Atelosteogenesis Type II

Mendelian MONDO:0009727 Pathograph 38 Show in embeddings browser Skeletal Dysplasia Lethal Skeletal Dysplasia

Atelosteogenesis type II (AOII) is an autosomal-recessive SLC26A2-related chondrodysplasia caused by defective sulfate transport and cartilage-matrix sulfation. It is characterized by severe limb shortening, hitchhiker thumbs, cleft palate, abnormal vertebral and long-bone ossification, and a small thorax. Pulmonary hypoplasia and tracheobronchomalacia make the disorder usually lethal at birth or shortly thereafter, although longer survival has been reported. AOII is distinct from the monoallelic FLNB disorders atelosteogenesis types I and III and occupies the severe middle of the SLC26A2 spectrum between achondrogenesis type IB and diastrophic dysplasia.

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1
Mappings
1
Definitions
1
Inheritance
6
Pathophys.
30
Phenotypes
38
Pathograph
1
Genes
3
Medical Actions
4
Differentials
1
Models
11
References
2
Deep Research
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Classifications

ISDS Skeletal Nosology
sulphation disorders
🔗

Mappings

MONDO
MONDO:0009727 atelosteogenesis type II
skos:exactMatch Orphanet ORPHA:56304
The pinned Orphanet structured record lists MONDO:0009727 as an exact cross-reference for atelosteogenesis type II.
📘

Definitions

1
Orphanet atelosteogenesis type II definition
A rare lethal perinatal bone dysplasia with limb shortening, a normal-sized skull with cleft palate, hitchhiker thumbs, distinctive facial and radiographic skeletal findings, and a DTDST/SLC26A2 molecular basis.
OTHER
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"A rare, lethal perinatal bone dysplasia characterized by limb shortening, normal sized skull with cleft palate, hitchhiker thumbs, distinctive facial dysmorphism and radiographic skeletal features, caused by mutations in the diastrophic dysplasia sulfate transporter gene."
The structured Orphanet definition fixes the clinical and molecular scope of this record.
👪

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 (3 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.
ORPHA:56304 SUPPORT Other
"Autosomal recessive"
The pinned Orphanet record independently records autosomal-recessive inheritance.
⚙

Pathophysiology

6
Loss of SLC26A2 Sulfate Transport in Chondrocytes
Biallelic pathogenic SLC26A2 variants reduce sulfate import into chondrocytes. This is the initiating molecular defect shared across the SLC26A2 chondrodysplasia spectrum.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
SLC26A2 hgnc:10994 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC26A2 (hgnc:10994). hgnc:10994 is a gene from the HUGO Gene Nomenclature Committee.
sulfate transmembrane transport GO:1902358 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves sulfate transmembrane transport (GO:1902358). GO:1902358 is a biological process from the Gene Ontology.
sulfate transmembrane transporter activity GO:0015116 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves sulfate transmembrane transporter activity (GO:0015116). GO:0015116 is a molecular function from the Gene Ontology.
Downstream
Proteoglycan and Cartilage-Matrix Undersulfation Reduced cellular sulfate uptake limits sulfation of cartilage proteoglycans and other matrix macromolecules.
Collagen Retention, ATF6-UPR, and FGFR3 Overactivation A Slc26a2-null mouse study identifies a parallel cellular-stress branch; this branch is preclinical rather than an established patient biomarker.
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."
Functional expression work defines the transporter activity and its cartilage substrate context.
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."
Patient-derived cells directly connect AOII variants with impaired sulfate uptake.
Proteoglycan and Cartilage-Matrix Undersulfation
Inadequate sulfate availability produces insufficiently sulfated proteoglycans and other cartilage-matrix macromolecules, compromising matrix composition and organization.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
Downstream
Abnormal Cartilage Matrix and Endochondral Ossification Matrix-macromolecule disturbance is linked to the distinctive chondro-osseous histopathology and impaired skeletal development of AOII.
Show evidence (2 references)
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."
AOII patient cells directly demonstrate macromolecule undersulfation.
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."
Functional analysis identifies proteoglycan sulfation as the downstream biochemical requirement of SLC26A2 transport.
Abnormal Cartilage Matrix and Endochondral Ossification
Abnormal cartilage-matrix composition and organization impair the cartilage templates and growth-plate processes required for endochondral bone formation.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
cartilage development GO:0051216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cartilage development (GO:0051216). GO:0051216 is a biological process from the Gene Ontology. endochondral ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology.
Downstream
Appendicular, Axial, and Craniofacial Skeletal Dysplasia Tissue-level cartilage and ossification failure produces the characteristic multiregional skeletal pattern.
Thoracic and Airway Cartilage Insufficiency The cartilage disorder extends to the thorax and respiratory tract, producing the lethal respiratory phenotype.
Show evidence (2 references)
PMID:9133349 SUPPORT Human Clinical
"Atelosteogenesis type II shows distinctive chondro-osseous histopathology with a major disturbance in cartilage matrix macromolecules."
The pathologic review supports a cartilage-matrix-driven chondro-osseous lesion.
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)."
Human clinical and histologic observations establish severe cartilage and bone developmental pathology.
Appendicular, Axial, and Craniofacial Skeletal Dysplasia
Disordered fetal cartilage growth and ossification generate severe limb shortening, characteristic hand and foot positioning, vertebral and long-bone abnormalities, and craniofacial malformations.
skeletal system development GO:0001501 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves skeletal system development (GO:0001501). GO:0001501 is a biological process from the Gene Ontology.
Downstream
Rhizomelia
Severe Micromelia
Hitchhiker Thumb
Ulnar Deviation of Hands
Sandal Gap
Cleft Palate
Midface Retrusion
Depressed Nasal Bridge
Epicanthus
Micrognathia
Talipes Equinovarus
Coronal Cleft Vertebrae
Cervical Kyphosis
Bowed Long Bones
Brachydactyly
Broad Metacarpals
Camptodactyly
Short Femur
Dumbbell-Shaped Femur
Thoracolumbar Kyphoscoliosis
Hypoplastic Cervical Vertebrae
Short Neck
Protuberant Abdomen
Show evidence (2 references)
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)."
GeneReviews defines the characteristic appendicular and craniofacial pattern.
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..."
Prenatal imaging documents axial, appendicular, and acral patterning abnormalities.
Thoracic and Airway Cartilage Insufficiency
Small thoracic dimensions restrict fetal lung growth, while abnormal laryngeal, tracheal, and bronchial cartilage produces stenosis and dynamic airway collapse. Together these lesions explain the usual perinatal respiratory lethality.
Downstream
Narrow Chest
Pulmonary Hypoplasia
Tracheobronchomalacia
Laryngeal Stenosis
Short Ribs
Bell-Shaped Thorax
Laryngeal Cartilage Malformation
Show evidence (2 references)
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."
The case series directly identifies the lethal respiratory-tract triad.
PMID:20301493 SUPPORT Human Clinical
"SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia."
GeneReviews confirms pulmonary and airway cartilage disease as the usual cause of early death.
Collagen Retention, ATF6-UPR, and FGFR3 Overactivation
In Slc26a2-null mouse chondrocytes, impaired type II/type IX collagen secretion causes intracellular collagen retention, preferential ATF6 unfolded-protein-response activation, and excessive FGFR3 signaling. This is a provisional preclinical branch and is not yet established as a human AOII biomarker or treatment target.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Downstream
Abnormal Cartilage Matrix and Endochondral Ossification
Show evidence (1 reference)
PMID:30685387 SUPPORT Model Organism
"Unexpectedly, slc26a2-/- chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3..."
The knockout study directly supports the full preclinical cellular branch.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Atelosteogenesis Type 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.
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Phenotypes

30
Head and Neck 6
Cleft Palate FREQUENT HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0000175 | Cleft palate | Frequent (79-30%)"
Orphanet assigns cleft palate to the frequent 30-79% band.
Midface Retrusion OCCASIONAL HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0011800 | Midface retrusion | Occasional (29-5%)"
Orphanet assigns midface retrusion to the occasional 5-29% band.
Depressed Nasal Bridge HP:0005280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depressed nasal bridge (HP:0005280). HP:0005280 is a phenotype from the Human Phenotype Ontology.
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 OCCASIONAL HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0000286 | Epicanthus | Occasional (29-5%)"
Orphanet assigns epicanthus to the occasional 5-29% band.
Micrognathia OCCASIONAL HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0000347 | Micrognathia | Occasional (29-5%)"
Orphanet assigns micrognathia to the occasional 5-29% band.
Short Neck FREQUENT HP:0000470 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short neck (HP:0000470). HP:0000470 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0000470 | Short neck | Frequent (79-30%)"
Orphanet assigns short neck to the frequent 30-79% band.
Limbs 8
Severe Micromelia OCCASIONAL HP:0002983 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is abnormal Severe Micromelia, annotated with Micromelia (HP:0002983). HP:0002983 is a phenotype from the Human Phenotype Ontology.
⚠ ABNORMAL
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0002983 | Micromelia | Occasional (29-5%)"
Orphanet assigns the specific Micromelia HPO annotation to the occasional 5-29% band; broader limb undergrowth has a higher frequency annotation.
Hitchhiker Thumb FREQUENT HP:0001234 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hitchhiker thumb (HP:0001234). HP:0001234 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0001234 | Hitchhiker thumb | Frequent (79-30%)"
Orphanet assigns hitchhiker thumb to the frequent 30-79% band.
Ulnar Deviation of Hands FREQUENT Ulnar deviation of the hand or of fingers of the hand HP:0001193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ulnar deviation of the hand, annotated with Ulnar deviation of the hand or of fingers of the hand (HP:0001193). HP:0001193 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0001193 | Ulnar deviation of the hand or of fingers of the hand | Frequent (79-30%)"
Orphanet assigns ulnar hand/finger deviation to the frequent 30-79% band.
Sandal Gap FREQUENT HP:0001852 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sandal gap (HP:0001852). HP:0001852 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0001852 | Sandal gap | Frequent (79-30%)"
Orphanet assigns sandal gap to the frequent 30-79% band.
Talipes Equinovarus FREQUENT HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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).
ORPHA:56304 SUPPORT Other
"HP:0001776 | Bilateral talipes equinovarus | Frequent (79-30%)"
The more specific bilateral clubfoot annotation supports the frequent band used for the broader talipes equinovarus phenotype.
Bowed Long Bones Bowing of the long bones HP:0006487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bowed long bones, annotated with Bowing of the long bones (HP:0006487). HP:0006487 is a phenotype from the Human Phenotype Ontology.
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.
Brachydactyly FREQUENT HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0001156 | Brachydactyly | Frequent (79-30%)"
Orphanet assigns brachydactyly to the frequent 30-79% band.
Short Femur FREQUENT HP:0003097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short femur (HP:0003097). HP:0003097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0003097 | Short femur | Frequent (79-30%)"
Orphanet assigns short femur to the frequent 30-79% band.
Musculoskeletal 5
Narrow Chest FREQUENT HP:0000774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow chest (HP:0000774). HP:0000774 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0000774 | Narrow chest | Frequent (79-30%)"
Orphanet assigns narrow chest to the frequent 30-79% band.
Coronal Cleft Vertebrae HP:0003417 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coronal cleft vertebrae (HP:0003417). HP:0003417 is a phenotype from the Human Phenotype Ontology.
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 OCCASIONAL HP:0002947 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cervical kyphosis (HP:0002947). HP:0002947 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0002947 | Cervical kyphosis | Occasional (29-5%)"
Orphanet assigns cervical kyphosis to the occasional 5-29% band.
Camptodactyly FREQUENT HP:0012385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly (HP:0012385). HP:0012385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0012385 | Camptodactyly | Frequent (79-30%)"
Orphanet assigns camptodactyly to the frequent 30-79% band.
Short Ribs FREQUENT HP:0000773 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short ribs (HP:0000773). HP:0000773 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0000773 | Short ribs | Frequent (79-30%)"
Orphanet assigns short ribs to the frequent 30-79% band.
Respiratory 2
Pulmonary Hypoplasia FREQUENT HP:0002089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypoplasia (HP:0002089). HP:0002089 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0002089 | Pulmonary hypoplasia | Frequent (79-30%)"
Orphanet assigns pulmonary hypoplasia to the frequent 30-79% band.
Tracheobronchomalacia FREQUENT HP:0002786 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tracheobronchomalacia (HP:0002786). HP:0002786 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0002786 | Tracheobronchomalacia | Frequent (79-30%)"
Orphanet assigns tracheobronchomalacia to the frequent 30-79% band.
Growth 1
Rhizomelia FREQUENT HP:0008905 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhizomelia (HP:0008905). HP:0008905 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0008905 | Rhizomelia | Frequent (79-30%)"
Orphanet assigns rhizomelia to the frequent 30-79% band.
Other 8
Laryngeal Stenosis FREQUENT HP:0001602 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngeal stenosis (HP:0001602). HP:0001602 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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.
ORPHA:56304 SUPPORT Other
"HP:0001602 | Laryngeal stenosis | Frequent (79-30%)"
Orphanet assigns laryngeal stenosis to the frequent 30-79% band.
Broad Metacarpals FREQUENT HP:0001230 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad metacarpals (HP:0001230). HP:0001230 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0001230 | Broad metacarpals | Frequent (79-30%)"
Orphanet assigns broad metacarpals to the frequent 30-79% band.
Dumbbell-Shaped Femur FREQUENT HP:0006375 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dumbbell-shaped femur (HP:0006375). HP:0006375 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0006375 | Dumbbell-shaped femur | Frequent (79-30%)"
Orphanet assigns dumbbell-shaped femur to the frequent 30-79% band.
Thoracolumbar Kyphoscoliosis FREQUENT HP:0003423 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thoracolumbar kyphoscoliosis (HP:0003423). HP:0003423 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0003423 | Thoracolumbar kyphoscoliosis | Frequent (79-30%)"
Orphanet assigns thoracolumbar kyphoscoliosis to the frequent 30-79% band.
Hypoplastic Cervical Vertebrae OCCASIONAL HP:0008434 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic cervical vertebrae (HP:0008434). HP:0008434 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0008434 | Hypoplastic cervical vertebrae | Occasional (29-5%)"
Orphanet assigns hypoplastic cervical vertebrae to the occasional 5-29% band.
Protuberant Abdomen OCCASIONAL HP:0001538 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protuberant abdomen (HP:0001538). HP:0001538 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0001538 | Protuberant abdomen | Occasional (29-5%)"
Orphanet assigns protuberant abdomen to the occasional 5-29% band.
Bell-Shaped Thorax FREQUENT HP:0001591 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bell-shaped thorax (HP:0001591). HP:0001591 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0001591 | Bell-shaped thorax | Frequent (79-30%)"
Orphanet assigns bell-shaped thorax to the frequent 30-79% band.
Laryngeal Cartilage Malformation FREQUENT HP:0008752 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngeal cartilage malformation (HP:0008752). HP:0008752 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"HP:0008752 | Laryngeal cartilage malformation | Frequent (79-30%)"
Orphanet assigns laryngeal cartilage malformation to the frequent 30-79% band.
🧬

Genetic Associations

1
SLC26A2 Pathogenic Variants (Causative)
Gene: SLC26A2 hgnc:10994 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC26A2 (hgnc:10994). hgnc:10994 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 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.
ORPHA:56304 SUPPORT Other
"SLC26A2 | solute carrier family 26 member 2 | hgnc:10994 | Disease-causing germline mutation(s) in"
Orphanet independently asserts disease-causing germline SLC26A2 variants.
+ 1 more reference
🗃️

External Assertions

1
Orphanet atelosteogenesis type II structured disease record
Orphanet structured disease record ORPHA:56304
ORPHA:56304 supplies the disease identity, synonyms, definition, inheritance, point-prevalence class, SLC26A2 gene assertion, and HPO phenotype-frequency rows used in this entry.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"MONDO:0009727 | Exact"
Orphanet maps ORPHA:56304 exactly to the MONDO identifier used here.
💊

Medical Actions

3
Individualized Perinatal Airway and Respiratory Support
Category: Therapeutic
Delivery planning should anticipate a small thorax, pulmonary hypoplasia, laryngeal stenosis, and tracheobronchomalacia. Immediate airway assessment and respiratory stabilization may be offered when consistent with the infant's anatomy, clinical status, prognosis, and family goals. The evidence does not establish a disease-modifying benefit or a uniform ventilation strategy.
Target Phenotypes: Pulmonary hypoplasia HP:0002089 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pulmonary hypoplasia (HP:0002089). HP:0002089 is a phenotype from the Human Phenotype Ontology. Tracheobronchomalacia HP:0002786 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Tracheobronchomalacia (HP:0002786). HP:0002786 is a phenotype from the Human Phenotype Ontology. Laryngeal stenosis HP:0001602 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Laryngeal stenosis (HP:0001602). HP:0001602 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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."
The airway and pulmonary triad establishes the anatomic problems that perinatal respiratory planning must address.
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."
GeneReviews supports individualizing active support according to clinical status and respiratory prognosis.
Palliative and Comfort-Focused Care
Category: Therapeutic Action: palliative careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is palliative care, annotated with Palliative Therapy (NCIT:C15292). NCIT:C15292 is a clinical intervention from the NCI Thesaurus. Ontology label: Palliative Therapy NCIT:C15292
Because respiratory disease is usually lethal and no specific treatment is available, comfort-focused care is an appropriate option after transparent multidisciplinary counseling. The choice between supportive and palliative goals should be individualized and revisited if the observed course differs from the usual 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."
GeneReviews directly supports palliative as well as supportive goals and explicitly ties the decision to the individual respiratory prognosis.
Genetic Counseling and Reproductive Testing Options
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counsel parents about autosomal-recessive inheritance, the 25% recurrence risk when both are carriers, carrier testing for relatives, and prenatal or preimplantation testing once both familial variants are known. Early fetal ultrasound is complementary but does not eliminate molecular uncertainty.
Show evidence (2 references)
PMID:20301493 SUPPORT Human Clinical
"Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible if both pathogenic variants in the family are known."
GeneReviews directly supports carrier, prenatal, and preimplantation testing after familial variants are defined.
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 provides the recurrence-risk basis for family counseling.
🔬

Diagnosis

3
Prenatal Fetal Ultrasonography
Detailed fetal ultrasonography can identify severe limb shortening, abnormal thumb/toe position, vertebral coronal clefts, cervical kyphosis, metaphyseal/epiphyseal abnormalities, and abnormal pelvic ossification. These findings raise suspicion for AOII but overlap other lethal skeletal dysplasias and require molecular confirmation when possible.
fetal ultrasonography NCIT:C222238 NCI Thesaurus (NCIT)
Results: A compatible fetal skeletal pattern supports prenatal suspicion; it does not by itself distinguish SLC26A2-AOII from every FLNB- or SLC26A2-spectrum differential.
Show evidence (2 references)
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 documents the fetal sonographic pattern used to recognize AOII.
PMID:20301493 SUPPORT Human Clinical
"Ultrasound examination early in pregnancy is a reasonable complement or alternative to molecular genetic prenatal testing."
GeneReviews supports early-pregnancy ultrasound as an adjunct or alternative when familial molecular prenatal testing is being considered.
Clinical, Skeletal-Radiographic, and Histopathologic Evaluation
Examination and a complete skeletal radiographic survey define the limb, vertebral, pelvic, and hand/foot pattern. Cartilage histopathology can support classification, especially after perinatal death, but neither imaging nor histology replaces molecular testing because AO subtypes and other lethal skeletal dysplasias overlap.
radiograph imaging procedure NCIT:C38101 NCI Thesaurus (NCIT)
Results: Characteristic clinical, radiologic, and histopathologic findings establish the phenotypic diagnosis and direct SLC26A2 testing.
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."
GeneReviews defines the integrated phenotypic, radiologic, histopathologic, and molecular framework.
PMID:9133349 SUPPORT Human Clinical
"Atelosteogenesis type II shows distinctive chondro-osseous histopathology with a major disturbance in cartilage matrix macromolecules."
The review supports the diagnostic value of the distinctive cartilage lesion while documenting overlap across atelosteogenesis syndromes.
Molecular SLC26A2 Testing
Sequence and copy-number analysis of SLC26A2, either directly or within a skeletal-dysplasia panel/exome/genome workflow, should identify two pathogenic variants in trans. Molecular confirmation distinguishes AOII from FLNB-related AOI/AOIII and places the result within the broader SLC26A2 spectrum.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic SLC26A2 variants in a fetus or infant with the compatible phenotype establish SLC26A2-related atelosteogenesis; phenotype and radiology remain necessary for subtype assignment.
Show evidence (1 reference)
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 molecular confirmation.
📈

Progression

3
Congenital skeletal dysplasia with prenatal detectability
Age: Fetal period to birth
The malformations are congenital and may be recognized by fetal imaging; prenatal detection is not modeled as a separate post-conception disease onset.
Show evidence (1 reference)
PMID:1279661 SUPPORT Human Clinical
"We present a case diagnosed at 21 weeks of gestation in which antenatal sonographic and post-mortem radiological findings were correlated."
This directly establishes prenatal detectability of the congenital skeletal phenotype.
Usually lethal perinatal respiratory course
Age: Birth or shortly thereafter
Thoracic restriction, pulmonary hypoplasia, and airway cartilage weakness usually cause death at birth or soon afterward.
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."
GeneReviews directly supports the typical perinatal respiratory course.
Exceptional longer survival
Age: Beyond the neonatal period
AOII forms a continuum with diastrophic dysplasia, and rare individuals survive longer than the usual perinatal course; prognosis therefore should be individualized rather than treated as uniformly lethal.
Show evidence (1 reference)
PMID:20301493 SUPPORT Human Clinical
"However, it exists in a continuous phenotypic spectrum with SLC26A2-related diastrophic dysplasia, and long-term survivors have been reported."
This supports an explicitly non-absolute lethality statement.
📊

Prevalence

1
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet provides a validated class-only point-prevalence band rather than a population-derived point estimate, so no normalized rate is assigned.
Show evidence (1 reference)
ORPHA:56304 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
Orphanet classifies worldwide AOII point prevalence below one per million.
⚖️

Clinical Burden

High
AOII is a severe congenital skeletal dysplasia with profound limb and axial abnormalities, airway instability, pulmonary hypoplasia, and a high risk of death at birth or shortly thereafter. Rare longer survival does not remove the intensive respiratory and supportive-care burden.
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."
The typical lethality and respiratory mechanism justify a high disease-level burden classification.
🔀

Differential Diagnoses

4

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

Atelosteogenesis Type I MONDO:0007167
Overlapping Features AOI overlaps AOII in lethal short-limbed skeletal dysplasia, vertebral abnormalities, and perinatal respiratory compromise. AOI belongs to the monoallelic FLNB spectrum, whereas AOII requires biallelic SLC26A2 variants and a sulfate-transport/cartilage-matrix defect.
Distinguishing Features
  • Heterozygous FLNB missense variants, usually de novo, support AOI; biallelic SLC26A2 variants support AOII.
  • AOI/AOIII prominently feature joint dislocations and disharmonious skeletal maturation; AOII classically combines hitchhiker thumbs, cleft palate, and SLC26A2-spectrum histopathology.
  • Dominant versus recessive inheritance changes recurrence counseling.
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 defines the dominant FLNB AOI/AOIII spectrum and its major overlapping skeletal findings.
PMID:8571951 SUPPORT Human Clinical
"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."
The AOII genetic and biochemical basis separates it from FLNB-AOI.
Atelosteogenesis Type III MONDO:0007168
Overlapping Features AOIII overlaps AOI and AOII in severe limb, vertebral, joint, and airway disease, but it is a monoallelic FLNB disorder and can show substantially longer survival and vertical transmission. Molecular testing is the most reliable boundary when morphology overlaps.
Distinguishing Features
  • Heterozygous FLNB variants support AOIII; biallelic SLC26A2 variants support AOII.
  • Documented adult survival and vertical transmission establish that AOIII is not uniformly perinatal lethal.
  • AOIII belongs to the dominant FLNB/Larsen spectrum rather than the recessive SLC26A2 sulfation spectrum.
Show evidence (2 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 directly assigns AOIII to the FLNB spectrum.
PMID:10076882 SUPPORT Human Clinical
"This is the first documentation of survival to adulthood of an individual with this disorder, of prenatal diagnostic assessment of an affected individual, and of vertical transmission suggestive of autosomal dominant inheritance."
Adult survival and vertical transmission help distinguish the AOIII spectrum while confirming dominant inheritance.
Achondrogenesis Type IB
Overlapping Features ACG1B and AOII are both lethal autosomal-recessive SLC26A2 chondrodysplasias. ACG1B generally lies at the more severe end of the continuum and is more often associated with two alleles having minimal transport function, but overlap and imperfect genotype-phenotype prediction require integrated radiologic and pathologic classification.
Distinguishing Features
  • ACG1B is generally more severe than AOII within the same SLC26A2 continuum.
  • Two near-null alleles favor ACG1B, whereas AOII often retains more transporter function; this is a tendency, not an absolute rule.
  • Radiographic and histopathologic severity should accompany genotype when assigning the subtype.
Show evidence (2 references)
PMID:8571951 SUPPORT Human Clinical
"Together with our recent observation that a third even more severe chondrodysplasia, achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene."
The discovery study places ACG1B above AOII in severity within the same gene-defined series.
PMID:11448940 SUPPORT In Vitro
"However, in the X.laevis oocyte expression system, the correlation between residual transport function and the severity of phenotype was not absolute, suggesting that factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals..."
Functional testing supports the severity trend while preventing an overconfident genotype-only distinction.
Diastrophic Dysplasia MONDO:0009107
Overlapping Features Diastrophic dysplasia shares biallelic SLC26A2 variants, hitchhiker thumbs, clubfoot, cleft palate, and abnormal cartilage sulfation with AOII, but is usually much less severe and compatible with survival. Intermediate phenotypes reinforce that this is a continuum rather than a perfectly sharp molecular boundary.
Distinguishing Features
  • Survival with chronic skeletal morbidity favors diastrophic dysplasia over classic perinatal-lethal AOII.
  • AOII has more profound micromelia, thoracic restriction, pulmonary hypoplasia, and airway malacia.
  • Genotype contributes to severity but does not replace clinicoradiologic classification.
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 directly describes the shared pathology and large severity difference.
PMID:21077202 SUPPORT Human Clinical
"Analysis suggests that, while the DTDST family of disorders contains at least seven different conditions, mutations in the DTDST gene, in fact, appear to cause a phenotypic continuum. Furthermore, DTDST genotype alone is an imperfect predictor of clinical severity along this continuum."
A family spanning AOII and a diastrophic phenotype supports a continuous, overlapping boundary.
🐁

Animal Models

1
Slc26a2-/- global knockout and Col2a1-Cre; Slc26a2fl/fl cartilage-specific knockout Mus musculus
Complete or cartilage-specific Slc26a2 loss phenocopies the lethal ACG1B/AOII end of the human spectrum and supports skeleton-specific pathology. Prenatal FGFR inhibition improved knockout-mouse cartilage and skeletal pathology, but this remains preclinical and is not an established human AOII treatment.
Lethal SLC26A2-related chondrodysplasia Impaired cartilage growth Abnormal chondrocyte proliferation and apoptosis
Species
Mus musculus
Genotype
Slc26a2-/- global knockout and Col2a1-Cre; Slc26a2fl/fl cartilage-specific knockout
Genes
SLC26A2 hgnc:10994 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SLC26A2 (hgnc:10994). hgnc:10994 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:30685387 SUPPORT Model Organism
"Two lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2-/- mice."
The study directly validates the null mouse as a model of the lethal human SLC26A2 spectrum.
PMID:30685387 SUPPORT Model Organism
"Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2-/- newborns."
This supports a preclinical prenatal intervention signal without implying human efficacy or trial availability.
{ }

Source YAML

click to show 
name: Atelosteogenesis Type II
creation_date: '2026-03-04T07:56:34Z'
category: Mendelian
description: >-
  Atelosteogenesis type II (AOII) is an autosomal-recessive SLC26A2-related
  chondrodysplasia caused by defective sulfate transport and cartilage-matrix
  sulfation. It is characterized by severe limb shortening, hitchhiker thumbs,
  cleft palate, abnormal vertebral and long-bone ossification, and a small
  thorax. Pulmonary hypoplasia and tracheobronchomalacia make the disorder
  usually lethal at birth or shortly thereafter, although longer survival has
  been reported. AOII is distinct from the monoallelic FLNB disorders
  atelosteogenesis types I and III and occupies the severe middle of the
  SLC26A2 spectrum between achondrogenesis type IB and diastrophic dysplasia.
disease_term:
  preferred_term: atelosteogenesis type II
  term:
    id: MONDO:0009727
    label: atelosteogenesis type II
parents:
- Skeletal Dysplasia
- Lethal Skeletal Dysplasia
synonyms:
- AO2
- AOII
- Atelosteogenesis type 2
- De la Chapelle dysplasia
- Neonatal osseous dysplasia type 1
classifications:
  isds_skeletal_category:
  - classification_value: sulphation_disorders
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 4 "Sulphation
      disorders group"; listed as "Atelosteogenesis type 2 (AO2)".
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009727
      label: atelosteogenesis type II
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:56304
    mapping_justification: >-
      The pinned Orphanet structured record lists MONDO:0009727 as an exact
      cross-reference for atelosteogenesis type II.
external_assertions:
- name: Orphanet atelosteogenesis type II structured disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:56304
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=56304
  description: >-
    ORPHA:56304 supplies the disease identity, synonyms, definition,
    inheritance, point-prevalence class, SLC26A2 gene assertion, and HPO
    phenotype-frequency rows used in this entry.
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0009727 | Exact"
    explanation: >-
      Orphanet maps ORPHA:56304 exactly to the MONDO identifier used here.
definitions:
- name: Orphanet atelosteogenesis type II definition
  definition_type: OTHER
  description: >-
    A rare lethal perinatal bone dysplasia with limb shortening, a normal-sized
    skull with cleft palate, hitchhiker thumbs, distinctive facial and
    radiographic skeletal findings, and a DTDST/SLC26A2 molecular basis.
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare, lethal perinatal bone dysplasia characterized by limb shortening, normal sized skull with cleft palate, hitchhiker thumbs, distinctive facial dysmorphism and radiographic skeletal features, caused by mutations in the diastrophic dysplasia sulfate transporter gene.
    explanation: >-
      The structured Orphanet definition fixes the clinical and molecular scope
      of this record.
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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Autosomal recessive
    explanation: >-
      The pinned Orphanet record independently records autosomal-recessive
      inheritance.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet provides a validated class-only point-prevalence band rather than
    a population-derived point estimate, so no normalized rate is assigned.
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: >-
      Orphanet classifies worldwide AOII point prevalence below one per million.
progression:
- phase: Congenital skeletal dysplasia with prenatal detectability
  age_range: Fetal period to birth
  notes: >-
    The malformations are congenital and may be recognized by fetal imaging;
    prenatal detection is not modeled as a separate post-conception disease
    onset.
  evidence:
  - reference: PMID:1279661
    reference_title: "Atelosteogenesis type II: sonographic and radiological correlation."
    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: >-
      This directly establishes prenatal detectability of the congenital
      skeletal phenotype.
- phase: Usually lethal perinatal respiratory course
  age_range: Birth or shortly thereafter
  notes: >-
    Thoracic restriction, pulmonary hypoplasia, and airway cartilage weakness
    usually cause death at birth or soon afterward.
  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: >-
      GeneReviews directly supports the typical perinatal respiratory course.
- phase: Exceptional longer survival
  age_range: Beyond the neonatal period
  notes: >-
    AOII forms a continuum with diastrophic dysplasia, and rare individuals
    survive longer than the usual perinatal course; prognosis therefore should
    be individualized rather than treated as uniformly lethal.
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, it exists in a continuous phenotypic spectrum with SLC26A2-related diastrophic dysplasia, and long-term survivors have been reported.
    explanation: >-
      This supports an explicitly non-absolute lethality statement.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    AOII is a severe congenital skeletal dysplasia with profound limb and axial
    abnormalities, airway instability, pulmonary hypoplasia, and a high risk of
    death at birth or shortly thereafter. Rare longer survival does not remove
    the intensive respiratory and supportive-care burden.
  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: >-
      The typical lethality and respiratory mechanism justify a high
      disease-level burden classification.
pathophysiology:
- name: Loss of SLC26A2 Sulfate Transport in Chondrocytes
  description: >-
    Biallelic pathogenic SLC26A2 variants reduce sulfate import into
    chondrocytes. This is the initiating molecular defect shared across the
    SLC26A2 chondrodysplasia spectrum.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  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
  biological_processes:
  - preferred_term: sulfate transmembrane transport
    term:
      id: GO:1902358
      label: sulfate transmembrane transport
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  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: >-
      Functional expression work defines the transporter activity and its
      cartilage substrate context.
  - 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: >-
      Patient-derived cells directly connect AOII variants with impaired sulfate
      uptake.
  downstream:
  - target: Proteoglycan and Cartilage-Matrix Undersulfation
    causal_link_type: DIRECT
    description: >-
      Reduced cellular sulfate uptake limits sulfation of cartilage
      proteoglycans and other matrix macromolecules.
    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: 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: >-
        The same patient-cell experiment establishes both source and target of
        this edge.
  - target: Collagen Retention, ATF6-UPR, and FGFR3 Overactivation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Defective collagen secretion and intracellular type II/type IX collagen retention
    - Preferential ATF6 unfolded-protein-response activation
    description: >-
      A Slc26a2-null mouse study identifies a parallel cellular-stress branch;
      this branch is preclinical rather than an established patient biomarker.
    evidence:
    - reference: PMID:30685387
      reference_title: Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Unexpectedly, slc26a2-/- chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2-/- chondrocytes.
      explanation: >-
        The knockout study specifies the intervening collagen-retention and UPR
        events linking transporter loss to FGFR3 overactivation.
- name: Proteoglycan and Cartilage-Matrix Undersulfation
  description: >-
    Inadequate sulfate availability produces insufficiently sulfated
    proteoglycans and other cartilage-matrix macromolecules, compromising matrix
    composition and organization.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  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: 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: >-
      AOII patient cells directly demonstrate macromolecule undersulfation.
  - 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: >-
      Functional analysis identifies proteoglycan sulfation as the downstream
      biochemical requirement of SLC26A2 transport.
  downstream:
  - target: Abnormal Cartilage Matrix and Endochondral Ossification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered proteoglycan charge and cartilage extracellular-matrix organization
    - Disrupted chondrocyte growth-plate architecture and cartilage bone templates
    description: >-
      Matrix-macromolecule disturbance is linked to the distinctive
      chondro-osseous histopathology and impaired skeletal development of AOII.
    evidence:
    - reference: PMID:9133349
      reference_title: "Atelosteogenesis syndromes: a review, with comments on their pathogenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Atelosteogenesis type II shows distinctive chondro-osseous histopathology with a major disturbance in cartilage matrix macromolecules.
      explanation: >-
        The clinicopathologic review directly joins cartilage-matrix disturbance
        to AOII chondro-osseous pathology.
- name: Abnormal Cartilage Matrix and Endochondral Ossification
  description: >-
    Abnormal cartilage-matrix composition and organization impair the cartilage
    templates and growth-plate processes required for endochondral bone
    formation.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  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:9133349
    reference_title: "Atelosteogenesis syndromes: a review, with comments on their pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type II shows distinctive chondro-osseous histopathology with a major disturbance in cartilage matrix macromolecules.
    explanation: >-
      The pathologic review supports a cartilage-matrix-driven chondro-osseous
      lesion.
  - 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: >-
      Human clinical and histologic observations establish severe cartilage and
      bone developmental pathology.
  downstream:
  - target: Appendicular, Axial, and Craniofacial Skeletal Dysplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired cartilage templates and growth-plate organization
    - Disturbed fetal long-bone, vertebral, acral, and craniofacial patterning
    description: >-
      Tissue-level cartilage and ossification failure produces the characteristic
      multiregional skeletal pattern.
    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: >-
        The radiologic report documents the multiregional skeletal output of the
        chondrodysplasia.
  - target: Thoracic and Airway Cartilage Insufficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Abnormal rib and thoracic cartilage development with restricted fetal lung growth
    - Abnormal laryngeal, tracheal, and bronchial cartilage with airway weakness
    description: >-
      The cartilage disorder extends to the thorax and respiratory tract,
      producing the lethal respiratory phenotype.
    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: >-
        The original clinical series connects AOII chondrodysplasia with a
        consistent respiratory-tract malformation triad.
- name: Appendicular, Axial, and Craniofacial Skeletal Dysplasia
  description: >-
    Disordered fetal cartilage growth and ossification generate severe limb
    shortening, characteristic hand and foot positioning, vertebral and
    long-bone abnormalities, and craniofacial malformations.
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
  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: >-
      GeneReviews defines the characteristic appendicular and craniofacial
      pattern.
  - 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: >-
      Prenatal imaging documents axial, appendicular, and acral patterning
      abnormalities.
  downstream:
  - target: Rhizomelia
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the skeletal dysplasia pattern.
  - target: Severe Micromelia
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the skeletal dysplasia pattern.
  - target: Hitchhiker Thumb
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the skeletal dysplasia pattern.
  - target: Ulnar Deviation of Hands
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the skeletal dysplasia pattern.
  - target: Sandal Gap
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the skeletal dysplasia pattern.
  - target: Cleft Palate
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the craniofacial dysplasia pattern.
  - target: Midface Retrusion
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the craniofacial dysplasia pattern.
  - target: Depressed Nasal Bridge
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the craniofacial dysplasia pattern.
  - target: Epicanthus
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the craniofacial dysplasia pattern.
  - target: Micrognathia
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the craniofacial dysplasia pattern.
  - target: Talipes Equinovarus
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the skeletal dysplasia pattern.
  - target: Coronal Cleft Vertebrae
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the axial skeletal dysplasia pattern.
  - target: Cervical Kyphosis
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the axial skeletal dysplasia pattern.
  - target: Bowed Long Bones
    causal_link_type: DIRECT
    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: >-
        The phenotype is a direct component of the appendicular skeletal
        dysplasia pattern.
  - target: Brachydactyly
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001156 | Brachydactyly | Frequent (79-30%)"
      explanation: >-
        Orphanet records brachydactyly as a frequent acral manifestation.
  - target: Broad Metacarpals
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001230 | Broad metacarpals | Frequent (79-30%)"
      explanation: >-
        Orphanet records broad metacarpals as a frequent hand manifestation.
  - target: Camptodactyly
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012385 | Camptodactyly | Frequent (79-30%)"
      explanation: >-
        Orphanet records camptodactyly as a frequent acral manifestation.
  - target: Short Femur
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003097 | Short femur | Frequent (79-30%)"
      explanation: >-
        Orphanet records short femur as a frequent long-bone manifestation.
  - target: Dumbbell-Shaped Femur
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0006375 | Dumbbell-shaped femur | Frequent (79-30%)"
      explanation: >-
        Orphanet records the dumbbell-shaped femur radiographic pattern as frequent.
  - target: Thoracolumbar Kyphoscoliosis
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003423 | Thoracolumbar kyphoscoliosis | Frequent (79-30%)"
      explanation: >-
        Orphanet records thoracolumbar kyphoscoliosis as a frequent axial manifestation.
  - target: Hypoplastic Cervical Vertebrae
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008434 | Hypoplastic cervical vertebrae | Occasional (29-5%)"
      explanation: >-
        Orphanet records hypoplastic cervical vertebrae as an occasional axial manifestation.
  - target: Short Neck
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000470 | Short neck | Frequent (79-30%)"
      explanation: >-
        Orphanet records short neck as a frequent skeletal-body-habitus manifestation.
  - target: Protuberant Abdomen
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Disproportionate small thorax and shortened trunk
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001538 | Protuberant abdomen | Occasional (29-5%)"
      explanation: >-
        Orphanet records protuberant abdomen as an occasional component of the
        syndromic body-habitus pattern.
- name: Thoracic and Airway Cartilage Insufficiency
  description: >-
    Small thoracic dimensions restrict fetal lung growth, while abnormal
    laryngeal, tracheal, and bronchial cartilage produces stenosis and dynamic
    airway collapse. Together these lesions explain the usual perinatal
    respiratory lethality.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  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: >-
      The case series directly identifies the lethal respiratory-tract triad.
  - 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: >-
      GeneReviews confirms pulmonary and airway cartilage disease as the usual
      cause of early death.
  downstream:
  - target: Narrow Chest
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000774 | Narrow chest | Frequent (79-30%)"
      explanation: >-
        Orphanet records narrow chest as a frequent thoracic manifestation.
  - target: Pulmonary Hypoplasia
    causal_link_type: DIRECT
    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: >-
        Pulmonary hypoplasia is a direct component of the respiratory mechanism.
  - target: Tracheobronchomalacia
    causal_link_type: DIRECT
    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: >-
        Tracheobronchomalacia is a direct component of the respiratory mechanism.
  - target: Laryngeal Stenosis
    causal_link_type: DIRECT
    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: >-
        Laryngeal stenosis is a direct component of the respiratory mechanism.
  - target: Short Ribs
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000773 | Short ribs | Frequent (79-30%)"
      explanation: >-
        Orphanet records short ribs as a frequent thoracic manifestation.
  - target: Bell-Shaped Thorax
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001591 | Bell-shaped thorax | Frequent (79-30%)"
      explanation: >-
        Orphanet records a bell-shaped thorax as a frequent thoracic manifestation.
  - target: Laryngeal Cartilage Malformation
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:56304
      reference_title: Atelosteogenesis type II
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008752 | Laryngeal cartilage malformation | Frequent (79-30%)"
      explanation: >-
        Orphanet records laryngeal cartilage malformation as a frequent airway manifestation.
- name: Collagen Retention, ATF6-UPR, and FGFR3 Overactivation
  description: >-
    In Slc26a2-null mouse chondrocytes, impaired type II/type IX collagen
    secretion causes intracellular collagen retention, preferential ATF6
    unfolded-protein-response activation, and excessive FGFR3 signaling. This
    is a provisional preclinical branch and is not yet established as a human
    AOII biomarker or treatment target.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:30685387
    reference_title: Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly, slc26a2-/- chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2-/- chondrocytes.
    explanation: >-
      The knockout study directly supports the full preclinical cellular branch.
  downstream:
  - target: Abnormal Cartilage Matrix and Endochondral Ossification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Excess FGFR3 signaling
    - Altered cartilage growth and chondrocyte proliferation-apoptosis balance
    evidence:
    - reference: PMID:30685387
      reference_title: Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2-/- cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis.
      explanation: >-
        Rescue of knockout cartilage growth supports a causal link from the
        signaling branch to cartilage-growth failure.
genetic:
- name: SLC26A2 Pathogenic Variants
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  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 continuum. Residual transport activity contributes
    to severity, but genotype alone is an imperfect predictor and a single
    variant should not be used to force an AOII-versus-ACG1B-versus-DTD label.
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC26A2 | solute carrier family 26 member 2 | hgnc:10994 | Disease-causing germline mutation(s) in"
    explanation: >-
      Orphanet independently asserts disease-causing germline SLC26A2 variants.
  - reference: PMID:21077202
    reference_title: "Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis suggests that, while the DTDST family of disorders contains at least seven different conditions, mutations in the DTDST gene, in fact, appear to cause a phenotypic continuum. Furthermore, DTDST genotype alone is an imperfect predictor of clinical severity along this continuum.
    explanation: >-
      The family study supports a continuum model and cautions against
      deterministic genotype-only subtype assignment.
phenotypes:
- name: Rhizomelia
  description: >
    Rhizomelic shortening of the proximal limbs is a characteristic AOII skeletal phenotype.
  frequency: FREQUENT
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008905 | Rhizomelia | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns rhizomelia to the frequent 30-79% band.
- name: Severe Micromelia
  description: >
    Generalized marked limb shortening is part of the reported AOII skeletal phenotype.
  frequency: OCCASIONAL
  severity: SEVERE
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002983 | Micromelia | Occasional (29-5%)"
    explanation: >-
      Orphanet assigns the specific Micromelia HPO annotation to the occasional
      5-29% band; broader limb undergrowth has a higher frequency annotation.
- name: Hitchhiker Thumb
  description: >
    Medially deviated abducted thumbs are characteristic of AOII.
  frequency: FREQUENT
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001234 | Hitchhiker thumb | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns hitchhiker thumb to the frequent 30-79% band.
- name: Ulnar Deviation of Hands
  description: >
    Ulnar deviation of the fingers is part of the characteristic hand phenotype.
  frequency: FREQUENT
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001193 | Ulnar deviation of the hand or of fingers of the hand | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns ulnar hand/finger deviation to the frequent 30-79% band.
- name: Sandal Gap
  description: >
    A widened gap between the first and second toes is part of the typical pedal phenotype.
  frequency: FREQUENT
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001852 | Sandal gap | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns sandal gap to the frequent 30-79% band.
- name: Narrow Chest
  description: >
    Thoracic narrowing is part of the described neonatal skeletal phenotype.
  frequency: FREQUENT
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000774 | Narrow chest | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns narrow chest to the frequent 30-79% band.
- name: Cleft Palate
  description: >
    Orofacial clefting is a recurrent craniofacial feature in AOII.
  frequency: FREQUENT
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000175 | Cleft palate | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns cleft palate to the frequent 30-79% band.
- name: Midface Retrusion
  description: >
    Midface retrusion contributes to the characteristic facial appearance.
  frequency: OCCASIONAL
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011800 | Midface retrusion | Occasional (29-5%)"
    explanation: >-
      Orphanet assigns midface retrusion to the occasional 5-29% band.
- 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.
  frequency: OCCASIONAL
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000286 | Epicanthus | Occasional (29-5%)"
    explanation: >-
      Orphanet assigns epicanthus to the occasional 5-29% band.
- name: Micrognathia
  description: >
    Mandibular hypoplasia is part of the reported craniofacial phenotype.
  frequency: OCCASIONAL
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000347 | Micrognathia | Occasional (29-5%)"
    explanation: >-
      Orphanet assigns micrognathia to the occasional 5-29% band.
- name: Talipes Equinovarus
  description: >
    Clubfoot is part of the typical lower-limb phenotype.
  frequency: FREQUENT
  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).
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001776 | Bilateral talipes equinovarus | Frequent (79-30%)"
    explanation: >-
      The more specific bilateral clubfoot annotation supports the frequent
      band used for the broader talipes equinovarus phenotype.
- 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.
  frequency: OCCASIONAL
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002947 | Cervical kyphosis | Occasional (29-5%)"
    explanation: >-
      Orphanet assigns cervical kyphosis to the occasional 5-29% band.
- 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.
  frequency: FREQUENT
  severity: SEVERE
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002089 | Pulmonary hypoplasia | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns pulmonary hypoplasia to the frequent 30-79% band.
- name: Tracheobronchomalacia
  description: >
    Airway malacia is part of the severe respiratory phenotype.
  frequency: FREQUENT
  severity: SEVERE
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002786 | Tracheobronchomalacia | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns tracheobronchomalacia to the frequent 30-79% band.
- name: Laryngeal Stenosis
  description: >
    Laryngeal stenosis is part of the reported respiratory tract malformation triad.
  frequency: FREQUENT
  severity: SEVERE
  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.
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001602 | Laryngeal stenosis | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns laryngeal stenosis to the frequent 30-79% band.
- name: Brachydactyly
  frequency: FREQUENT
  description: >-
    Short digits are part of the characteristic AOII hand and foot dysplasia.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001156 | Brachydactyly | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns brachydactyly to the frequent 30-79% band.
- name: Broad Metacarpals
  frequency: FREQUENT
  description: >-
    Broad metacarpals contribute to the characteristic acral radiographic pattern.
  phenotype_term:
    preferred_term: Broad metacarpals
    term:
      id: HP:0001230
      label: Broad metacarpals
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001230 | Broad metacarpals | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns broad metacarpals to the frequent 30-79% band.
- name: Camptodactyly
  frequency: FREQUENT
  description: >-
    Fixed flexion of one or more digits is part of the AOII acral phenotype.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012385 | Camptodactyly | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns camptodactyly to the frequent 30-79% band.
- name: Short Femur
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    Marked femoral shortening contributes to the rhizomelic and micromelic
    long-bone pattern.
  phenotype_term:
    preferred_term: Short femur
    term:
      id: HP:0003097
      label: Short femur
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003097 | Short femur | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns short femur to the frequent 30-79% band.
- name: Dumbbell-Shaped Femur
  frequency: FREQUENT
  description: >-
    A dumbbell-shaped femur is a distinctive long-bone radiographic finding in AOII.
  phenotype_term:
    preferred_term: Dumbbell-shaped femur
    term:
      id: HP:0006375
      label: Dumbbell-shaped femur
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006375 | Dumbbell-shaped femur | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns dumbbell-shaped femur to the frequent 30-79% band.
- name: Thoracolumbar Kyphoscoliosis
  frequency: FREQUENT
  description: >-
    Combined thoracolumbar kyphosis and scoliosis is part of the axial skeletal pattern.
  phenotype_term:
    preferred_term: Thoracolumbar kyphoscoliosis
    term:
      id: HP:0003423
      label: Thoracolumbar kyphoscoliosis
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003423 | Thoracolumbar kyphoscoliosis | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns thoracolumbar kyphoscoliosis to the frequent 30-79% band.
- name: Hypoplastic Cervical Vertebrae
  frequency: OCCASIONAL
  description: >-
    Underdeveloped cervical vertebrae contribute to the abnormal axial ossification pattern.
  phenotype_term:
    preferred_term: Hypoplastic cervical vertebrae
    term:
      id: HP:0008434
      label: Hypoplastic cervical vertebrae
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008434 | Hypoplastic cervical vertebrae | Occasional (29-5%)"
    explanation: >-
      Orphanet assigns hypoplastic cervical vertebrae to the occasional 5-29% band.
- name: Short Neck
  frequency: FREQUENT
  description: >-
    A short neck is part of the disproportionate skeletal body habitus.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000470 | Short neck | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns short neck to the frequent 30-79% band.
- name: Protuberant Abdomen
  frequency: OCCASIONAL
  description: >-
    Abdominal prominence contributes to the disproportionate thoracoabdominal
    appearance.
  phenotype_term:
    preferred_term: Protuberant abdomen
    term:
      id: HP:0001538
      label: Protuberant abdomen
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001538 | Protuberant abdomen | Occasional (29-5%)"
    explanation: >-
      Orphanet assigns protuberant abdomen to the occasional 5-29% band.
- name: Short Ribs
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    Short ribs contribute to thoracic hypoplasia and restriction of fetal lung growth.
  phenotype_term:
    preferred_term: Short ribs
    term:
      id: HP:0000773
      label: Short ribs
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000773 | Short ribs | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns short ribs to the frequent 30-79% band.
- name: Bell-Shaped Thorax
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    A bell-shaped thorax is a characteristic form of the severe thoracic dysplasia.
  phenotype_term:
    preferred_term: Bell-shaped thorax
    term:
      id: HP:0001591
      label: Bell-shaped thorax
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001591 | Bell-shaped thorax | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns bell-shaped thorax to the frequent 30-79% band.
- name: Laryngeal Cartilage Malformation
  frequency: FREQUENT
  severity: SEVERE
  description: >-
    Abnormal laryngeal cartilage development contributes to upper-airway
    instability and stenosis.
  phenotype_term:
    preferred_term: Laryngeal cartilage malformation
    term:
      id: HP:0008752
      label: Laryngeal cartilage malformation
  evidence:
  - reference: ORPHA:56304
    reference_title: Atelosteogenesis type II
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008752 | Laryngeal cartilage malformation | Frequent (79-30%)"
    explanation: >-
      Orphanet assigns laryngeal cartilage malformation to the frequent 30-79% band.
diagnosis:
- name: Prenatal Fetal Ultrasonography
  diagnosis_term:
    preferred_term: fetal ultrasonography
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  description: >-
    Detailed fetal ultrasonography can identify severe limb shortening,
    abnormal thumb/toe position, vertebral coronal clefts, cervical kyphosis,
    metaphyseal/epiphyseal abnormalities, and abnormal pelvic ossification.
    These findings raise suspicion for AOII but overlap other lethal skeletal
    dysplasias and require molecular confirmation when possible.
  results: >-
    A compatible fetal skeletal pattern supports prenatal suspicion; it does
    not by itself distinguish SLC26A2-AOII from every FLNB- or
    SLC26A2-spectrum differential.
  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 documents the fetal sonographic pattern used to recognize AOII.
  - 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: >-
      GeneReviews supports early-pregnancy ultrasound as an adjunct or
      alternative when familial molecular prenatal testing is being considered.
- name: Clinical, Skeletal-Radiographic, and Histopathologic Evaluation
  diagnosis_term:
    preferred_term: radiograph imaging procedure
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  description: >-
    Examination and a complete skeletal radiographic survey define the limb,
    vertebral, pelvic, and hand/foot pattern. Cartilage histopathology can
    support classification, especially after perinatal death, but neither
    imaging nor histology replaces molecular testing because AO subtypes and
    other lethal skeletal dysplasias overlap.
  results: >-
    Characteristic clinical, radiologic, and histopathologic findings establish
    the phenotypic diagnosis and direct SLC26A2 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: >-
      GeneReviews defines the integrated phenotypic, radiologic,
      histopathologic, and molecular framework.
  - reference: PMID:9133349
    reference_title: "Atelosteogenesis syndromes: a review, with comments on their pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atelosteogenesis type II shows distinctive chondro-osseous histopathology with a major disturbance in cartilage matrix macromolecules.
    explanation: >-
      The review supports the diagnostic value of the distinctive cartilage
      lesion while documenting overlap across atelosteogenesis syndromes.
- name: Molecular SLC26A2 Testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    Sequence and copy-number analysis of SLC26A2, either directly or within a
    skeletal-dysplasia panel/exome/genome workflow, should identify two
    pathogenic variants in trans. Molecular confirmation distinguishes AOII
    from FLNB-related AOI/AOIII and places the result within the broader
    SLC26A2 spectrum.
  results: >-
    Biallelic pathogenic SLC26A2 variants in a fetus or infant with the
    compatible phenotype establish SLC26A2-related atelosteogenesis; phenotype
    and radiology remain necessary for subtype assignment.
  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 molecular confirmation.
treatments:
- name: Individualized Perinatal Airway and Respiratory Support
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: airway management
  description: >-
    Delivery planning should anticipate a small thorax, pulmonary hypoplasia,
    laryngeal stenosis, and tracheobronchomalacia. Immediate airway assessment
    and respiratory stabilization may be offered when consistent with the
    infant's anatomy, clinical status, prognosis, and family goals. The evidence
    does not establish a disease-modifying benefit or a uniform ventilation
    strategy.
  target_phenotypes:
  - preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  - preferred_term: Tracheobronchomalacia
    term:
      id: HP:0002786
      label: Tracheobronchomalacia
  - 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: >-
      The airway and pulmonary triad establishes the anatomic problems that
      perinatal respiratory planning must address.
  - 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: >-
      GeneReviews supports individualizing active support according to clinical
      status and respiratory prognosis.
- name: Palliative and Comfort-Focused Care
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: palliative care
    term:
      id: NCIT:C15292
      label: Palliative Therapy
  description: >-
    Because respiratory disease is usually lethal and no specific treatment is
    available, comfort-focused care is an appropriate option after transparent
    multidisciplinary counseling. The choice between supportive and palliative
    goals should be individualized and revisited if the observed course differs
    from the usual prognosis.
  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: >-
      GeneReviews directly supports palliative as well as supportive goals and
      explicitly ties the decision to the individual respiratory prognosis.
- name: Genetic Counseling and Reproductive Testing Options
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  description: >-
    Counsel parents about autosomal-recessive inheritance, the 25% recurrence
    risk when both are carriers, carrier testing for relatives, and prenatal or
    preimplantation testing once both familial variants are known. Early fetal
    ultrasound is complementary but does not eliminate molecular uncertainty.
  evidence:
  - reference: PMID:20301493
    reference_title: "SLC26A2-Related Atelosteogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible if both pathogenic variants in the family are known.
    explanation: >-
      GeneReviews directly supports carrier, prenatal, and preimplantation
      testing after familial variants are defined.
  - 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 provides the recurrence-risk basis for family counseling.
differential_diagnoses:
- name: Atelosteogenesis Type I
  disease_term:
    preferred_term: atelosteogenesis type I
    term:
      id: MONDO:0007167
      label: atelosteogenesis type I
  description: >-
    AOI overlaps AOII in lethal short-limbed skeletal dysplasia, vertebral
    abnormalities, and perinatal respiratory compromise. AOI belongs to the
    monoallelic FLNB spectrum, whereas AOII requires biallelic SLC26A2 variants
    and a sulfate-transport/cartilage-matrix defect.
  distinguishing_features:
  - Heterozygous FLNB missense variants, usually de novo, support AOI; biallelic SLC26A2 variants support AOII.
  - AOI/AOIII prominently feature joint dislocations and disharmonious skeletal maturation; AOII classically combines hitchhiker thumbs, cleft palate, and SLC26A2-spectrum histopathology.
  - Dominant versus recessive inheritance changes recurrence counseling.
  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 defines the dominant FLNB AOI/AOIII spectrum and its major overlapping
      skeletal findings.
  - 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: >-
      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: >-
      The AOII genetic and biochemical basis separates it from FLNB-AOI.
- name: Atelosteogenesis Type III
  disease_term:
    preferred_term: atelosteogenesis type III
    term:
      id: MONDO:0007168
      label: atelosteogenesis type III
  description: >-
    AOIII overlaps AOI and AOII in severe limb, vertebral, joint, and airway
    disease, but it is a monoallelic FLNB disorder and can show substantially
    longer survival and vertical transmission. Molecular testing is the most
    reliable boundary when morphology overlaps.
  distinguishing_features:
  - Heterozygous FLNB variants support AOIII; biallelic SLC26A2 variants support AOII.
  - Documented adult survival and vertical transmission establish that AOIII is not uniformly perinatal lethal.
  - AOIII belongs to the dominant FLNB/Larsen spectrum rather than the recessive SLC26A2 sulfation spectrum.
  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 directly assigns AOIII to the FLNB spectrum.
  - reference: PMID:10076882
    reference_title: "Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first documentation of survival to adulthood of an individual with this disorder, of prenatal diagnostic assessment of an affected individual, and of vertical transmission suggestive of autosomal dominant inheritance.
    explanation: >-
      Adult survival and vertical transmission help distinguish the AOIII
      spectrum while confirming dominant inheritance.
- name: Achondrogenesis Type IB
  description: >-
    ACG1B and AOII are both lethal autosomal-recessive SLC26A2
    chondrodysplasias. ACG1B generally lies at the more severe end of the
    continuum and is more often associated with two alleles having minimal
    transport function, but overlap and imperfect genotype-phenotype prediction
    require integrated radiologic and pathologic classification.
  distinguishing_features:
  - ACG1B is generally more severe than AOII within the same SLC26A2 continuum.
  - Two near-null alleles favor ACG1B, whereas AOII often retains more transporter function; this is a tendency, not an absolute rule.
  - Radiographic and histopathologic severity should accompany genotype when assigning the subtype.
  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: >-
      Together with our recent observation that a third even more severe chondrodysplasia, achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene.
    explanation: >-
      The discovery study places ACG1B above AOII in severity within the same
      gene-defined series.
  - 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: >-
      However, in the X.laevis oocyte expression system, the correlation between residual transport function and the severity of phenotype was not absolute, suggesting that factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations.
    explanation: >-
      Functional testing supports the severity trend while preventing an
      overconfident genotype-only distinction.
- name: Diastrophic Dysplasia
  disease_term:
    preferred_term: diastrophic dysplasia
    term:
      id: MONDO:0009107
      label: diastrophic dysplasia
  description: >-
    Diastrophic dysplasia shares biallelic SLC26A2 variants, hitchhiker thumbs,
    clubfoot, cleft palate, and abnormal cartilage sulfation with AOII, but is
    usually much less severe and compatible with survival. Intermediate
    phenotypes reinforce that this is a continuum rather than a perfectly sharp
    molecular boundary.
  distinguishing_features:
  - Survival with chronic skeletal morbidity favors diastrophic dysplasia over classic perinatal-lethal AOII.
  - AOII has more profound micromelia, thoracic restriction, pulmonary hypoplasia, and airway malacia.
  - Genotype contributes to severity but does not replace clinicoradiologic classification.
  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 directly describes the shared pathology and large severity difference.
  - reference: PMID:21077202
    reference_title: "Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis suggests that, while the DTDST family of disorders contains at least seven different conditions, mutations in the DTDST gene, in fact, appear to cause a phenotypic continuum. Furthermore, DTDST genotype alone is an imperfect predictor of clinical severity along this continuum.
    explanation: >-
      A family spanning AOII and a diastrophic phenotype supports a continuous,
      overlapping boundary.
animal_models:
- species: Mus musculus
  genotype: Slc26a2-/- global knockout and Col2a1-Cre; Slc26a2fl/fl cartilage-specific knockout
  genes:
  - preferred_term: SLC26A2
    term:
      id: hgnc:10994
      label: SLC26A2
  associated_phenotypes:
  - Lethal SLC26A2-related chondrodysplasia
  - Impaired cartilage growth
  - Abnormal chondrocyte proliferation and apoptosis
  description: >-
    Complete or cartilage-specific Slc26a2 loss phenocopies the lethal ACG1B/AOII
    end of the human spectrum and supports skeleton-specific pathology. Prenatal
    FGFR inhibition improved knockout-mouse cartilage and skeletal pathology,
    but this remains preclinical and is not an established human AOII treatment.
  evidence:
  - reference: PMID:30685387
    reference_title: Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Two lethal forms of human SLC26A2-related chondrodysplasias, achondrogenesis type IB (ACG1B) and atelosteogenesis type II (AO2), are phenocopied by slc26a2-/- mice.
    explanation: >-
      The study directly validates the null mouse as a model of the lethal human
      SLC26A2 spectrum.
  - reference: PMID:30685387
    reference_title: Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2-/- newborns.
    explanation: >-
      This supports a preclinical prenatal intervention signal without implying
      human efficacy or trial availability.
clinical_trials: []
datasets: []
notes: >-
  AOII is curated as SLC26A2-related atelosteogenesis, not as an FLNB disorder.
  Its usual perinatal lethality is not absolute. Residual sulfate-transport
  activity contributes to the ACG1B-AOII-DTD-rMED severity continuum, but
  published families and functional testing show that genotype alone does not
  perfectly predict the named clinical subtype. The Slc26a2-null
  UPR-FGFR3/FGFR-inhibitor work is preclinical and is therefore represented as
  a provisional mechanism and animal-model finding rather than a treatment.
review_notes: >-
  Full re-review completed against the pinned Orphadata 2025-12-09 snapshot and
  literature caches. ClinicalTrials.gov API exact-condition searches for
  "Atelosteogenesis type II" and AOII returned no disease-specific studies on
  2026-07-20; seven broad full-text matches were unrelated studies and were
  excluded. No AOII-specific public molecular dataset was identified, so both
  clinical_trials and datasets are intentionally empty. Orphanet frequency
  bands are retained as curated categorical assertions and are not converted
  into unsupported exact percentages.
references:
- reference: ORPHA:56304
  title: Atelosteogenesis type II
  findings: []
- reference: PMID:20301493
  title: "SLC26A2-Related Atelosteogenesis."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:8571951
  title: "Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias."
  findings: []
- reference: PMID:11448940
  title: "Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype."
  findings: []
- reference: PMID:9133349
  title: "Atelosteogenesis syndromes: a review, with comments on their pathogenesis."
  findings: []
- reference: PMID:1279661
  title: "Atelosteogenesis type II: sonographic and radiological correlation."
  findings: []
- reference: PMID:3799721
  title: "de la Chapelle dysplasia."
  findings: []
- reference: PMID:16752402
  title: Mutations in two regions of FLNB result in atelosteogenesis I and III.
  findings: []
- reference: PMID:10076882
  title: "Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission."
  findings: []
- reference: PMID:21077202
  title: "Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family."
  findings: []
- reference: PMID:30685387
  title: Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
  findings: []
📚

References & Deep Research

References

11
ORPHA:56304
Atelosteogenesis type II
No top-level findings curated for this source.
PMID:20301493
SLC26A2-Related Atelosteogenesis.
No top-level findings curated for this source.
PMID:8571951
Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.
No top-level findings curated for this source.
PMID:11448940
Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype.
No top-level findings curated for this source.
PMID:9133349
Atelosteogenesis syndromes: a review, with comments on their pathogenesis.
No top-level findings curated for this source.
PMID:1279661
Atelosteogenesis type II: sonographic and radiological correlation.
No top-level findings curated for this source.
PMID:3799721
de la Chapelle dysplasia.
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:10076882
Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission.
No top-level findings curated for this source.
PMID:21077202
Genotype-phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family.
No top-level findings curated for this source.
PMID:30685387
Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias.
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).