Steel Syndrome

Mendelian MONDO:0014061 Pathograph 36 Show in embeddings browser Skeletal dysplasia Osteochondrodysplasia

Steel syndrome (STLS, MIM #615155) is a rare autosomal recessive osteochondrodysplasia caused by biallelic pathogenic variants in COL27A1, the gene encoding the pro-alpha-1 chain of fibrillar collagen type XXVII. It was delineated in 1993 by H. H. Steel in twenty-three Puerto Rican children who shared bilateral irreducible hip dislocation, dislocated radial heads, carpal coalitions, short stature, scoliosis and pes cavus, with a characteristic long oval face, prominent forehead, hypertelorism and broad nasal bridge. The causative gene was identified in 2015, when a homozygous p.(Gly697Arg) missense variant was found to segregate in a non-consanguineous Puerto Rican family; that allele is a Puerto Rican founder mutation and accounts for most molecularly confirmed cases. Non-Puerto Rican families carry private missense, frameshift and splice alleles, and these tend to produce a more severe, loss-of-function phenotype that extends the syndrome to congenital sensorineural hearing loss and, in isolated reports, ocular coloboma, cleft palate, and dental and genital anomalies. Collagen XXVII is a minor fibrillar collagen of the cartilage pericellular matrix that is most abundant in the proliferative and prehypertrophic zones of the growth plate and at the primary ossification centre, where cartilage is calcified and replaced by bone. Loss or structural disruption of the protein does not block chondrocyte differentiation; instead it disorganises the pericellular matrix, collapses the proliferative zone and abolishes the columnar arrangement of chondrocytes, so endochondral bone growth and the ossification of articular elements proceed abnormally. This produces the short stature, the under-ossified and dysplastic femoral heads and acetabula, the absent capitulum humeri that underlies radial head dislocation, and the axial deformity of the syndrome. Management is entirely supportive and orthopaedic; surgical reduction of the dislocated hips has an unfavourable record, with every operatively augmented reduction in the original series redislocating.

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1
Inheritance
7
Pathophys.
28
Phenotypes
1
Gaps
36
Pathograph
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Genes
5
Medical Actions
2
Models
3
References
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Inheritance

1
Autosomal recessive HP:0000007
Steel syndrome segregates as an autosomal recessive trait. Affected individuals are homozygous or compound heterozygous for COL27A1 variants and unaffected parents are heterozygous carriers; heterozygotes have neither short stature nor congenital hip dislocation.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:32376988 SUPPORT Human Clinical
"We have demonstrated apodictically that Steel syndrome is an AR disorder clinically characterized by congenital bilateral hip dislocation, short stature, scoliosis, radial head dislocation, carpal coalitions, and foot deformities"
States the autosomal recessive mode of inheritance for Steel syndrome.
PMID:28276056 SUPPORT Human Clinical
"Exome sequencing identified 2 novel compound heterozygous variants c.521_528del (p.(Cys174Serfs*34)) and c.2119C>T (p.(Arg707*)) in COL27A1 in this child and the parents were heterozygous carriers."
Biallelic variants in the proband with heterozygous unaffected parents fit recessive inheritance.
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Discussions and Knowledge Gaps

1
Why is loss of collagen XXVII perinatally lethal from a lung defect in mice while humans with markedly reduced or absent COL27A1 protein survive with no reported respiratory disease, and what does that species difference imply for using the murine growth-plate phenotype as a model of the human lesion?
HUMAN MODEL MISMATCH OPEN hmm_col27a1_murine_lung_lethality
Attached to
pathophysiology#Structurally Defective or Absent Collagen XXVII pathophysiology#Collapse of the Growth Plate Proliferative Zone
Both published mouse models, the engineered 87-amino-acid deletion and the knock-in of the human founder allele, kill most homozygotes perinatally through a lung defect or presumed respiratory insufficiency. Human patients carrying frameshift, nonsense and splice alleles that abolish the protein are viable and are not reported to have respiratory problems. The growth-plate readouts from these mice are the main mechanistic evidence in this entry, so the weight they can carry depends on whether the murine dependence on collagen XXVII in lung is a species-specific requirement or a difference in residual protein.
Proposed experiments
Cross-species comparison of the collagen XXVII requirement in lung
exp_col27a1_lung_requirement
Compare COL27A1 expression, matrix localisation and pulmonary architecture in human fetal lung against mouse, and assess pulmonary function and imaging in a cohort of adults with biallelic loss-of-function COL27A1 alleles, to establish whether the murine lung requirement has a human counterpart that has simply not been looked for.
Would support
pathophysiology#Structurally Defective or Absent Collagen XXVII
Show evidence (2 references)
PMID:32376988 SUPPORT Human Clinical
"Interestingly, STLS patients do not appear to have respiratory problems or lung abnormalities."
States the human side of the mismatch, with no respiratory phenotype despite loss-of-function alleles.
PMID:22206015 SUPPORT Model Organism
"Mice expressing an 87 amino acid deletion in the collagenous domain of collagen XXVII were phenotypically normal as heterozygotes whereas homozygotes exhibited a severe chondrodysplasia and died perinatally from a lung defect."
States the murine side of the mismatch, perinatal lethality from a lung defect.
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Pathophysiology

7
COL27A1 Biallelic Pathogenic Variants
Steel syndrome is initiated by biallelic pathogenic variants in COL27A1 on chromosome 9q32. The Puerto Rican founder allele c.2089G>C substitutes arginine for a conserved glycine of a Gly-Xaa-Yaa repeat inside the triple-helical domain. Elsewhere in the world, private missense alleles and null alleles (frameshift, nonsense, splice-site and multi-exon deletion) have been reported in consanguineous and non-consanguineous families.
COL27A1 hgnc:22986 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COL27A1 (hgnc:22986). hgnc:22986 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Structurally Defective or Absent Collagen XXVII Missense glycine substitutions in the triple helix yield a misfolded protein, while frameshift and splice alleles introduce premature termination codons whose transcripts are cleared, so both classes converge on a deficit of functional collagen XXVII.
Show evidence (2 references)
PMID:24986830 SUPPORT Human Clinical
"We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity."
Identifies COL27A1 as the causative gene and names the founder missense allele.
PMID:35568358 SUPPORT Human Clinical
"Seven missense variants and eight null variants are reported in COL27A1 until date."
Documents that the allelic spectrum comprises both missense and null variants.
Structurally Defective or Absent Collagen XXVII
Collagen XXVII is a fibrillar collagen whose triple-helical domain depends on an uninterrupted Gly-Xaa-Yaa repeat. Substituting a helical glycine causes modest endoplasmic-reticulum retention of the mutant protein in chondrogenic cells, consistent with abnormal folding and impaired secretion, and behaves as a hypomorph; null alleles remove the protein outright.
COL27A1 hgnc:22986 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COL27A1 (hgnc:22986). hgnc:22986 is a gene from the HUGO Gene Nomenclature Committee.
collagen biosynthetic process GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology. ↓ DECREASED retention of misfolded procollagen XXVII in the endoplasmic reticulum GO:0006621 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased retention of misfolded procollagen XXVII in the endoplasmic reticulum, annotated with protein retention in ER lumen (GO:0006621). GO:0006621 is a biological process from the Gene Ontology. ↑ INCREASED
extracellular matrix structural constituent conferring tensile strength GO:0030020 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased extracellular matrix structural constituent conferring tensile strength (GO:0030020). GO:0030020 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Growth Plate Pericellular Matrix Collagen XXVII normally accumulates in the pericellular matrix around growth-plate chondrocytes, so its structural disruption or absence is directly a defect of that matrix.
Collagen XXVII Deficiency in Inner Ear Cartilage The same collagen deficit applies wherever the protein is normally deposited, and the gene is expressed in the cartilaginous structures of the developing inner ear. This is the branch point at which the auditory arm of the phenotype separates from the growth-plate arm.
Show evidence (2 references)
PMID:24986830 SUPPORT Human Clinical
"This p.(Gly697Arg) variant most likely leads to a hypomorphic allele, since all carrier individuals are phenotypically normal."
Characterises the founder allele as hypomorphic rather than a complete null.
PMID:32376988 SUPPORT In Vitro
"Our experiments showed modest ER-retention of the mutant proteins as compared with the WT in both W20 and ATDC5 cells"
Cell-based assay showing that the glycine substitutions impair folding and retain the protein in the ER.
Disrupted Growth Plate Pericellular Matrix
Collagen XXVII is expressed throughout the growth plate, most strongly in the resting and proliferative zones, and accumulates in the pericellular matrix around chondrocytes at the cartilage-to-bone transition. In mice expressing a mutant form the pericellular matrix of proliferative chondrocytes is disrupted, and the knock-in of the human founder allele shows abnormal collagen deposition in the extracellular matrix.
growth plate chondrocyte CL:1000217 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves growth plate chondrocyte, annotated with growth plate cartilage chondrocyte (CL:1000217). CL:1000217 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Cartilage-specific Col27a1 87-amino-acid deletion mouse Mus musculus recapitulates Cartilage-targeted disruption of collagen XXVII directly demonstrates that the protein organises the pericellular matrix and the proliferative zone.
Downstream
Collapse of the Growth Plate Proliferative Zone The pericellular matrix is the scaffold that lets proliferative chondrocytes flatten and stack into columns; when it is disorganised, that architecture fails.
Show evidence (3 references)
PMID:17693149 SUPPORT Human Clinical
"Immunohistochemical analyses showed that type XXVII collagen was most evident in hypertrophic cartilage at the primary ossification center and at the growth plate and that it accumulated in the pericellular matrix."
Localises collagen XXVII protein to the growth-plate pericellular matrix in developing human skeletal tissue.
PMID:22206015 SUPPORT Model Organism
"The pericellular matrix of proliferative chondrocytes was disrupted and the proliferative cells exhibited a decreased tendency to flatten and form vertical columns."
Directly demonstrates pericellular matrix disruption when collagen XXVII is mutated.
PMID:32376988 SUPPORT Model Organism
"Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate."
Confirms abnormal matrix collagen deposition in a knock-in model of the human founder allele.
Collapse of the Growth Plate Proliferative Zone
Chondrocytes still differentiate, but they lose their columnar organisation. Homozygous knock-in mice carrying the murine equivalent of the Steel founder allele lose the normal architecture of the proliferative zone, with absence and disorganisation of columnar chondrocytes, while proteoglycan accumulation, mineralisation, and collagen II and X staining are not overtly changed. Human fetal material shows the corresponding lesion, with severely disorganised metaphyseal cartilage and hypercellular resting cartilage arranged in irregular nests bounded by acellular matrix.
growth plate chondrocyte CL:1000217 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves growth plate chondrocyte, annotated with growth plate cartilage chondrocyte (CL:1000217). CL:1000217 is a cell type from the Cell Ontology.
regulation of growth plate cartilage chondrocyte proliferation GO:0003420 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of growth plate cartilage chondrocyte proliferation (GO:0003420). GO:0003420 is a biological process from the Gene Ontology. ⚠ ABNORMAL cartilage development GO:0051216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cartilage development (GO:0051216). GO:0051216 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Col27a1 G682R knock-in mouse (Steel founder allele) Mus musculus recapitulates The knock-in reproduces the growth-plate lesion attributed to the human founder allele, with loss of the proliferative-zone architecture and of columnar chondrocytes.
Downstream
Impaired Endochondral Bone Growth Columnar proliferative chondrocytes drive longitudinal growth, so their loss prevents normal endochondral bone growth.
Show evidence (4 references)
PMID:32376988 SUPPORT Model Organism
"Stained sections of femoral and tibial growth plates of homozygous KI mice showed loss of the normal architecture of the proliferative zone with absence and disorganization of columnar chondrocytes"
Histological demonstration of proliferative-zone collapse in the knock-in model of the human founder allele.
PMID:33411029 SUPPORT Human Clinical
"Resting cartilage was hypercellular, organized in irregular nests limited by acellular matrix."
Human fetal histology showing the same loss of orderly chondrocyte arrangement.
PMID:33411029 SUPPORT Human Clinical
"Metaphyseal cartilage showed severe disorganization."
Confirms metaphyseal cartilage disorganisation in molecularly confirmed human fetuses.
+ 1 more reference
Impaired Endochondral Bone Growth
Cartilage calcification and its replacement by bone are the processes in which collagen XXVII normally participates. With the growth plate disorganised, longitudinal growth is curtailed and the ossification of epiphyseal and articular elements is delayed or incomplete.
hypertrophic chondrocyte CL:0000743 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hypertrophic chondrocyte (CL:0000743). CL:0000743 is a cell type from the Cell Ontology.
endochondral ossification GO:0001958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endochondral ossification (GO:0001958). GO:0001958 is a biological process from the Gene Ontology. ↓ DECREASED bone development GO:0060348 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal bone development (GO:0060348). GO:0060348 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Col27a1 G682R knock-in mouse (Steel founder allele) Mus musculus partially recapitulates Homozygotes reproduce reduced body length, scoliosis and a rounded skull, the growth consequences of the human lesion.
Downstream
Short stature
Scoliosis
Delayed femoral head ossification
Dysplastic Articular Element Formation Articular surfaces are themselves products of endochondral ossification, so the same defect leaves epiphyses under-ossified and joint-forming elements malformed or absent.
Rhizomelia The proximal long bones are the segments most dependent on growth-plate output, so a proliferative-zone defect shortens them disproportionately.
Hyperlordosis Lordosis accompanies the scoliosis as part of the axial deformity that follows impaired vertebral endochondral growth.
Short middle phalanx of finger The phalanges are endochondral bones, so shortened middle phalanges are a direct expression of the same growth deficit that shortens the long bones.
Pectus excavatum The chest wall deformity is grouped with the other consequences of abnormal cartilage growth at the costochondral junctions; the intermediate steps are not established.
Prominent forehead The cranial base is endochondral bone, and the knock-in mouse reproduces an altered skull shape, which is the mechanistic basis for grouping the craniofacial features under the same growth defect. The intermediate steps in humans are not established.
Wide nasal bridge
Hypertelorism
Midface retrusion
Show evidence (2 references)
PMID:17693149 SUPPORT Human Clinical
"The timing and location of synthesis suggest that type XXVII collagen plays a role during the calcification of cartilage and the transition of cartilage to bone."
Places collagen XXVII at the cartilage-to-bone transition that is impaired in the disease.
PMID:22206015 SUPPORT Model Organism
"Animals expressing the 87 amino acid deletion targeted specifically to cartilage were viable but severely dwarfed."
Cartilage-restricted disruption of collagen XXVII is sufficient to stunt skeletal growth.
Dysplastic Articular Element Formation
Joint-forming skeletal elements are malformed. Radiographs in the gene-discovery family showed dislocated femoral heads with under-ossification of the capital femoral epiphysis and shallow acetabula; fetal autopsy showed bilateral absence of the capitulum humeri, which mechanically explains the dislocated radial heads. Failure of orderly cartilage segmentation and ossification in the wrist yields carpal coalitions.
skeletal system development GO:0001501 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal skeletal system development (GO:0001501). GO:0001501 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Congenital hip dislocation
Dislocated radial head
Carpal synostosis
Delayed ossification of carpal bones
Patellar dislocation The same failure of articular element formation that dislocates the hip and radial head applies at the knee, where a dysplastic trochlear groove permits dislocation.
Genu valgum Knee deformity is a recurrent feature and is grouped here with the other dysplastic articular consequences; the intermediate steps between the growth-plate lesion and the valgus alignment are not established.
Pes cavus Foot deformity follows the same pattern of dysplastic articular element formation in the tarsus; the intermediate steps are not established.
Rocker bottom foot The vertical-talus foot deformity reported in fetal Steel syndrome is grouped with the other dysplastic articular consequences in the tarsus.
Hypoplasia of the odontoid process The odontoid process is an endochondral element of the axis, and its hypoplasia is the cervical-spine expression of the same defective articular element formation. It is the feature behind the atlantoaxial instability surveillance in this entry.
Clinodactyly of the 5th finger Fifth-finger clinodactyly reflects dysplastic formation of the middle phalanx, the same class of lesion seen in the carpus.
Show evidence (2 references)
PMID:33411029 SUPPORT Human Clinical
"Bilateral capitulum humeri absence explained radial head dislocation in STLS."
Identifies the structural skeletal defect that produces radial head dislocation.
PMID:24986830 SUPPORT Human Clinical
"radiographs of the lower extremities showed bilateral hip dislocations, poorly ossified femoral heads and shallow bilateral acetabula"
Documents under-ossified femoral heads and shallow acetabula, the dysplastic articular elements of the hip.
Collagen XXVII Deficiency in Inner Ear Cartilage
Col27a1 is expressed in the cartilaginous structures of the developing inner ear and in the cochlear epithelium in mouse, which offers a route from the same collagen deficit to the sensorineural hearing loss seen in patients with severe and loss-of-function COL27A1 alleles. In patients homozygous for the milder Puerto Rican founder missense allele, hearing loss appears instead in adult life.
cartilage development GO:0051216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cartilage development (GO:0051216). GO:0051216 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Sensorineural hearing impairment
Show evidence (2 references)
PMID:32376988 SUPPORT Model Organism
"Mouse Col27a1 was found to be expressed in the cartilaginous structures associated with inner ear development and cochlear epithelium"
Establishes an inner-ear expression domain for the gene, the anatomical basis for the auditory phenotype.
PMID:32376988 SUPPORT Human Clinical
"all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
Documents adult-onset bilateral hearing loss in molecularly confirmed founder-allele homozygotes.
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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 Steel Syndrome 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

28
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28322503 SUPPORT Human Clinical
"In addition, the affected child had severe non-progressive sensorineural hearing loss not reported previously."
First report extending the Steel syndrome phenotype to sensorineural hearing loss.
PMID:32376988 SUPPORT Human Clinical
"all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
Shows adult-onset hearing loss in founder-allele homozygotes, an age-dependent presentation.
Eye 2
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33963180 SUPPORT Human Clinical
"Physical examination revealed prominent forehead, hypertelorism, broad nasal bridge, midface hypoplasia with mild prognathism, pectus excavatum, short hands, genu valgum, and fixed patellar dislocation on the right side"
Records hypertelorism in a molecularly confirmed patient.
Coloboma HP:0000589 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iris and chorioretinal coloboma, annotated with Coloboma (HP:0000589). HP:0000589 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31913554 SUPPORT Human Clinical
"However, she was also born with bilateral colobomata of the irides and choroido-retinae with unilateral affection of the macula."
The single reported ocular finding, in a molecularly confirmed patient.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral cryptorchidism, annotated with Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33963180 SUPPORT Human Clinical
"routine newborn examinations revealed bilateral cryptorchidism and bilateral hearing impairment"
Documents bilateral cryptorchidism in a molecularly confirmed patient.
PMID:33359165 SUPPORT Human Clinical
"we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome"
Reports genital anomalies as a newly observed feature in COL27A1 disease.
Head and Neck 5
Abnormality of the dentition OCCASIONAL HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental abnormality, annotated with Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33359165 SUPPORT Human Clinical
"These novel, compound heterozygous COL27A1 variants might indicate an association of the gene with tooth and genital abnormalities."
The authors' own conclusion that COL27A1 may be associated with tooth abnormalities; the hedged wording is why this is recorded as occasional and single-report.
Prominent forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead with frontal bossing, annotated with Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24986830 SUPPORT Human Clinical
"Oval-shaped face with prominent forehead and mild frontal bossing and broad nasal bridge in both patients."
Describes the facial gestalt in the two siblings of the gene-discovery family.
Wide nasal bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal bridge, annotated with Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24986830 SUPPORT Human Clinical
"Oval-shaped face with prominent forehead and mild frontal bossing and broad nasal bridge in both patients."
Documents the broad nasal bridge in the gene-discovery family.
Midface retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface hypoplasia, annotated with Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24986830 SUPPORT Human Clinical
"showed short stature (<5%), mild midface hypoplasia with slightly anteverted nares, bilateral fifth finger clinodactyly, decreased adduction of the hips bilaterally"
Documents midface hypoplasia on follow-up of the gene-discovery siblings.
Cleft palate 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 (1 reference)
PMID:35568358 SUPPORT Human Clinical
"We describe for the first time, cleft palate and delayed carpal bone ossification as features of Steel syndrome."
First description of cleft palate as a Steel syndrome feature.
Limbs 12
Cutaneous syndactyly HP:0012725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild skin syndactyly, annotated with Cutaneous syndactyly (HP:0012725). HP:0012725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32360765 SUPPORT Human Clinical
"The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss."
Documents mild skin syndactyly in a molecularly confirmed patient.
Short middle phalanx of finger HP:0005819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short mid phalanges, annotated with Short middle phalanx of finger (HP:0005819). HP:0005819 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32360765 SUPPORT Human Clinical
"The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss."
Documents short middle phalanges in a molecularly confirmed patient.
Congenital hip dislocation VERY_FREQUENT HP:0001374 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral congenital hip dislocation, annotated with Congenital hip dislocation (HP:0001374). HP:0001374 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:8423186 SUPPORT Human Clinical
"Characteristics shared by all twenty-three children included Hispanic descent, residence in Puerto Rico, bilateral dislocation of the hip, dislocated radial heads, short stature, and other osseous anomalies."
Bilateral hip dislocation was present in every child of the defining series.
PMID:33411029 SUPPORT Human Clinical
"Steel syndrome (STLS) encompasses characteristic facies, dwarfness, irreducible bilateral hip and radial head dislocation, and carpal bone coalition due to COL27A1 mutations."
Records that the bilateral hip dislocation of Steel syndrome is characteristically irreducible.
Delayed femoral head ossification HP:0008829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Under-ossification of the capital femoral epiphysis, annotated with Delayed femoral head ossification (HP:0008829). HP:0008829 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32360765 SUPPORT Human Clinical
"The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss."
Reports absent hip ossification centres in a molecularly confirmed patient.
PMID:24986830 SUPPORT Human Clinical
"radiographs of the lower extremities showed bilateral hip dislocations, poorly ossified femoral heads and shallow bilateral acetabula"
Documents poorly ossified femoral heads in the gene-discovery family.
Dislocated radial head FREQUENT HP:0003083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dislocated radial head (HP:0003083). HP:0003083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8423186 SUPPORT Human Clinical
"Of the forty-six elbows in the twenty-three children, thirty-three were dislocated, as seen clinically and radiographically; eight were normal, both clinically and radiographically; and there was dysplasia at the radiocapitellar articulation of the remaining five."
Quantifies radial head dislocation across the elbows of the original cohort.
Carpal synostosis VERY_FREQUENT HP:0009702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carpal coalition, annotated with Carpal synostosis (HP:0009702). HP:0009702 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:8423186 SUPPORT Human Clinical
"Twenty of the twenty-three children were found to have carpal coalitions."
Establishes carpal coalition as a near-universal feature in the defining cohort.
PMID:24986830 SUPPORT Human Clinical
"Both had bilateral capitate and hamate bone coalitions"
Identifies capitate-hamate coalition as the specific fusion in the gene-discovery siblings.
Delayed ossification of carpal bones HP:0001216 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed carpal bone ossification, annotated with Delayed ossification of carpal bones (HP:0001216). HP:0001216 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35568358 SUPPORT Human Clinical
"We describe for the first time, cleft palate and delayed carpal bone ossification as features of Steel syndrome."
First report of delayed carpal ossification as a Steel syndrome feature.
Pes cavus OCCASIONAL HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes cavus, annotated with Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8423186 SUPPORT Human Clinical
"Eight patients had talipes cavus bilaterally, which was not treated."
Documents bilateral pes cavus in the original series.
Rocker bottom foot HP:0001838 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertical talus, annotated with Rocker bottom foot (HP:0001838). HP:0001838 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28276056 SUPPORT Human Clinical
"Steel syndrome is a rare disorder of the skeleton characterized by facial dysmorphism, short stature, carpal coalition, dislocated radial heads, bilateral hip dislocation and vertical talus."
Lists vertical talus among the defining skeletal features.
Genu valgum HP:0002857 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu valgum (HP:0002857). HP:0002857 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33963180 SUPPORT Human Clinical
"An 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome."
Reports genu valgum in a molecularly confirmed patient.
Patellar dislocation HP:0002999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fixed patellar dislocation, annotated with Patellar dislocation (HP:0002999). HP:0002999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33963180 SUPPORT Human Clinical
"An 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome."
Reports fixed patellar dislocation in a molecularly confirmed patient.
Clinodactyly of the 5th finger HP:0004209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral fifth finger clinodactyly, annotated with Clinodactyly of the 5th finger (HP:0004209). HP:0004209 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24986830 SUPPORT Human Clinical
"Follow-up examinations of patients II-1 and II-2 at 14 and 12 years of age, respectively, showed short stature (<5%), mild midface hypoplasia with slightly anteverted nares, bilateral fifth finger clinodactyly, decreased adduction of the hips bilaterally andpes planus."
Records bilateral fifth finger clinodactyly in the gene-discovery siblings.
PMID:35568358 SUPPORT Human Clinical
"Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
Confirms fifth finger clinodactyly across the mutation-proven cohort.
Musculoskeletal 4
Hyperlordosis HP:0003307 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lordosis, annotated with Hyperlordosis (HP:0003307). HP:0003307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35568358 SUPPORT Human Clinical
"Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
Lists lordosis among the recurrent features of the syndrome.
Pectus excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33963180 SUPPORT Human Clinical
"Physical examination revealed prominent forehead, hypertelorism, broad nasal bridge, midface hypoplasia with mild prognathism, pectus excavatum, short hands, genu valgum, and fixed patellar dislocation on the right side"
Documents pectus excavatum in a patient with biallelic COL27A1 variants.
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8423186 SUPPORT Human Clinical
"Fourteen children had scoliosis, and five of them were managed with spinal arthrodesis and correction."
Quantifies scoliosis frequency and its surgical burden in the original cohort.
Hypoplasia of the odontoid process HP:0003311 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Odontoid hypoplasia, annotated with Hypoplasia of the odontoid process (HP:0003311). HP:0003311 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:8423186 SUPPORT Human Clinical
"Three patients had an anomaly of the cervical spine, with one deformity causing symptoms and signs that were treated with decompression."
Documents symptomatic cervical spine anomaly in the original cohort.
PMID:24986830 SUPPORT Human Clinical
"The cervical spine was significant for odontoid hypoplasia."
Odontoid hypoplasia in the proband of the gene-discovery family.
Nervous System 1
Global developmental delay OCCASIONAL HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35568358 SUPPORT Human Clinical
"Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
Lists developmental delay among the features of mutation-proven Steel syndrome.
PMID:24986830 REFUTE Human Clinical
"Patient II-1 had unilateral radial head dislocation. Both had normal intelligence."
In the gene-discovery family both affected siblings had normal intelligence, so developmental delay is not a constant feature.
Growth 2
Rhizomelia 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 (1 reference)
PMID:33359165 SUPPORT Human Clinical
"we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome"
Documents rhizomelia in two brothers with confirmed biallelic COL27A1 variants.
Short stature VERY_FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35568358 SUPPORT Human Clinical
"Short stature and dislocation/subluxation of hip joint are consistently observed."
A review of all mutation-proven patients reports short stature as consistently present.
PMID:8423186 SUPPORT Human Clinical
"Characteristics shared by all twenty-three children included Hispanic descent, residence in Puerto Rico, bilateral dislocation of the hip, dislocated radial heads, short stature, and other osseous anomalies."
Short stature was shared by all twenty-three children in the original series.
🧬

Genetic Associations

1
COL27A1 biallelic pathogenic variants (Causative)
Gene: COL27A1 hgnc:22986 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COL27A1 (hgnc:22986). hgnc:22986 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (3 references)
PMID:24986830 SUPPORT Human Clinical
"We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity."
Establishes COL27A1 as the causative gene for Steel syndrome.
PMID:24986830 SUPPORT Human Clinical
"Interestingly, the identified variant seems to have arisen as a founder mutation in the Puerto Rican population."
Records the founder-allele origin of the common Puerto Rican variant.
PMID:31913554 SUPPORT Human Clinical
"The condition is caused by a deficient matrix protein, collagen type XXVII alpha 1 chain, due to bi-allelic loss of function mutations in the gene COL27A1."
States the biallelic loss-of-function mechanism and the deficient matrix protein.
💊

Medical Actions

5
Hip Reduction Surgery
Action: hip reduction surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hip reduction surgery, annotated with Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Platform: Surgery
Operative reduction of the dislocated hips has an unfavourable record in Steel syndrome. In the original series every hip treated by reduction augmented by an operation redislocated, and among closed reductions the results were satisfactory only in patients still skeletally immature at review. Untreated hips functioned satisfactorily over the reported follow-up. This history is why surgical reduction is approached cautiously rather than as routine.
Mechanism Target:
Congenital hip dislocation — The operation addresses the dislocated hip itself, not the underlying collagen defect.
Show evidence (2 references)
PMID:8423186 REFUTE Human Clinical
"Eighteen hips in nine patients were treated with a reduction augmented by some form of operation. All of these hips redislocated."
Every operatively augmented reduction failed, which argues against surgical reduction as an effective treatment.
PMID:8423186 SUPPORT Human Clinical
"Of these eight patients, the four who were skeletally immature at the time of the review had a satisfactory result, and the four who were skeletally mature had an unsatisfactory result because of discomfort or fibrous ankylosis."
Closed reduction gave satisfactory results only in patients not yet skeletally mature, the qualified benefit this entry records.
Spinal Arthrodesis for Scoliosis
Action: spinal arthrodesis with correctionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is spinal arthrodesis with correction, annotated with Spinal Fusion (NCIT:C157986). NCIT:C157986 is a clinical intervention from the NCI Thesaurus. Ontology label: Spinal Fusion NCIT:C157986
Platform: Surgery
Progressive scoliosis is managed by spinal arthrodesis with correction. Five of the fourteen children with scoliosis in the original series were treated this way.
Mechanism Target:
Scoliosis — Arthrodesis corrects and stabilises the curve; it does not alter the growth-plate lesion that produced it.
Show evidence (1 reference)
PMID:8423186 SUPPORT Human Clinical
"Fourteen children had scoliosis, and five of them were managed with spinal arthrodesis and correction."
Documents spinal arthrodesis as the scoliosis management used in the original cohort.
Cervical Spine Surveillance and Decompression
Action: cervical spinal decompressionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cervical spinal decompression, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Cervical spine anomalies including odontoid hypoplasia occur and may become symptomatic; one child in the original series required decompression. Cervical imaging before general anaesthesia and before elective spinal procedures is prudent for that reason.
Mechanism Target:
Hypoplasia of the odontoid process — Decompression relieves cord or root compression arising from the cervical anomaly.
Show evidence (1 reference)
PMID:8423186 SUPPORT Human Clinical
"Three patients had an anomaly of the cervical spine, with one deformity causing symptoms and signs that were treated with decompression."
Records symptomatic cervical spine anomaly treated by decompression in Steel syndrome.
Hearing Amplification
Action: hearing amplification with a hearing aidNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing amplification with a hearing aid, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
Hearing loss is congenital in patients with severe or loss-of-function alleles and adult-onset in founder-allele homozygotes. A patient with congenital hearing impairment was fitted with a hearing aid in infancy. The audiologic assessment that detects the deficit, and the lifelong surveillance the adult-onset form requires, are diagnostic activities and are recorded under diagnosis rather than here.
Mechanism Target:
Sensorineural hearing impairment — Assessment and amplification address the hearing deficit; neither modifies the collagen defect.
Show evidence (2 references)
PMID:32376988 SUPPORT Human Clinical
"all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
Adult-onset hearing loss in founder-allele homozygotes is why surveillance must continue into adulthood.
PMID:33963180 SUPPORT Human Clinical
"At 1 year of age, he underwent orchiopexy and was provided with a hearing aid."
Documents hearing amplification as the management used for congenital hearing impairment in Steel syndrome.
Genetic Counseling and Carrier Testing
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. NCIT:C15240
Platform: Behavioral / lifestyle
Identification of COL27A1 enables molecular confirmation, carrier testing for relatives and recurrence-risk counselling. This matters particularly in Puerto Rican families, where a single founder allele can be targeted directly and the estimated carrier frequency is about one in fifty-one.
Show evidence (2 references)
PMID:24986830 SUPPORT Human Clinical
"will enable molecular testing for individuals with the clinical presentation characteristic of Steel syndrome, as well as genetic counseling for carrier individuals"
The gene-discovery paper names carrier genetic counselling as a direct clinical consequence of the finding.
PMID:32376988 SUPPORT Human Clinical
"It has been estimated that the carrier frequency for the COL27A1 c.2089G>C (p.Gly697Arg) variant in Puerto Ricans is 1:51"
Quantifies the carrier burden that makes targeted carrier testing worthwhile in this population.
🔬

Diagnosis

2
Clinical, Radiographic and Molecular Diagnosis
Steel syndrome is suspected from the combination of short stature, bilateral irreducible hip dislocation, dislocated radial heads, carpal coalition, scoliosis and the characteristic facies, and is confirmed by finding biallelic COL27A1 variants. Targeted testing for the c.2089G>C p.(Gly697Arg) allele is appropriate in patients of Puerto Rican ancestry; exome sequencing is used otherwise, and copy-number analysis matters because at least one reported allele is a multi-exon deletion.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:24986830 SUPPORT Human Clinical
"Based on the clinical and radiographic findings in all three children, a clinical diagnosis of Steel syndrome was made."
Shows that the diagnosis is made clinically and radiographically before molecular confirmation.
PMID:33963180 SUPPORT Human Clinical
"The maternal mutation was a large deletion encompassing exons 38-60, which was challenging to detect."
Justifies including copy-number analysis in the molecular workup.
Audiologic Assessment and Surveillance
Audiologic assessment belongs in the initial workup and should be repeated through adult life. The reason surveillance cannot stop in childhood is that the two allele classes differ in timing: hearing loss is congenital with severe or loss-of-function alleles but first appears after the age of thirty in founder-allele homozygotes.
audiometric assessment NCIT:C38036 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:32376988 SUPPORT Human Clinical
"all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
Adult-onset hearing loss in founder-allele homozygotes is why audiologic surveillance must continue into adulthood.
PMID:28322503 SUPPORT Human Clinical
"we conclude that the novel splice-site variant identified in COL27A1 is the most likely cause for Steel syndrome in this family and that the hearing loss is part of this syndrome's phenotype"
Establishes hearing loss as part of the syndrome, which is what puts audiologic assessment in the workup.
📊

Prevalence

2
Puerto Rico
Carrier Frequency 1960.8 per 100,000 >1 in 1,000 (carriers)
Published carrier-frequency estimate of 1:51 for the COL27A1 c.2089G>C (p.Gly697Arg) founder allele in Puerto Ricans, normalised to 1960.8 carriers per 100,000. This is a heterozygous carrier rate, not a disease prevalence, and it applies only to the single founder allele.
Show evidence (1 reference)
PMID:32376988 SUPPORT Human Clinical
"It has been estimated that the carrier frequency for the COL27A1 c.2089G>C (p.Gly697Arg) variant in Puerto Ricans is 1:51"
Source of the founder-allele carrier frequency in the Puerto Rican population.
Worldwide
Cases In Literature Unknown
No population-based prevalence estimate exists. Case counting is the only available measure. 51 patients had been reported by 2020, of whom 14 were genetically confirmed, and a 2022 review recorded disease-causing variants in twenty Puerto Rican and nine non-Puerto Rican families. The two counts use different inclusion rules and should not be combined.
Show evidence (2 references)
PMID:31903681 SUPPORT Human Clinical
"There are now 51 patients in the literature with Steel syndrome, including the 3 patients in this article, and 14 patients with a genetically confirmed Steel syndrome diagnosis."
Gives the cumulative reported case count and the molecularly confirmed subset.
PMID:35568358 SUPPORT Human Clinical
"However, disease causing variants have been identified only in twenty Puerto Rican and nine non-Puerto Rican families."
Independent review confirming that molecularly solved families remain few and are concentrated in Puerto Rico.
🐁

Animal Models

2
Col27a1 G682R knock-in mouse (Steel founder allele)
A mouse carrying the murine orthologue of the human Steel syndrome founder allele p.Gly697Arg. Homozygotes are dwarfed and kyphotic with a shorter snout and a rounded skull, and their growth plates lose the columnar architecture of the proliferative zone. Most homozygotes die perinatally, presumably from respiratory insufficiency, which human patients do not show.
Reduced body length Scoliosis Rounded skull shape
Species
Mus musculus
Genotype
Col27a1 G682R knock-in, homozygous and heterozygous
Genes
COL27A1 hgnc:22986 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns COL27A1 (hgnc:22986). hgnc:22986 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:32376988
Pathograph links
Collapse of the Growth Plate Proliferative Zone recapitulates fidelity: high The knock-in reproduces the growth-plate lesion attributed to the human founder allele, with loss of the proliferative-zone architecture and of columnar chondrocytes.
Limitations: Proteoglycan accumulation, mineralisation and collagen II and X staining were not overtly different from wild type, so the model speaks to chondrocyte architecture rather than to matrix mineralisation.
Readouts
Columnar chondrocyte organisation in the femoral and tibial growth plate
Direction: ABOLISHED
Interpretation: Histological correlate of proliferative-zone collapse in homozygous knock-in mice.
Show evidence (1 reference)
PMID:32376988 SUPPORT Model Organism
"Stained sections of femoral and tibial growth plates of homozygous KI mice showed loss of the normal architecture of the proliferative zone with absence and disorganization of columnar chondrocytes"
Reports the histological measurement behind this readout.
Show evidence (1 reference)
PMID:32376988 SUPPORT Model Organism
"Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate."
Supports treating this model as informative for the growth-plate node.
Impaired Endochondral Bone Growth partially recapitulates fidelity: moderate Homozygotes reproduce reduced body length, scoliosis and a rounded skull, the growth consequences of the human lesion.
Limitations: Most homozygous knock-in mice die perinatally from presumed respiratory insufficiency, a lethality with no counterpart in Steel syndrome patients, so the severity of the murine growth phenotype overstates the human one.
Show evidence (1 reference)
PMID:32376988 SUPPORT Model Organism
"We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
States which human skeletal features the model reproduces and that the recapitulation is partial.
Show evidence (1 reference)
PMID:32376988 SUPPORT Model Organism
"Our STLS KI animal model (Col27a1G682R/G682R) recapitulates the short stature and some of the skeletal abnormalities observed in the human subjects, however most homozygous KI mice die perinatally, presumably due to respiratory insufficiency consistent with previous Col27a1 mouse models"
Establishes the model as an allele-matched in vivo system and states its principal limitation.
Cartilage-specific Col27a1 87-amino-acid deletion mouse
Mice expressing an 87-amino-acid deletion in the collagenous domain of collagen XXVII. Ubiquitous homozygotes have severe chondrodysplasia and die perinatally from a lung defect; restricting the deletion to cartilage makes them viable but severely dwarfed, with a disrupted pericellular matrix around proliferative chondrocytes.
Severe dwarfism Disrupted pericellular matrix
Species
Mus musculus
Genotype
Col27a1 87-amino-acid collagenous-domain deletion, cartilage-targeted homozygote
Genes
COL27A1 hgnc:22986 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns COL27A1 (hgnc:22986). hgnc:22986 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:22206015
Pathograph links
Disrupted Growth Plate Pericellular Matrix recapitulates fidelity: moderate Cartilage-targeted disruption of collagen XXVII directly demonstrates that the protein organises the pericellular matrix and the proliferative zone.
Limitations: An engineered 87-amino-acid in-frame deletion is not an allele observed in patients, and the ubiquitous homozygote is perinatally lethal from a lung defect that Steel syndrome patients do not have.
Readouts
Pericellular matrix organisation around proliferative chondrocytes
Direction: ALTERED
Interpretation: Structural correlate of the pericellular matrix node in this model.
Show evidence (1 reference)
PMID:22206015 SUPPORT Model Organism
"The pericellular matrix of proliferative chondrocytes was disrupted and the proliferative cells exhibited a decreased tendency to flatten and form vertical columns."
Reports the histological observation behind this readout.
Show evidence (1 reference)
PMID:22206015 SUPPORT Model Organism
"Collagen XXVII plays an important structural role in the pericellular extracellular matrix of the growth plate and is required for the organisation of the proliferative zone."
Supports treating this model as informative for the pericellular matrix node.
Show evidence (1 reference)
PMID:22206015 SUPPORT Model Organism
"Animals expressing the 87 amino acid deletion targeted specifically to cartilage were viable but severely dwarfed."
Establishes the cartilage-restricted model and its skeletal phenotype.
{ }

Source YAML

click to show 
name: Steel Syndrome
synonyms:
- STLS
- Steel syndrome
- dislocated hips and radial heads, carpal coalition, scoliosis, and short stature
- bilateral hip and radial head dislocations-short stature-scoliosis-carpal coalitions-pes
  cavus-facial dysmorphism syndrome
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
description: >
  Steel syndrome (STLS, MIM #615155) is a rare autosomal recessive osteochondrodysplasia
  caused by biallelic pathogenic variants in COL27A1, the gene encoding the pro-alpha-1
  chain of fibrillar collagen type XXVII. It was delineated in 1993 by H. H. Steel in
  twenty-three Puerto Rican children who shared bilateral irreducible hip dislocation,
  dislocated radial heads, carpal coalitions, short stature, scoliosis and pes cavus,
  with a characteristic long oval face, prominent forehead, hypertelorism and broad nasal
  bridge. The causative gene was identified in 2015, when a homozygous p.(Gly697Arg)
  missense variant was found to segregate in a non-consanguineous Puerto Rican family;
  that allele is a Puerto Rican founder mutation and accounts for most molecularly
  confirmed cases. Non-Puerto Rican families carry private missense, frameshift and
  splice alleles, and these tend to produce a more severe, loss-of-function phenotype
  that extends the syndrome to congenital sensorineural hearing loss and, in isolated
  reports, ocular coloboma, cleft palate, and dental and genital anomalies.

  Collagen XXVII is a minor fibrillar collagen of the cartilage pericellular matrix that
  is most abundant in the proliferative and prehypertrophic zones of the growth plate and
  at the primary ossification centre, where cartilage is calcified and replaced by bone.
  Loss or structural disruption of the protein does not block chondrocyte differentiation;
  instead it disorganises the pericellular matrix, collapses the proliferative zone and
  abolishes the columnar arrangement of chondrocytes, so endochondral bone growth and the
  ossification of articular elements proceed abnormally. This produces the short stature,
  the under-ossified and dysplastic femoral heads and acetabula, the absent capitulum
  humeri that underlies radial head dislocation, and the axial deformity of the syndrome.
  Management is entirely supportive and orthopaedic; surgical reduction of the dislocated
  hips has an unfavourable record, with every operatively augmented reduction in the
  original series redislocating.
disease_term:
  preferred_term: Steel syndrome
  term:
    id: MONDO:0014061
    label: Steel syndrome
parents:
- Skeletal dysplasia
- Osteochondrodysplasia
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Steel syndrome segregates as an autosomal recessive trait. Affected individuals are
    homozygous or compound heterozygous for COL27A1 variants and unaffected parents are
    heterozygous carriers; heterozygotes have neither short stature nor congenital hip
    dislocation.
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have demonstrated apodictically that Steel syndrome is an AR disorder clinically characterized by congenital bilateral hip dislocation, short stature, scoliosis, radial head dislocation, carpal coalitions, and foot deformities"
    explanation: States the autosomal recessive mode of inheritance for Steel syndrome.
  - reference: PMID:28276056
    reference_title: "Second family provides further evidence for causation of Steel syndrome by biallelic mutations in COL27A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified 2 novel compound heterozygous variants c.521_528del (p.(Cys174Serfs*34)) and c.2119C>T (p.(Arg707*)) in COL27A1 in this child and the parents were heterozygous carriers."
    explanation: Biallelic variants in the proband with heterozygous unaffected parents fit recessive inheritance.
prevalence:
- population: Puerto Rico
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1960.8
  notes: >-
    Published carrier-frequency estimate of 1:51 for the COL27A1 c.2089G>C (p.Gly697Arg)
    founder allele in Puerto Ricans, normalised to 1960.8 carriers per 100,000. This is a
    heterozygous carrier rate, not a disease prevalence, and it applies only to the single
    founder allele.
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It has been estimated that the carrier frequency for the COL27A1 c.2089G>C (p.Gly697Arg) variant in Puerto Ricans is 1:51"
    explanation: Source of the founder-allele carrier frequency in the Puerto Rican population.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population-based prevalence estimate exists. Case counting is the only available
    measure. 51 patients had been reported by 2020, of whom 14 were genetically confirmed,
    and a 2022 review recorded disease-causing variants in twenty Puerto Rican and nine
    non-Puerto Rican families. The two counts use different inclusion rules and should not
    be combined.
  evidence:
  - reference: PMID:31903681
    reference_title: "Three new patients with Steel syndrome and a Puerto Rican specific COL27A1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are now 51 patients in the literature with Steel syndrome, including the 3 patients in this article, and 14 patients with a genetically confirmed Steel syndrome diagnosis."
    explanation: Gives the cumulative reported case count and the molecularly confirmed subset.
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, disease causing variants have been identified only in twenty Puerto Rican and nine non-Puerto Rican families."
    explanation: Independent review confirming that molecularly solved families remain few and are concentrated in Puerto Rico.
pathophysiology:
- name: COL27A1 Biallelic Pathogenic Variants
  biological_scale: MOLECULAR
  description: >
    Steel syndrome is initiated by biallelic pathogenic variants in COL27A1 on chromosome
    9q32. The Puerto Rican founder allele c.2089G>C substitutes arginine for a conserved
    glycine of a Gly-Xaa-Yaa repeat inside the triple-helical domain. Elsewhere in the
    world, private missense alleles and null alleles (frameshift, nonsense, splice-site
    and multi-exon deletion) have been reported in consanguineous and non-consanguineous
    families.
  genes:
  - preferred_term: COL27A1
    term:
      id: hgnc:22986
      label: COL27A1
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity."
    explanation: Identifies COL27A1 as the causative gene and names the founder missense allele.
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven missense variants and eight null variants are reported in COL27A1 until date."
    explanation: Documents that the allelic spectrum comprises both missense and null variants.
  downstream:
  - target: Structurally Defective or Absent Collagen XXVII
    causal_link_type: DIRECT
    description: >
      Missense glycine substitutions in the triple helix yield a misfolded protein, while
      frameshift and splice alleles introduce premature termination codons whose
      transcripts are cleared, so both classes converge on a deficit of functional
      collagen XXVII.
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The two additional variants reported here are predicted to introduce frameshift or splice changes that result in the introduction of early termination codons that lead to nonsense mediated processing and clearance of the mutant transcripts, effectively resulting in loss-of-function (LoF) alleles with consequent loss of the COL27A1 protein."
      explanation: States the step from null COL27A1 alleles to loss of the protein product.
- name: Structurally Defective or Absent Collagen XXVII
  biological_scale: MOLECULAR
  description: >
    Collagen XXVII is a fibrillar collagen whose triple-helical domain depends on an
    uninterrupted Gly-Xaa-Yaa repeat. Substituting a helical glycine causes modest
    endoplasmic-reticulum retention of the mutant protein in chondrogenic cells,
    consistent with abnormal folding and impaired secretion, and behaves as a hypomorph;
    null alleles remove the protein outright.
  genes:
  - preferred_term: COL27A1
    term:
      id: hgnc:22986
      label: COL27A1
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent conferring tensile strength
    term:
      id: GO:0030020
      label: extracellular matrix structural constituent conferring tensile strength
    modifier: DECREASED
  biological_processes:
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: DECREASED
  - preferred_term: retention of misfolded procollagen XXVII in the endoplasmic reticulum
    term:
      id: GO:0006621
      label: protein retention in ER lumen
    modifier: INCREASED
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This p.(Gly697Arg) variant most likely leads to a hypomorphic allele, since all carrier individuals are phenotypically normal."
    explanation: Characterises the founder allele as hypomorphic rather than a complete null.
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our experiments showed modest ER-retention of the mutant proteins as compared with the WT in both W20 and ATDC5 cells"
    explanation: Cell-based assay showing that the glycine substitutions impair folding and retain the protein in the ER.
  downstream:
  - target: Disrupted Growth Plate Pericellular Matrix
    causal_link_type: DIRECT
    description: >
      Collagen XXVII normally accumulates in the pericellular matrix around growth-plate
      chondrocytes, so its structural disruption or absence is directly a defect of that
      matrix.
    evidence:
    - reference: PMID:22206015
      reference_title: "Collagen XXVII organises the pericellular matrix in the growth plate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Collagen XXVII plays an important structural role in the pericellular extracellular matrix of the growth plate and is required for the organisation of the proliferative zone."
      explanation: Establishes that mutant collagen XXVII acts by disorganising the growth-plate pericellular matrix.
  - target: Collagen XXVII Deficiency in Inner Ear Cartilage
    causal_link_type: DIRECT
    description: >
      The same collagen deficit applies wherever the protein is normally deposited, and
      the gene is expressed in the cartilaginous structures of the developing inner ear.
      This is the branch point at which the auditory arm of the phenotype separates from
      the growth-plate arm.
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mouse Col27a1 was found to be expressed in the cartilaginous structures associated with inner ear development and cochlear epithelium"
      explanation: Establishes the inner-ear expression domain that makes the cartilage there subject to the same collagen deficit.
- name: Disrupted Growth Plate Pericellular Matrix
  biological_scale: TISSUE
  description: >
    Collagen XXVII is expressed throughout the growth plate, most strongly in the resting
    and proliferative zones, and accumulates in the pericellular matrix around
    chondrocytes at the cartilage-to-bone transition. In mice expressing a mutant form the
    pericellular matrix of proliferative chondrocytes is disrupted, and the knock-in of
    the human founder allele shows abnormal collagen deposition in the extracellular
    matrix.
  cell_types:
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17693149
    reference_title: "Type XXVII collagen at the transition of cartilage to bone during skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemical analyses showed that type XXVII collagen was most evident in hypertrophic cartilage at the primary ossification center and at the growth plate and that it accumulated in the pericellular matrix."
    explanation: Localises collagen XXVII protein to the growth-plate pericellular matrix in developing human skeletal tissue.
  - reference: PMID:22206015
    reference_title: "Collagen XXVII organises the pericellular matrix in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The pericellular matrix of proliferative chondrocytes was disrupted and the proliferative cells exhibited a decreased tendency to flatten and form vertical columns."
    explanation: Directly demonstrates pericellular matrix disruption when collagen XXVII is mutated.
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate."
    explanation: Confirms abnormal matrix collagen deposition in a knock-in model of the human founder allele.
  downstream:
  - target: Collapse of the Growth Plate Proliferative Zone
    causal_link_type: DIRECT
    description: >
      The pericellular matrix is the scaffold that lets proliferative chondrocytes flatten
      and stack into columns; when it is disorganised, that architecture fails.
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However abnormal or absent collagen XXVII protein in the ECM results in collapse of the proliferative zone and disorganization of the cartilaginous zones of the growth plate preventing normal endochondral bone growth"
      explanation: States the causal step from abnormal matrix collagen XXVII to proliferative-zone collapse.
- name: Collapse of the Growth Plate Proliferative Zone
  biological_scale: CELLULAR
  description: >
    Chondrocytes still differentiate, but they lose their columnar organisation. Homozygous
    knock-in mice carrying the murine equivalent of the Steel founder allele lose the
    normal architecture of the proliferative zone, with absence and disorganisation of
    columnar chondrocytes, while proteoglycan accumulation, mineralisation, and collagen II
    and X staining are not overtly changed. Human fetal material shows the corresponding
    lesion, with severely disorganised metaphyseal cartilage and hypercellular resting
    cartilage arranged in irregular nests bounded by acellular matrix.
  cell_types:
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:1000217
      label: growth plate cartilage chondrocyte
  biological_processes:
  - preferred_term: regulation of growth plate cartilage chondrocyte proliferation
    term:
      id: GO:0003420
      label: regulation of growth plate cartilage chondrocyte proliferation
    modifier: ABNORMAL
  - preferred_term: cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Stained sections of femoral and tibial growth plates of homozygous KI mice showed loss of the normal architecture of the proliferative zone with absence and disorganization of columnar chondrocytes"
    explanation: Histological demonstration of proliferative-zone collapse in the knock-in model of the human founder allele.
  - reference: PMID:33411029
    reference_title: "Histopathology of recurrent Steel syndrome in fetuses caused by novel variants of COL27A1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Resting cartilage was hypercellular, organized in irregular nests limited by acellular matrix."
    explanation: Human fetal histology showing the same loss of orderly chondrocyte arrangement.
  - reference: PMID:33411029
    reference_title: "Histopathology of recurrent Steel syndrome in fetuses caused by novel variants of COL27A1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metaphyseal cartilage showed severe disorganization."
    explanation: Confirms metaphyseal cartilage disorganisation in molecularly confirmed human fetuses.
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "it appears that disease associated alterations in COL27A1 do not prevent chondrocytes from differentiating properly"
    explanation: Bounds the claim, since the lesion is architectural rather than a block of chondrocyte differentiation.
  downstream:
  - target: Impaired Endochondral Bone Growth
    causal_link_type: DIRECT
    description: >
      Columnar proliferative chondrocytes drive longitudinal growth, so their loss prevents
      normal endochondral bone growth.
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However abnormal or absent collagen XXVII protein in the ECM results in collapse of the proliferative zone and disorganization of the cartilaginous zones of the growth plate preventing normal endochondral bone growth"
      explanation: Names proliferative-zone collapse as what prevents normal endochondral bone growth.
- name: Impaired Endochondral Bone Growth
  biological_scale: TISSUE
  description: >
    Cartilage calcification and its replacement by bone are the processes in which collagen
    XXVII normally participates. With the growth plate disorganised, longitudinal growth is
    curtailed and the ossification of epiphyseal and articular elements is delayed or
    incomplete.
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  biological_processes:
  - preferred_term: endochondral ossification
    term:
      id: GO:0001958
      label: endochondral ossification
    modifier: DECREASED
  - preferred_term: bone development
    term:
      id: GO:0060348
      label: bone development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:17693149
    reference_title: "Type XXVII collagen at the transition of cartilage to bone during skeletogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The timing and location of synthesis suggest that type XXVII collagen plays a role during the calcification of cartilage and the transition of cartilage to bone."
    explanation: Places collagen XXVII at the cartilage-to-bone transition that is impaired in the disease.
  - reference: PMID:22206015
    reference_title: "Collagen XXVII organises the pericellular matrix in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Animals expressing the 87 amino acid deletion targeted specifically to cartilage were viable but severely dwarfed."
    explanation: Cartilage-restricted disruption of collagen XXVII is sufficient to stunt skeletal growth.
  downstream:
  - target: Short stature
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
      explanation: The knock-in of the human allele reproduces reduced body length, linking the growth-plate lesion to short stature.
  - target: Scoliosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
      explanation: The same knock-in reproduces scoliosis, tying axial deformity to the COL27A1 lesion.
  - target: Delayed femoral head ossification
    causal_link_type: DIRECT
  - target: Dysplastic Articular Element Formation
    causal_link_type: DIRECT
    description: >
      Articular surfaces are themselves products of endochondral ossification, so the same
      defect leaves epiphyses under-ossified and joint-forming elements malformed or absent.
  - target: Rhizomelia
    causal_link_type: DIRECT
    description: >
      The proximal long bones are the segments most dependent on growth-plate output, so a
      proliferative-zone defect shortens them disproportionately.
    evidence:
    - reference: PMID:33359165
      reference_title: "Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome"
      explanation: Documents rhizomelic limb shortening in molecularly confirmed COL27A1 siblings.
  - target: Hyperlordosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Lordosis accompanies the scoliosis as part of the axial deformity that follows
      impaired vertebral endochondral growth.
    evidence:
    - reference: PMID:35568358
      reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
      explanation: Lists lordosis among the recurrent axial features of the syndrome.
  - target: Short middle phalanx of finger
    causal_link_type: DIRECT
    description: >
      The phalanges are endochondral bones, so shortened middle phalanges are a direct
      expression of the same growth deficit that shortens the long bones.
    evidence:
    - reference: PMID:32360765
      reference_title: "First reported case of Steel syndrome in the European population: A novel homozygous mutation in COL27A1 and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss."
      explanation: Reports short mid phalanges together with the short stature produced by the same growth defect.
  - target: Pectus excavatum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The chest wall deformity is grouped with the other consequences of abnormal cartilage
      growth at the costochondral junctions; the intermediate steps are not established.
    evidence:
    - reference: PMID:33963180
      reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Physical examination revealed prominent forehead, hypertelorism, broad nasal bridge, midface hypoplasia with mild prognathism, pectus excavatum, short hands, genu valgum, and fixed patellar dislocation on the right side"
      explanation: Documents pectus excavatum in a molecularly confirmed patient.
  - target: Prominent forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The cranial base is endochondral bone, and the knock-in mouse reproduces an altered
      skull shape, which is the mechanistic basis for grouping the craniofacial features
      under the same growth defect. The intermediate steps in humans are not established.
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
      explanation: The knock-in reproduces altered skull shape, tying craniofacial form to the COL27A1 lesion.
  - target: Wide nasal bridge
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
      explanation: Groups the midface features with the altered skull shape reproduced in the model.
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
      explanation: Groups orbital spacing with the altered skull shape reproduced in the model.
  - target: Midface retrusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
      explanation: Groups midface hypoplasia with the altered skull shape reproduced in the model.
- name: Dysplastic Articular Element Formation
  biological_scale: TISSUE
  description: >
    Joint-forming skeletal elements are malformed. Radiographs in the gene-discovery family
    showed dislocated femoral heads with under-ossification of the capital femoral
    epiphysis and shallow acetabula; fetal autopsy showed bilateral absence of the
    capitulum humeri, which mechanically explains the dislocated radial heads. Failure of
    orderly cartilage segmentation and ossification in the wrist yields carpal coalitions.
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33411029
    reference_title: "Histopathology of recurrent Steel syndrome in fetuses caused by novel variants of COL27A1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bilateral capitulum humeri absence explained radial head dislocation in STLS."
    explanation: Identifies the structural skeletal defect that produces radial head dislocation.
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "radiographs of the lower extremities showed bilateral hip dislocations, poorly ossified femoral heads and shallow bilateral acetabula"
    explanation: Documents under-ossified femoral heads and shallow acetabula, the dysplastic articular elements of the hip.
  downstream:
  - target: Congenital hip dislocation
    causal_link_type: DIRECT
  - target: Dislocated radial head
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33411029
      reference_title: "Histopathology of recurrent Steel syndrome in fetuses caused by novel variants of COL27A1 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bilateral capitulum humeri absence explained radial head dislocation in STLS."
      explanation: States the causal link from the missing capitulum humeri to radial head dislocation.
  - target: Carpal synostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed ossification of carpal bones
    causal_link_type: DIRECT
  - target: Patellar dislocation
    causal_link_type: DIRECT
    description: >
      The same failure of articular element formation that dislocates the hip and radial
      head applies at the knee, where a dysplastic trochlear groove permits dislocation.
    evidence:
    - reference: PMID:33963180
      reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Physical examination revealed prominent forehead, hypertelorism, broad nasal bridge, midface hypoplasia with mild prognathism, pectus excavatum, short hands, genu valgum, and fixed patellar dislocation on the right side"
      explanation: Documents fixed patellar dislocation alongside the other articular dislocations in a molecularly confirmed patient.
  - target: Genu valgum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Knee deformity is a recurrent feature and is grouped here with the other dysplastic
      articular consequences; the intermediate steps between the growth-plate lesion and
      the valgus alignment are not established.
    evidence:
    - reference: PMID:33963180
      reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Physical examination revealed prominent forehead, hypertelorism, broad nasal bridge, midface hypoplasia with mild prognathism, pectus excavatum, short hands, genu valgum, and fixed patellar dislocation on the right side"
      explanation: Documents genu valgum in a molecularly confirmed patient.
  - target: Pes cavus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Foot deformity follows the same pattern of dysplastic articular element formation in
      the tarsus; the intermediate steps are not established.
    evidence:
    - reference: PMID:8423186
      reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eight patients had talipes cavus bilaterally, which was not treated."
      explanation: Records bilateral cavus foot deformity as a recurrent finding in the original patient series.
  - target: Rocker bottom foot
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The vertical-talus foot deformity reported in fetal Steel syndrome is grouped with
      the other dysplastic articular consequences in the tarsus.
    evidence:
    - reference: PMID:28276056
      reference_title: "Second family provides further evidence for causation of Steel syndrome by biallelic mutations in COL27A1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Steel syndrome is a rare disorder of the skeleton characterized by facial dysmorphism, short stature, carpal coalition, dislocated radial heads, bilateral hip dislocation and vertical talus."
      explanation: Names vertical talus, the deformity underlying rocker bottom foot, as a defining skeletal feature of the syndrome.
  - target: Hypoplasia of the odontoid process
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The odontoid process is an endochondral element of the axis, and its hypoplasia is
      the cervical-spine expression of the same defective articular element formation. It
      is the feature behind the atlantoaxial instability surveillance in this entry.
    evidence:
    - reference: PMID:24986830
      reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The cervical spine was significant for odontoid hypoplasia."
      explanation: Documents odontoid hypoplasia directly in a molecularly confirmed patient.
  - target: Clinodactyly of the 5th finger
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Fifth-finger clinodactyly reflects dysplastic formation of the middle phalanx, the
      same class of lesion seen in the carpus.
    evidence:
    - reference: PMID:35568358
      reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
      explanation: Lists fifth-finger clinodactyly among the recurrent skeletal features of the syndrome.
- name: Collagen XXVII Deficiency in Inner Ear Cartilage
  biological_scale: TISSUE
  description: >
    Col27a1 is expressed in the cartilaginous structures of the developing inner ear and in
    the cochlear epithelium in mouse, which offers a route from the same collagen deficit
    to the sensorineural hearing loss seen in patients with severe and loss-of-function
    COL27A1 alleles. In patients homozygous for the milder Puerto Rican founder missense
    allele, hearing loss appears instead in adult life.
  biological_processes:
  - preferred_term: cartilage development
    term:
      id: GO:0051216
      label: cartilage development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mouse Col27a1 was found to be expressed in the cartilaginous structures associated with inner ear development and cochlear epithelium"
    explanation: Establishes an inner-ear expression domain for the gene, the anatomical basis for the auditory phenotype.
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
    explanation: Documents adult-onset bilateral hearing loss in molecularly confirmed founder-allele homozygotes.
  downstream:
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28322503
      reference_title: "A novel aberrant splice site mutation in COL27A1 is responsible for Steel syndrome and extension of the phenotype to include hearing loss."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we conclude that the novel splice-site variant identified in COL27A1 is the most likely cause for Steel syndrome in this family and that the hearing loss is part of this syndrome's phenotype"
      explanation: Attributes the hearing loss to the COL27A1 lesion after excluding other candidate deafness variants.
phenotypes:
- category: Skeletal
  name: Rhizomelia
  description: >
    Disproportionate shortening of the proximal limb segments, reported in molecularly
    confirmed siblings alongside the characteristic hip dislocation.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: PMID:33359165
    reference_title: "Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome"
    explanation: Documents rhizomelia in two brothers with confirmed biallelic COL27A1 variants.
- category: Skeletal
  name: Hyperlordosis
  description: >
    Lordosis is reported alongside scoliosis as part of the axial deformity of the
    syndrome.
  phenotype_term:
    preferred_term: Lordosis
    term:
      id: HP:0003307
      label: Hyperlordosis
  evidence:
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
    explanation: Lists lordosis among the recurrent features of the syndrome.
- category: Skeletal
  name: Pectus excavatum
  description: >
    Anterior chest wall depression, reported on physical examination in a molecularly
    confirmed patient.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:33963180
    reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination revealed prominent forehead, hypertelorism, broad nasal bridge, midface hypoplasia with mild prognathism, pectus excavatum, short hands, genu valgum, and fixed patellar dislocation on the right side"
    explanation: Documents pectus excavatum in a patient with biallelic COL27A1 variants.
- category: Skeletal
  name: Cutaneous syndactyly
  description: >
    Mild skin syndactyly, reported in a single molecularly confirmed patient.
  phenotype_term:
    preferred_term: Mild skin syndactyly
    term:
      id: HP:0012725
      label: Cutaneous syndactyly
  evidence:
  - reference: PMID:32360765
    reference_title: "First reported case of Steel syndrome in the European population: A novel homozygous mutation in COL27A1 and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss."
    explanation: Documents mild skin syndactyly in a molecularly confirmed patient.
- category: Skeletal
  name: Short middle phalanx of finger
  description: >
    Shortened middle phalanges, reported in the same molecularly confirmed patient as the
    skin syndactyly.
  phenotype_term:
    preferred_term: Short mid phalanges
    term:
      id: HP:0005819
      label: Short middle phalanx of finger
  evidence:
  - reference: PMID:32360765
    reference_title: "First reported case of Steel syndrome in the European population: A novel homozygous mutation in COL27A1 and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss."
    explanation: Documents short middle phalanges in a molecularly confirmed patient.
- category: Dental
  name: Abnormality of the dentition
  frequency: OCCASIONAL
  description: >
    Dental abnormalities were reported in two molecularly confirmed brothers and have not
    been described in other Steel syndrome patients. The report does not specify which
    dental anomaly, so the general term is bound rather than a narrower one. This rests on
    a single report, the same standing as the coloboma, cleft palate and genital findings.
  phenotype_term:
    preferred_term: Dental abnormality
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:33359165
    reference_title: "Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These novel, compound heterozygous COL27A1 variants might indicate an association of the gene with tooth and genital abnormalities."
    explanation: The authors' own conclusion that COL27A1 may be associated with tooth abnormalities; the hedged wording is why this is recorded as occasional and single-report.
- category: Skeletal
  name: Short stature
  frequency: VERY_FREQUENT
  description: >
    Short stature is one of the two features found in essentially every reported patient.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short stature and dislocation/subluxation of hip joint are consistently observed."
    explanation: A review of all mutation-proven patients reports short stature as consistently present.
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristics shared by all twenty-three children included Hispanic descent, residence in Puerto Rico, bilateral dislocation of the hip, dislocated radial heads, short stature, and other osseous anomalies."
    explanation: Short stature was shared by all twenty-three children in the original series.
- category: Skeletal
  name: Congenital hip dislocation
  frequency: VERY_FREQUENT
  description: >
    Bilateral congenital dislocation of the hips, characteristically irreducible, is the
    presenting feature. Acetabular dysplasia and under-ossified capital femoral epiphyses
    accompany it.
  phenotype_term:
    preferred_term: Bilateral congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristics shared by all twenty-three children included Hispanic descent, residence in Puerto Rico, bilateral dislocation of the hip, dislocated radial heads, short stature, and other osseous anomalies."
    explanation: Bilateral hip dislocation was present in every child of the defining series.
  - reference: PMID:33411029
    reference_title: "Histopathology of recurrent Steel syndrome in fetuses caused by novel variants of COL27A1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Steel syndrome (STLS) encompasses characteristic facies, dwarfness, irreducible bilateral hip and radial head dislocation, and carpal bone coalition due to COL27A1 mutations."
    explanation: Records that the bilateral hip dislocation of Steel syndrome is characteristically irreducible.
- category: Skeletal
  name: Delayed femoral head ossification
  description: >
    The capital femoral epiphyses are under-ossified or their ossification centres are
    absent, contributing to the instability of the hip.
  phenotype_term:
    preferred_term: Under-ossification of the capital femoral epiphysis
    term:
      id: HP:0008829
      label: Delayed femoral head ossification
  evidence:
  - reference: PMID:32360765
    reference_title: "First reported case of Steel syndrome in the European population: A novel homozygous mutation in COL27A1 and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss."
    explanation: Reports absent hip ossification centres in a molecularly confirmed patient.
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "radiographs of the lower extremities showed bilateral hip dislocations, poorly ossified femoral heads and shallow bilateral acetabula"
    explanation: Documents poorly ossified femoral heads in the gene-discovery family.
- category: Skeletal
  name: Dislocated radial head
  frequency: FREQUENT
  description: >
    Dislocation of the radial heads, usually bilateral, restricts elbow extension and
    forearm rotation. In the original series thirty-three of forty-six elbows were
    dislocated and a further five showed radiocapitellar dysplasia.
  phenotype_term:
    preferred_term: Dislocated radial head
    term:
      id: HP:0003083
      label: Dislocated radial head
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the forty-six elbows in the twenty-three children, thirty-three were dislocated, as seen clinically and radiographically; eight were normal, both clinically and radiographically; and there was dysplasia at the radiocapitellar articulation of the remaining five."
    explanation: Quantifies radial head dislocation across the elbows of the original cohort.
- category: Skeletal
  name: Carpal synostosis
  frequency: VERY_FREQUENT
  description: >
    Carpal coalition, most often capitate-hamate fusion, is a hallmark radiographic sign.
    Twenty of the twenty-three children in the original series had carpal coalitions.
  phenotype_term:
    preferred_term: Carpal coalition
    term:
      id: HP:0009702
      label: Carpal synostosis
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty of the twenty-three children were found to have carpal coalitions."
    explanation: Establishes carpal coalition as a near-universal feature in the defining cohort.
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both had bilateral capitate and hamate bone coalitions"
    explanation: Identifies capitate-hamate coalition as the specific fusion in the gene-discovery siblings.
- category: Skeletal
  name: Delayed ossification of carpal bones
  description: >
    Delayed carpal bone ossification was described as a feature of Steel syndrome in a
    review that also added cleft palate to the phenotype.
  phenotype_term:
    preferred_term: Delayed carpal bone ossification
    term:
      id: HP:0001216
      label: Delayed ossification of carpal bones
  evidence:
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe for the first time, cleft palate and delayed carpal bone ossification as features of Steel syndrome."
    explanation: First report of delayed carpal ossification as a Steel syndrome feature.
- category: Skeletal
  name: Scoliosis
  frequency: FREQUENT
  description: >
    Scoliosis affected fourteen of the twenty-three children in the original series, five
    of whom required spinal arthrodesis.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fourteen children had scoliosis, and five of them were managed with spinal arthrodesis and correction."
    explanation: Quantifies scoliosis frequency and its surgical burden in the original cohort.
- category: Skeletal
  name: Pes cavus
  frequency: OCCASIONAL
  description: >
    Bilateral talipes cavus was present in eight of the twenty-three children originally
    described and was not treated.
  phenotype_term:
    preferred_term: Talipes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight patients had talipes cavus bilaterally, which was not treated."
    explanation: Documents bilateral pes cavus in the original series.
- category: Skeletal
  name: Rocker bottom foot
  description: >
    Vertical talus has been reported among the defining skeletal features in molecularly
    confirmed non-Puerto Rican patients.
  phenotype_term:
    preferred_term: Vertical talus
    term:
      id: HP:0001838
      label: Rocker bottom foot
  evidence:
  - reference: PMID:28276056
    reference_title: "Second family provides further evidence for causation of Steel syndrome by biallelic mutations in COL27A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Steel syndrome is a rare disorder of the skeleton characterized by facial dysmorphism, short stature, carpal coalition, dislocated radial heads, bilateral hip dislocation and vertical talus."
    explanation: Lists vertical talus among the defining skeletal features.
- category: Skeletal
  name: Hypoplasia of the odontoid process
  description: >
    Cervical spine anomalies, including odontoid hypoplasia, occur and can be symptomatic.
    One child in the original series required decompression.
  phenotype_term:
    preferred_term: Odontoid hypoplasia
    term:
      id: HP:0003311
      label: Hypoplasia of the odontoid process
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had an anomaly of the cervical spine, with one deformity causing symptoms and signs that were treated with decompression."
    explanation: Documents symptomatic cervical spine anomaly in the original cohort.
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cervical spine was significant for odontoid hypoplasia."
    explanation: Odontoid hypoplasia in the proband of the gene-discovery family.
- category: Skeletal
  name: Genu valgum
  description: >
    Knee deformity, including genu valgum and fixed patellar dislocation, has been reported.
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:33963180
    reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome."
    explanation: Reports genu valgum in a molecularly confirmed patient.
- category: Skeletal
  name: Patellar dislocation
  description: >
    Fixed patellar dislocation was described in a molecularly confirmed Korean patient.
  phenotype_term:
    preferred_term: Fixed patellar dislocation
    term:
      id: HP:0002999
      label: Patellar dislocation
  evidence:
  - reference: PMID:33963180
    reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome."
    explanation: Reports fixed patellar dislocation in a molecularly confirmed patient.
- category: Craniofacial
  name: Prominent forehead
  description: >
    A long oval face with a prominent forehead and mild frontal bossing is part of the
    characteristic facial gestalt.
  phenotype_term:
    preferred_term: Prominent forehead with frontal bossing
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oval-shaped face with prominent forehead and mild frontal bossing and broad nasal bridge in both patients."
    explanation: Describes the facial gestalt in the two siblings of the gene-discovery family.
- category: Craniofacial
  name: Wide nasal bridge
  description: >
    A broad nasal bridge accompanies the long oval face and prominent forehead.
  phenotype_term:
    preferred_term: Broad nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oval-shaped face with prominent forehead and mild frontal bossing and broad nasal bridge in both patients."
    explanation: Documents the broad nasal bridge in the gene-discovery family.
- category: Craniofacial
  name: Hypertelorism
  description: >
    Hypertelorism was among the dysmorphic features recorded when the original patients
    were re-evaluated, and it recurs in molecularly confirmed patients.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:33963180
    reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination revealed prominent forehead, hypertelorism, broad nasal bridge, midface hypoplasia with mild prognathism, pectus excavatum, short hands, genu valgum, and fixed patellar dislocation on the right side"
    explanation: Records hypertelorism in a molecularly confirmed patient.
- category: Craniofacial
  name: Midface retrusion
  description: >
    Mild midface hypoplasia, sometimes with slightly anteverted nares, is part of the
    facial phenotype.
  phenotype_term:
    preferred_term: Midface hypoplasia
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed short stature (<5%), mild midface hypoplasia with slightly anteverted nares, bilateral fifth finger clinodactyly, decreased adduction of the hips bilaterally"
    explanation: Documents midface hypoplasia on follow-up of the gene-discovery siblings.
- category: Craniofacial
  name: Cleft palate
  description: >
    Cleft palate was added to the Steel syndrome phenotype by a review of mutation-proven
    patients and rests on that single report.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe for the first time, cleft palate and delayed carpal bone ossification as features of Steel syndrome."
    explanation: First description of cleft palate as a Steel syndrome feature.
- category: Skeletal
  name: Clinodactyly of the 5th finger
  description: >
    Bilateral fifth finger clinodactyly is a recurrent minor limb anomaly.
  phenotype_term:
    preferred_term: Bilateral fifth finger clinodactyly
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Follow-up examinations of patients II-1 and II-2 at 14 and 12 years of age, respectively,
      showed short stature (<5%), mild midface hypoplasia with slightly anteverted nares, bilateral
      fifth finger clinodactyly, decreased adduction of the hips bilaterally andpes planus.
    explanation: Records bilateral fifth finger clinodactyly in the gene-discovery siblings.
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
    explanation: Confirms fifth finger clinodactyly across the mutation-proven cohort.
- category: Neurosensory
  name: Sensorineural hearing impairment
  description: >
    Sensorineural hearing loss is not part of the original Puerto Rican description but is
    common in patients with severe or loss-of-function COL27A1 alleles, in whom it is
    congenital; in founder-allele homozygotes it appears in adult life.
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:28322503
    reference_title: "A novel aberrant splice site mutation in COL27A1 is responsible for Steel syndrome and extension of the phenotype to include hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, the affected child had severe non-progressive sensorineural hearing loss not reported previously."
    explanation: First report extending the Steel syndrome phenotype to sensorineural hearing loss.
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
    explanation: Shows adult-onset hearing loss in founder-allele homozygotes, an age-dependent presentation.
- category: Ocular
  name: Coloboma
  description: >
    Bilateral colobomata of the irides and choroido-retinae were reported in a single
    Syrian patient with compound heterozygous frameshift alleles, with no alternative
    cause identified. This remains an isolated observation.
  phenotype_term:
    preferred_term: Iris and chorioretinal coloboma
    term:
      id: HP:0000589
      label: Coloboma
  evidence:
  - reference: PMID:31913554
    reference_title: "A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, she was also born with bilateral colobomata of the irides and choroido-retinae with unilateral affection of the macula."
    explanation: The single reported ocular finding, in a molecularly confirmed patient.
- category: Genitourinary
  name: Cryptorchidism
  description: >
    Bilateral cryptorchidism has been reported in a molecularly confirmed patient, and
    genital anomalies were highlighted in a sibling pair with compound heterozygous
    variants.
  phenotype_term:
    preferred_term: Bilateral cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:33963180
    reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "routine newborn examinations revealed bilateral cryptorchidism and bilateral hearing impairment"
    explanation: Documents bilateral cryptorchidism in a molecularly confirmed patient.
  - reference: PMID:33359165
    reference_title: "Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome"
    explanation: Reports genital anomalies as a newly observed feature in COL27A1 disease.
- category: Neurodevelopmental
  name: Global developmental delay
  frequency: OCCASIONAL
  description: >
    Intelligence was normal in the gene-discovery family, but developmental delay is listed
    among the features of the wider mutation-proven cohort, so it is inconstant rather than
    characteristic.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35568358
    reference_title: "Steel syndrome: Report of three patients, including monozygotic twins and review of clinical and mutation profiles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay."
    explanation: Lists developmental delay among the features of mutation-proven Steel syndrome.
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient II-1 had unilateral radial head dislocation. Both had normal intelligence."
    explanation: In the gene-discovery family both affected siblings had normal intelligence, so developmental delay is not a constant feature.
genetic:
- name: COL27A1 biallelic pathogenic variants
  gene_term:
    preferred_term: COL27A1
    term:
      id: hgnc:22986
      label: COL27A1
  association: Causative
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal recessive
  frequency: the single known disease gene for Steel syndrome
  notes: >
    COL27A1 lies on chromosome 9q32, spans 61 exons and encodes a 1860-amino-acid
    pro-peptide of fibrillar collagen type XXVII. The Puerto Rican founder allele
    c.2089G>C p.(Gly697Arg) replaces a conserved glycine of the Gly-Xaa-Yaa repeat in the
    triple-helical domain and behaves as a hypomorph; carriers are phenotypically normal.
    Reported non-founder alleles include missense (p.Gly802Glu, p.Gly841Arg, p.Gly850Arg,
    p.Gly676Arg, p.Ala99Thr, p.Pro1019His), frameshift, nonsense, splice-site and
    multi-exon deletion variants.
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity."
    explanation: Establishes COL27A1 as the causative gene for Steel syndrome.
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, the identified variant seems to have arisen as a founder mutation in the Puerto Rican population."
    explanation: Records the founder-allele origin of the common Puerto Rican variant.
  - reference: PMID:31913554
    reference_title: "A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The condition is caused by a deficient matrix protein, collagen type XXVII alpha 1 chain, due to bi-allelic loss of function mutations in the gene COL27A1."
    explanation: States the biallelic loss-of-function mechanism and the deficient matrix protein.
  case_fractions:
  - population: Molecularly confirmed patients reported to 2020
    notes: >-
      Eight of the eleven patients with homozygous COL27A1 mutations reported before 2020
      carried the p.Gly697Arg founder allele, so the founder allele accounted for the
      majority of solved cases at that time.
    evidence:
    - reference: PMID:31903681
      reference_title: "Three new patients with Steel syndrome and a Puerto Rican specific COL27A1 mutation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eleven patients have previously been described with Steel syndrome and homozygous COL27A1 mutations, with eight having an apparent founder mutation, p.Gly697Arg."
      explanation: Gives the founder-allele share of previously reported homozygous patients.
animal_models:
- name: Col27a1 G682R knock-in mouse (Steel founder allele)
  species: Mus musculus
  genotype: Col27a1 G682R knock-in, homozygous and heterozygous
  genes:
  - preferred_term: COL27A1
    term:
      id: hgnc:22986
      label: COL27A1
  publication: PMID:32376988
  description: >
    A mouse carrying the murine orthologue of the human Steel syndrome founder allele
    p.Gly697Arg. Homozygotes are dwarfed and kyphotic with a shorter snout and a rounded
    skull, and their growth plates lose the columnar architecture of the proliferative
    zone. Most homozygotes die perinatally, presumably from respiratory insufficiency,
    which human patients do not show.
  associated_phenotypes:
  - Reduced body length
  - Scoliosis
  - Rounded skull shape
  modeled_mechanisms:
  - target: Collapse of the Growth Plate Proliferative Zone
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      The knock-in reproduces the growth-plate lesion attributed to the human founder
      allele, with loss of the proliferative-zone architecture and of columnar
      chondrocytes.
    limitations: >-
      Proteoglycan accumulation, mineralisation and collagen II and X staining were not
      overtly different from wild type, so the model speaks to chondrocyte architecture
      rather than to matrix mineralisation.
    readouts:
    - name: Columnar chondrocyte organisation in the femoral and tibial growth plate
      target: Collapse of the Growth Plate Proliferative Zone
      direction: ABOLISHED
      interpretation: >-
        Histological correlate of proliferative-zone collapse in homozygous knock-in mice.
      evidence:
      - reference: PMID:32376988
        reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Stained sections of femoral and tibial growth plates of homozygous KI mice showed loss of the normal architecture of the proliferative zone with absence and disorganization of columnar chondrocytes"
        explanation: Reports the histological measurement behind this readout.
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate."
      explanation: Supports treating this model as informative for the growth-plate node.
  - target: Impaired Endochondral Bone Growth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >
      Homozygotes reproduce reduced body length, scoliosis and a rounded skull, the growth
      consequences of the human lesion.
    limitations: >-
      Most homozygous knock-in mice die perinatally from presumed respiratory
      insufficiency, a lethality with no counterpart in Steel syndrome patients, so the
      severity of the murine growth phenotype overstates the human one.
    evidence:
    - reference: PMID:32376988
      reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape."
      explanation: States which human skeletal features the model reproduces and that the recapitulation is partial.
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our STLS KI animal model (Col27a1G682R/G682R) recapitulates the short stature and some of the skeletal abnormalities observed in the human subjects, however most homozygous KI mice die perinatally, presumably due to respiratory insufficiency consistent with previous Col27a1 mouse models"
    explanation: Establishes the model as an allele-matched in vivo system and states its principal limitation.
- name: Cartilage-specific Col27a1 87-amino-acid deletion mouse
  species: Mus musculus
  genotype: Col27a1 87-amino-acid collagenous-domain deletion, cartilage-targeted homozygote
  genes:
  - preferred_term: COL27A1
    term:
      id: hgnc:22986
      label: COL27A1
  publication: PMID:22206015
  description: >
    Mice expressing an 87-amino-acid deletion in the collagenous domain of collagen XXVII.
    Ubiquitous homozygotes have severe chondrodysplasia and die perinatally from a lung
    defect; restricting the deletion to cartilage makes them viable but severely dwarfed,
    with a disrupted pericellular matrix around proliferative chondrocytes.
  associated_phenotypes:
  - Severe dwarfism
  - Disrupted pericellular matrix
  modeled_mechanisms:
  - target: Disrupted Growth Plate Pericellular Matrix
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >
      Cartilage-targeted disruption of collagen XXVII directly demonstrates that the
      protein organises the pericellular matrix and the proliferative zone.
    limitations: >-
      An engineered 87-amino-acid in-frame deletion is not an allele observed in patients,
      and the ubiquitous homozygote is perinatally lethal from a lung defect that Steel
      syndrome patients do not have.
    readouts:
    - name: Pericellular matrix organisation around proliferative chondrocytes
      target: Disrupted Growth Plate Pericellular Matrix
      direction: ALTERED
      interpretation: >-
        Structural correlate of the pericellular matrix node in this model.
      evidence:
      - reference: PMID:22206015
        reference_title: "Collagen XXVII organises the pericellular matrix in the growth plate."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The pericellular matrix of proliferative chondrocytes was disrupted and the proliferative cells exhibited a decreased tendency to flatten and form vertical columns."
        explanation: Reports the histological observation behind this readout.
    evidence:
    - reference: PMID:22206015
      reference_title: "Collagen XXVII organises the pericellular matrix in the growth plate."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Collagen XXVII plays an important structural role in the pericellular extracellular matrix of the growth plate and is required for the organisation of the proliferative zone."
      explanation: Supports treating this model as informative for the pericellular matrix node.
  evidence:
  - reference: PMID:22206015
    reference_title: "Collagen XXVII organises the pericellular matrix in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Animals expressing the 87 amino acid deletion targeted specifically to cartilage were viable but severely dwarfed."
    explanation: Establishes the cartilage-restricted model and its skeletal phenotype.
diagnosis:
- name: Clinical, Radiographic and Molecular Diagnosis
  description: >
    Steel syndrome is suspected from the combination of short stature, bilateral
    irreducible hip dislocation, dislocated radial heads, carpal coalition, scoliosis and
    the characteristic facies, and is confirmed by finding biallelic COL27A1 variants.
    Targeted testing for the c.2089G>C p.(Gly697Arg) allele is appropriate in patients of
    Puerto Rican ancestry; exome sequencing is used otherwise, and copy-number analysis
    matters because at least one reported allele is a multi-exon deletion.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the clinical and radiographic findings in all three children, a clinical diagnosis of Steel syndrome was made."
    explanation: Shows that the diagnosis is made clinically and radiographically before molecular confirmation.
  - reference: PMID:33963180
    reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The maternal mutation was a large deletion encompassing exons 38-60, which was challenging to detect."
    explanation: Justifies including copy-number analysis in the molecular workup.
- name: Audiologic Assessment and Surveillance
  description: >
    Audiologic assessment belongs in the initial workup and should be repeated through
    adult life. The reason surveillance cannot stop in childhood is that the two allele
    classes differ in timing: hearing loss is congenital with severe or loss-of-function
    alleles but first appears after the age of thirty in founder-allele homozygotes.
  diagnosis_term:
    preferred_term: audiometric assessment
    term:
      id: NCIT:C38036
      label: Audiometric Test
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
    explanation: Adult-onset hearing loss in founder-allele homozygotes is why audiologic surveillance must continue into adulthood.
  - reference: PMID:28322503
    reference_title: "A novel aberrant splice site mutation in COL27A1 is responsible for Steel syndrome and extension of the phenotype to include hearing loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we conclude that the novel splice-site variant identified in COL27A1 is the most likely cause for Steel syndrome in this family and that the hearing loss is part of this syndrome's phenotype"
    explanation: Establishes hearing loss as part of the syndrome, which is what puts audiologic assessment in the workup.
treatments:
- name: Hip Reduction Surgery
  description: >
    Operative reduction of the dislocated hips has an unfavourable record in Steel
    syndrome. In the original series every hip treated by reduction augmented by an
    operation redislocated, and among closed reductions the results were satisfactory only
    in patients still skeletally immature at review. Untreated hips functioned
    satisfactorily over the reported follow-up. This history is why surgical reduction is
    approached cautiously rather than as routine.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: hip reduction surgery
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Congenital hip dislocation
    description: >
      The operation addresses the dislocated hip itself, not the underlying collagen
      defect.
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighteen hips in nine patients were treated with a reduction augmented by some form of operation. All of these hips redislocated."
    explanation: Every operatively augmented reduction failed, which argues against surgical reduction as an effective treatment.
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these eight patients, the four who were skeletally immature at the time of the review had a satisfactory result, and the four who were skeletally mature had an unsatisfactory result because of discomfort or fibrous ankylosis."
    explanation: Closed reduction gave satisfactory results only in patients not yet skeletally mature, the qualified benefit this entry records.
- name: Spinal Arthrodesis for Scoliosis
  description: >
    Progressive scoliosis is managed by spinal arthrodesis with correction. Five of the
    fourteen children with scoliosis in the original series were treated this way.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: spinal arthrodesis with correction
    term:
      id: NCIT:C157986
      label: Spinal Fusion
  target_mechanisms:
  - target: Scoliosis
    description: >
      Arthrodesis corrects and stabilises the curve; it does not alter the growth-plate
      lesion that produced it.
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fourteen children had scoliosis, and five of them were managed with spinal arthrodesis and correction."
    explanation: Documents spinal arthrodesis as the scoliosis management used in the original cohort.
- name: Cervical Spine Surveillance and Decompression
  description: >
    Cervical spine anomalies including odontoid hypoplasia occur and may become
    symptomatic; one child in the original series required decompression. Cervical imaging
    before general anaesthesia and before elective spinal procedures is prudent for that
    reason.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cervical spinal decompression
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Hypoplasia of the odontoid process
    description: >
      Decompression relieves cord or root compression arising from the cervical anomaly.
  evidence:
  - reference: PMID:8423186
    reference_title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had an anomaly of the cervical spine, with one deformity causing symptoms and signs that were treated with decompression."
    explanation: Records symptomatic cervical spine anomaly treated by decompression in Steel syndrome.
- name: Hearing Amplification
  description: >
    Hearing loss is congenital in patients with severe or loss-of-function alleles and
    adult-onset in founder-allele homozygotes. A patient with congenital hearing
    impairment was fitted with a hearing aid in infancy. The audiologic assessment that
    detects the deficit, and the lifelong surveillance the adult-onset form requires, are
    diagnostic activities and are recorded under diagnosis rather than here.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing amplification with a hearing aid
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  target_mechanisms:
  - target: Sensorineural hearing impairment
    description: >
      Assessment and amplification address the hearing deficit; neither modifies the
      collagen defect.
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all three affected individuals presented with bilateral hearing loss with onset after 30 years of age"
    explanation: Adult-onset hearing loss in founder-allele homozygotes is why surveillance must continue into adulthood.
  - reference: PMID:33963180
    reference_title: "Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 1 year of age, he underwent orchiopexy and was provided with a hearing aid."
    explanation: Documents hearing amplification as the management used for congenital hearing impairment in Steel syndrome.
- name: Genetic Counseling and Carrier Testing
  description: >
    Identification of COL27A1 enables molecular confirmation, carrier testing for relatives
    and recurrence-risk counselling. This matters particularly in Puerto Rican families,
    where a single founder allele can be targeted directly and the estimated carrier
    frequency is about one in fifty-one.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24986830
    reference_title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "will enable molecular testing for individuals with the clinical presentation characteristic of Steel syndrome, as well as genetic counseling for carrier individuals"
    explanation: The gene-discovery paper names carrier genetic counselling as a direct clinical consequence of the finding.
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It has been estimated that the carrier frequency for the COL27A1 c.2089G>C (p.Gly697Arg) variant in Puerto Ricans is 1:51"
    explanation: Quantifies the carrier burden that makes targeted carrier testing worthwhile in this population.
discussions:
- discussion_id: hmm_col27a1_murine_lung_lethality
  prompt: >-
    Why is loss of collagen XXVII perinatally lethal from a lung defect in mice while
    humans with markedly reduced or absent COL27A1 protein survive with no reported
    respiratory disease, and what does that species difference imply for using the murine
    growth-plate phenotype as a model of the human lesion?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Structurally Defective or Absent Collagen XXVII
  - pathophysiology#Collapse of the Growth Plate Proliferative Zone
  rationale: >-
    Both published mouse models, the engineered 87-amino-acid deletion and the knock-in of
    the human founder allele, kill most homozygotes perinatally through a lung defect or
    presumed respiratory insufficiency. Human patients carrying frameshift, nonsense and
    splice alleles that abolish the protein are viable and are not reported to have
    respiratory problems. The growth-plate readouts from these mice are the main
    mechanistic evidence in this entry, so the weight they can carry depends on whether
    the murine dependence on collagen XXVII in lung is a species-specific requirement or a
    difference in residual protein.
  proposed_experiments:
  - experiment_id: exp_col27a1_lung_requirement
    name: Cross-species comparison of the collagen XXVII requirement in lung
    description: >-
      Compare COL27A1 expression, matrix localisation and pulmonary architecture in human
      fetal lung against mouse, and assess pulmonary function and imaging in a cohort of
      adults with biallelic loss-of-function COL27A1 alleles, to establish whether the
      murine lung requirement has a human counterpart that has simply not been looked for.
    would_support:
    - pathophysiology#Structurally Defective or Absent Collagen XXVII
  evidence:
  - reference: PMID:32376988
    reference_title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, STLS patients do not appear to have respiratory problems or lung abnormalities."
    explanation: States the human side of the mismatch, with no respiratory phenotype despite loss-of-function alleles.
  - reference: PMID:22206015
    reference_title: "Collagen XXVII organises the pericellular matrix in the growth plate."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice expressing an 87 amino acid deletion in the collagenous domain of collagen XXVII were phenotypically normal as heterozygotes whereas homozygotes exhibited a severe chondrodysplasia and died perinatally from a lung defect."
    explanation: States the murine side of the mismatch, perinatal lethality from a lung defect.
notes: >
  No GeneReviews chapter exists for Steel syndrome. A PubMed search for
  "Steel syndrome GeneReviews" returned no records, so the GeneReviews phenotype baseline
  step was not applicable and the phenotype set here is built from the original clinical
  series, the gene-discovery report, and the subsequent molecularly confirmed case reports
  and reviews.

  Genotype-phenotype pattern. Patients homozygous for the Puerto Rican founder missense
  allele have the skeletal syndrome without congenital hearing loss, while patients with
  frameshift, nonsense and splice alleles more often have congenital sensorineural hearing
  loss and additional features. Coloboma, cleft palate, and dental and genital anomalies
  each rest on a single report and should be treated as provisional extensions of the
  phenotype rather than established features.

  Heterozygous carriers are not affected in the Mendelian sense. Two independent
  electronic-health-record interrogations found no significant phenotype association in
  carriers beyond non-significant enrichment of joint and spine degeneration codes; the
  proposal that the locus contributes to complex osteopathological traits in carriers is
  explicitly framed by its authors as a hypothesis and is not curated here as a disease
  mechanism.

  Curation provenance. No deep-research provider report was generated for this entry, and
  no artifact was committed under research/. This was not a scoping decision: the drafting
  run was cut short, and the reference set was assembled directly from PubMed on COL27A1
  and Steel syndrome. The consequence is that the usual deep-research completeness
  cross-check was not available, so the phenotype list should be read as assembled from
  the fourteen cited sources rather than as verified complete against an independent
  survey. Every snippet was verified as an exact substring of its cached reference.

  Unattached phenotypes and why. Coloboma, cryptorchidism and global developmental delay
  are deliberately left with no incoming causal edge: each rests on a single report and no
  mechanism connecting them to the collagen lesion is established, so drawing an edge
  would assert a causal claim the sources do not support. Cleft palate is likewise left
  unattached; palatal fusion is a distinct developmental process from the endochondral
  cranial-base growth that the craniofacial edges here rest on, and the single report does
  not bridge that gap. Cutaneous syndactyly is left unattached for the same reason: an
  interdigital soft-tissue web is not a product of endochondral ossification, and nothing
  cited connects it to the cartilage lesion. The dental abnormality is unattached because
  its own source states the association only as a possibility. The craniofacial features
  are attached to impaired endochondral bone growth on the strength of the knock-in mouse
  reproducing an altered skull shape, with the intermediate steps in humans recorded as
  unknown.
datasets:
references:
- reference: PMID:8423186
  title: "A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children."
  findings: []
- reference: PMID:24986830
  title: "Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population."
  findings: []
- reference: PMID:32376988
  title: "Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide."
  findings: []
📚

References & Deep Research

References

3
PMID:8423186
A syndrome of dislocated hips and radial heads, carpal coalition, and short stature in Puerto Rican children.
No top-level findings curated for this source.
PMID:24986830
Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population.
No top-level findings curated for this source.
PMID:32376988
Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.
No top-level findings curated for this source.