.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). Carrier screening for at-risk families and prenatal or preimplantation genetic testing can be offered if the familial SLC26A2 mutations are known (pubmed.ncbi.nlm.nih.gov). There is no curative treatment for AO2 – management is limited to supportive care, as most infants succumb shortly after birth due to respiratory failure (myriad.com). In the rare event of an affected infant surviving the neonatal period, aggressive respiratory support and orthopedic interventions (similar to those used in diastrophic dysplasia management) may be attempted, but the prognosis remains poor. Ongoing research in skeletal dysplasias is improving understanding of cartilage sulfation disorders, though atelosteogenesis II’s extreme severity currently precludes any definitive therapy (myriad.com). The emphasis remains on early diagnosis (including prenatal identification) and genetic counseling for families affected by this ultra-rare but devastating skeletal disorder (pubmed.ncbi.nlm.nih.gov) (www.orpha.net).