Spondylometaphyseal Dysplasia, Schmidt Type

Mendelian MONDO:0008478 Pathograph 23 Show in embeddings browser spondylometaphyseal dysplasia type 2 collagenopathy

Spondylometaphyseal dysplasia, Schmidt type - almost always written in the modern literature as spondylometaphyseal dysplasia Algerian type, SMD-A, and listed in the skeletal dysplasia nosology as "SMD with severe genu valgum" - is an autosomal dominant type II collagenopathy caused by heterozygous COL2A1 variants. The phenotype is a short trunk with severe genu valgum, progressive kyphoscoliosis, wrist deformity and myopia, on a radiological background of moderate platyspondyly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches, and generalised metaphyseal dysplasia that is most conspicuous at the hip and knee. The hands and feet are barely affected. The mechanism is the standard type II collagenopathy one. Both reported COL2A1 alleles are glycine substitutions in the Gly-X-Y repeat of the triple-helical domain - Gly861Val in exon 39 and Gly1092Asp in exon 47 - the class of change that prevents an obligatory glycine from occupying the sterically constrained interior position of the collagen triple helix. The consequence is an abnormal type II collagen network in the hyaline cartilage of the growth plate and the vertebral bodies, which is why the disease is a growth disorder of endochondral bone rather than a metabolic one, and why the eye is involved at all. What is specific to this entry is its nosological position rather than its mechanism, and it is genuinely unsettled. Kozlowski's 1988 report of an Algerian family proposed the disorder as a distinct skeletal dysplasia and suggested that a 1963 case of Schmidt's was the same entity, which is where the eponym in the MONDO label comes from. The 2013 report that first found a COL2A1 allele in the phenotype went further and argued that SMD-A and spondyloepimetaphyseal dysplasia Strudwick type should be lumped, on the grounds that dorsal vertebral flattening, iliac hypoplasia, extensive metaphyseal dysplasia and near-normal short tubular bones are shared, and that the one apparent difference - normal proximal femoral epiphyses in SMD-A - dissolved in their own patient, whose mottled femoral heads improved with age. This entry is curated separately because MONDO, OMIM and Orphanet all keep the concept distinct and dismech already curates Strudwick type as its own entry; the argument for merging them is recorded in `notes` rather than acted on.

Ask OpenScientist

Ask a research question about Spondylometaphyseal Dysplasia, Schmidt Type. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
7
Pathophys.
16
Phenotypes
23
Pathograph
1
Genes
3
Medical Actions
5
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Dominant transmission was established in the index Algerian family, in which five members were affected. The two molecularly characterised patients since have been sporadic, each carrying a heterozygous COL2A1 variant, consistent with a de novo dominant allele.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:3368247 SUPPORT Human Clinical
"A new, dominantly inherited, severe form of spondylometaphyseal dysplasia in five members of an Algerian family is reported."
Dominant transmission in the family that defines the entity.
PMID:38162154 SUPPORT Human Clinical
"Spondylometaphyseal dysplasia Algerian type (MIM no.: 184253) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the COL2A1 gene (MIM no.: 120140)."
States the mode of inheritance together with the gene and the OMIM identifier this entry is keyed to.
⚙

Pathophysiology

7
Heterozygous COL2A1 Glycine Substitution
A single heterozygous missense change replacing an obligatory glycine of the Gly-X-Y repeat in the triple-helical domain of the pro-alpha-1(II) collagen chain. Both molecularly solved patients carry one: Gly861Val in exon 39 and Gly1092Asp in exon 47.
COL2A1 hgnc:2200 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COL2A1 (hgnc:2200). hgnc:2200 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Disrupted Type II Collagen Triple-Helix Assembly Glycine is the only residue small enough for the interior position of the collagen triple helix, so substituting a bulkier side chain obstructs helix formation.
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"This mutation was assumed to substitute valine for a glycine in the triple helical domain (Gly861Val)."
The first COL2A1 allele found in this phenotype, and the reason the disorder is classed as a type II collagenopathy at all.
PMID:38162154 SUPPORT Human Clinical
"The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366-13C > A in intron 21."
The second reported allele, an independent glycine substitution in the same domain.
Disrupted Type II Collagen Triple-Helix Assembly
The mutant pro-alpha-1(II) chain interferes with assembly of the type II procollagen triple helix. Glycine substitutions of this class are the recognised pathogenic mechanism across the type II collagenopathies and are shared with spondyloepimetaphyseal dysplasia Strudwick type and with hypochondrogenesis / spondyloepiphyseal dysplasia congenita.
collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Abnormal Cartilage Extracellular Matrix Type II collagen is the principal fibrillar collagen of hyaline cartilage, so a defective helix yields a defective cartilage matrix.
Show evidence (1 reference)
PMID:23653587 SUPPORT INDIRECT Human Clinical
"It is well known that single nucleotide transitions that change an obligatory glycine residue in the Gly-X-Y triplet repeats to another bulkier amino acid are pathogenic."
States the mechanism of this allele class. Graded indirect because it is the paper's framing of established collagen biochemistry rather than an experiment on this patient's protein; no functional study of either allele has been published.
Abnormal Cartilage Extracellular Matrix
A structurally defective type II collagen network in hyaline cartilage. The consequences track the tissues in which type II collagen is the dominant structural protein: the growth plates of the long bones, the cartilaginous vertebral bodies and pelvis, and the vitreous humor.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Metaphyseal Growth Plate Dysplasia
Vertebral Body Growth Failure
Pelvic and Proximal Femoral Dysplasia
Abnormal Vitreous Collagen
Show evidence (1 reference)
PMID:23653587 SUPPORT INDIRECT Human Clinical
"COL2A1mutations create a multiplicity of clinical entities collectively termed type II collagenopathy."
Places the disorder in the allelic series whose shared substrate is cartilage type II collagen. Quoted as it appears in the cached full text, where the gene symbol has been run together with the following word; the sentence reads "COL2A1 mutations create a multiplicity of clinical entities collectively termed type II collagenopathy."
Metaphyseal Growth Plate Dysplasia
Disordered endochondral ossification at the metaphyses of the long bones, most severe at the hip and knee and only minimally affecting the short tubular bones of the hands and feet. Radiologically it appears as irregular radiolucencies intermingled with radiodensities, partial fragmentation, and metaphyseal corner fractures, and mechanically it produces the severe valgus deformity that names the entity in the skeletal dysplasia nosology.
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
Downstream
Metaphyseal Dysplasia
Metaphyseal Irregularity
Metaphyseal Corner Fracture
Genu Valgum
Wrist Deformity
Short Stature
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"The metaphyseal changes are most conspicuous in the hip and knee, and are associated with coxa vara and severe genu valgum."
Locates the metaphyseal lesion and links it to the two deformities it produces.
PMID:23653587 SUPPORT Human Clinical
"The metaphyses of the long bones manifested irregular radiolucencies intermingled with radiodensities and were in part fragmented."
The radiological appearance of the metaphyseal lesion in a solved patient.
Vertebral Body Growth Failure
Reduced and disordered growth of the cartilaginous vertebral bodies, giving moderate platyspondyly with a characteristic dorsal flattening. The short trunk of this disorder follows from it, as do the progressive spinal deformities.
bone development GO:0060348 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bone development (GO:0060348). GO:0060348 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Platyspondyly
Disproportionate Short-Trunk Short Stature
Kyphoscoliosis
Lumbar Hyperlordosis
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"The radiological hallmarks of SMD-A include moderate platyspondyly particularly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches and generalized metaphyseal dysplasia of the long bones."
The spinal component of the radiological definition of the entity.
Pelvic and Proximal Femoral Dysplasia
Short, broad ilia with narrow greater sciatic notches, irregular acetabula, and a short varus femoral neck. The proximal femoral epiphyses may be mottled early and then improve with age, which is the observation that undermined the "normal epiphyses" criterion once used to separate this entity from spondyloepimetaphyseal dysplasia Strudwick type.
Downstream
Hypoplastic Ilia
Narrow Greater Sciatic Notch
Coxa Vara
Delayed Proximal Femoral Epiphyseal Ossification
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"The ilia were broad and short with narrow greater sciatic notches. The iliac crests and acetabula appeared irregular. The proximal femoral epiphyses were mottled together with horizontal clefts. Coxa vara and short femoral necks were noted."
The pelvic and proximal femoral findings in the molecularly solved Japanese patient.
Abnormal Vitreous Collagen
Type II collagen is also the structural collagen of the vitreous humor, which is why an otherwise skeletal disorder carries an ocular component. Myopia was part of the original clinical definition and was present in the solved patient.
Downstream
Myopia Myopia is consistently reported in this disorder and in the type II collagenopathies generally, but no study cited here traces the refractive error to a measured vitreous or scleral collagen abnormality in these patients, so the step is recorded as indirect.
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"Myopia may be a syndromic component."
Myopia in the clinical definition of the entity.
PMID:30696995 SUPPORT INDIRECT Other
"Myopia is a common feature of type II collagen disorders"
The ocular involvement of the disorder class. Graded indirect and OTHER because it is an expert-consensus statement about type II collagen disorders as a group, not about this entity.
⬡

Pathograph

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

Phenotypes

16
Eye 1
Myopia HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:3368247 SUPPORT Human Clinical
"The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet."
Myopia in the index Algerian family.
PMID:23653587 SUPPORT Human Clinical
"Ophthalmologic examination showed myopia. He had a hearing impairment with bilateral ear canal stenosis."
Myopia in the first solved patient. The quote runs on into the hearing finding because the myopia sentence alone is too short to be a usable snippet; the hearing impairment is not curated as a phenotype here, since it is a single-patient finding that the entity's clinical definition does not include.
Head and Neck 1
Cleft Soft Palate HP:0000185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft soft palate (HP:0000185). HP:0000185 is a phenotype from the Human Phenotype Ontology.
Deliberately not wired to a pathophysiology node. Palatal clefting in a type II collagenopathy is plausibly a consequence of the same cartilage matrix defect, but none of the sources cited here says so for this disorder, and no node in this entry covers craniofacial development.
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"A cleft of the soft palate and micrognathia were noted."
Reported at birth in the first solved patient.
PMID:30696995 SUPPORT INDIRECT Other
"stature, radiographic spondyloepiphyseal dysplasia, palate abnormalities, myopia,"
Palate abnormalities among the features of the type II collagen disorders as a class. Graded indirect and OTHER because it is expert consensus about the group, not about this entity.
Limbs 6
Genu Valgum HP:0002857 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genu valgum (HP:0002857), qualified as severity severe. HP:0002857 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"Individuals with SMD-A manifest with short trunk and severe genu valgum."
The clinical definition of the entity.
PMID:38162154 SUPPORT Human Clinical
"we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum"
Severe genu valgum in the second molecularly solved patient.
Metaphyseal Dysplasia HP:0100255 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal dysplasia (HP:0100255). HP:0100255 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"The radiological hallmarks of SMD-A include moderate platyspondyly particularly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches and generalized metaphyseal dysplasia of the long bones."
The radiological definition of the entity.
Metaphyseal Irregularity HP:0003025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal irregularity (HP:0003025). HP:0003025 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38162154 SUPPORT Human Clinical
"Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures."
Radiological findings in the second solved patient.
Metaphyseal Corner Fracture Corner fracture of metaphysis HP:0003908 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corner fracture of metaphysis (HP:0003908). HP:0003908 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38162154 SUPPORT Human Clinical
"Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures."
The finding in that patient.
Wrist Deformity Abnormality of the wrist HP:0003019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wrist deformity, annotated with Abnormality of the wrist (HP:0003019). HP:0003019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3368247 SUPPORT Human Clinical
"The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet."
Wrist deformity in the index Algerian family.
Coxa Vara HP:0002812 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coxa vara (HP:0002812). HP:0002812 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"The metaphyseal changes are most conspicuous in the hip and knee, and are associated with coxa vara and severe genu valgum."
Coxa vara as a consequence of the hip metaphyseal lesion.
Musculoskeletal 6
Platyspondyly HP:0000926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Platyspondyly (HP:0000926). HP:0000926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"The radiological hallmarks of SMD-A include moderate platyspondyly particularly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches and generalized metaphyseal dysplasia of the long bones."
The spinal radiological hallmark of the entity.
Kyphoscoliosis HP:0002751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphoscoliosis (HP:0002751), qualified as course progressive. HP:0002751 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:3368247 SUPPORT Human Clinical
"The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet."
Progressive kyphoscoliosis in the index Algerian family.
Lumbar Hyperlordosis HP:0002938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lumbar hyperlordosis (HP:0002938). HP:0002938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38162154 SUPPORT Human Clinical
"we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum"
Lumbar hyperlordosis in the second solved patient.
Hypoplastic Ilia HP:0000946 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic ilia (HP:0000946). HP:0000946 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"The ilia were broad and short with narrow greater sciatic notches."
Pelvic finding in the first solved patient.
Narrow Greater Sciatic Notch HP:0003375 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow greater sciatic notch (HP:0003375). HP:0003375 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"The ilia were broad and short with narrow greater sciatic notches."
Pelvic finding in the first solved patient, and part of the radiological definition.
Delayed Proximal Femoral Epiphyseal Ossification Delayed epiphyseal ossification HP:0002663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed epiphyseal ossification (HP:0002663). HP:0002663 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"The proximal femoral epiphyses were mottled together with horizontal clefts."
The epiphyseal finding in the first solved patient.
PMID:23653587 SUPPORT Human Clinical
"Thereafter, ossification of the proximal femoral epiphyses has somewhat progressed"
The improvement with age, which is what makes "normal epiphyses" an unreliable discriminator against Strudwick type.
Growth 2
Disproportionate Short-Trunk Short Stature HP:0003521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disproportionate short-trunk short stature (HP:0003521). HP:0003521 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23653587 SUPPORT Human Clinical
"Individuals with SMD-A manifest with short trunk and severe genu valgum."
The clinical definition of the entity.
Short Stature 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:23653587 SUPPORT Human Clinical
"At age 7, he was referred to us because of short stature and severe deformity of the legs."
The presenting complaint of the first solved patient.
PMID:3368247 SUPPORT Human Clinical
"The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet."
Short stature, written as dwarfism in the 1988 idiom, in the index Algerian family.
🧬

Genetic Associations

1
COL2A1
Gene: COL2A1 hgnc:2200 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COL2A1 (hgnc:2200). hgnc:2200 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"Here we report a 7-year-old Japanese boy with a heterozygous missense mutation in COL2A1, 2582G>T (Gly861Val), whose phenotype matched that of SMD-A."
The first COL2A1 allele reported in this phenotype.
PMID:38162154 SUPPORT Human Clinical
"The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366-13C > A in intron 21."
The second reported allele, plus the intronic variant of uncertain significance this entry declines to treat as causal.
💊

Medical Actions

3
Realignment Osteotomy for Severe Genu Valgum
Action: Orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Platform: Surgery
The severe valgus deformity is the main surgical problem. Guided growth while growth remains, and realignment osteotomy otherwise, are the recommended interventions for severe genu valgum in type II collagen disorders; the first molecularly solved patient underwent bilateral valgus proximal femoral osteotomy at age 8.
Show evidence (2 references)
PMID:30696995 SUPPORT INDIRECT Other
"Guided growth techniques (if sufficient growth remains) and realignment osteotomies are effective in the treatment of severe genu valgum in children with type II collagen disorders"
The consensus recommendation. Graded indirect and OTHER: it is expert consensus about type II collagen disorders as a group, and no trial exists for this entity.
PMID:23653587 SUPPORT Human Clinical
"He underwent a bilateral valgus proximal femora osteotomy at age 8."
The operation actually performed in a patient with this disorder.
Ophthalmologic Surveillance
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Because myopia is part of this phenotype and the type II collagen disorders carry an increased risk of retinal detachment, routine ophthalmologic review is recommended.
Show evidence (1 reference)
PMID:30696995 SUPPORT INDIRECT Other
"Routine evaluation and surveillance by an ophthalmologist is necessary because the risk of retinal detachment and severe myopia are increased in type II collagen disorders"
The consensus surveillance recommendation. Graded indirect and OTHER for the same reason as the other treatment records: it addresses the class.
Spinal Deformity Monitoring
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Progressive kyphoscoliosis occurs in this disorder and in type II collagen disorders generally, and is recommended to be monitored clinically and radiographically.
Show evidence (1 reference)
PMID:30696995 SUPPORT INDIRECT Other
"Progressive kyphoscoliosis can occur in children with type II collagen disorders and should be clinically and radiographically monitored"
The consensus surveillance recommendation, graded indirect and OTHER because it addresses the disorder class.
🔬

Diagnosis

1
Molecular testing of COL2A1
Sequencing COL2A1 confirms the diagnosis and separates the entity from the non-collagen spondylometaphyseal dysplasias, notably the TRPV4-related Kozlowski type. The type II collagen disorder best-practice guideline recommends molecular confirmation whenever the clinical or radiographic picture suggests the group.
Show evidence (2 references)
PMID:30696995 SUPPORT INDIRECT Other
"In patients with clinical or radiographic features of a type II collagen disorder, molecular testing should be done to confirm diagnosis, allowing accurate recurrence risk counseling, prenatal diagnosis, and appropriate treatment options"
The consensus recommendation for the disorder class. Graded indirect and OTHER because it is expert consensus about the group.
PMID:23653587 SUPPORT Human Clinical
"The entire coding regions ofCOL2A1, along with flanking intronic regions, were amplified by PCR using previously described primer sets"
The method by which the first case was solved. Quoted as it appears in the cached full text, where the gene symbol has been run together with the preceding word.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
No population estimate exists. The published series is one Algerian family with five affected members, a sporadic Polish boy, a sporadic Japanese boy and a fourth sporadic case reported in 2023, so the denominator for any rate is unknown. This is also why no phenotype in this entry carries a frequency band.
Show evidence (2 references)
PMID:23653587 SUPPORT Human Clinical
"SMD-A is an autosomal dominant disorder, and the phenotypic definition is derived from 5 affected sibs in an Algerian family and a sporadic case of a Polish boy"
The size of the case base from which the entity was defined.
PMID:23653587 SUPPORT Human Clinical
"Afterwards, however, no additional report has emerged to date."
Records that a quarter of a century passed with no further published case, which is the reason no rate can be given.
{ }

Source YAML

click to show 
name: Spondylometaphyseal Dysplasia, Schmidt Type
creation_date: "2026-09-09T00:00:00Z"
category: Mendelian
description: >-
  Spondylometaphyseal dysplasia, Schmidt type - almost always written in the
  modern literature as spondylometaphyseal dysplasia Algerian type, SMD-A, and
  listed in the skeletal dysplasia nosology as "SMD with severe genu valgum" - is
  an autosomal dominant type II collagenopathy caused by heterozygous COL2A1
  variants. The phenotype is a short trunk with severe genu valgum, progressive
  kyphoscoliosis, wrist deformity and myopia, on a radiological background of
  moderate platyspondyly with dorsal vertebral flattening, short ilia with narrow
  greater sciatic notches, and generalised metaphyseal dysplasia that is most
  conspicuous at the hip and knee. The hands and feet are barely affected.

  The mechanism is the standard type II collagenopathy one. Both reported COL2A1
  alleles are glycine substitutions in the Gly-X-Y repeat of the triple-helical
  domain - Gly861Val in exon 39 and Gly1092Asp in exon 47 - the class of change
  that prevents an obligatory glycine from occupying the sterically constrained
  interior position of the collagen triple helix. The consequence is an abnormal
  type II collagen network in the hyaline cartilage of the growth plate and the
  vertebral bodies, which is why the disease is a growth disorder of endochondral
  bone rather than a metabolic one, and why the eye is involved at all.

  What is specific to this entry is its nosological position rather than its
  mechanism, and it is genuinely unsettled. Kozlowski's 1988 report of an Algerian
  family proposed the disorder as a distinct skeletal dysplasia and suggested that
  a 1963 case of Schmidt's was the same entity, which is where the eponym in the
  MONDO label comes from. The 2013 report that first found a COL2A1 allele in the
  phenotype went further and argued that SMD-A and spondyloepimetaphyseal
  dysplasia Strudwick type should be lumped, on the grounds that dorsal vertebral
  flattening, iliac hypoplasia, extensive metaphyseal dysplasia and near-normal
  short tubular bones are shared, and that the one apparent difference - normal
  proximal femoral epiphyses in SMD-A - dissolved in their own patient, whose
  mottled femoral heads improved with age. This entry is curated separately
  because MONDO, OMIM and Orphanet all keep the concept distinct and dismech
  already curates Strudwick type as its own entry; the argument for merging them
  is recorded in `notes` rather than acted on.
disease_term:
  preferred_term: spondylometaphyseal dysplasia, Schmidt type
  term:
    id: MONDO:0008478
    label: spondylometaphyseal dysplasia, Schmidt type
synonyms:
- SMD-A
- spondylometaphyseal dysplasia Algerian type
- spondylometaphyseal dysplasia, Algerian type
- spondylometaphyseal dysplasia with severe genu valgum
parents:
- spondylometaphyseal dysplasia
- type 2 collagenopathy
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Dominant transmission was established in the index Algerian family, in which
    five members were affected. The two molecularly characterised patients since
    have been sporadic, each carrying a heterozygous COL2A1 variant, consistent
    with a de novo dominant allele.
  evidence:
  - reference: PMID:3368247
    reference_title: "A new type of spondylo-metaphyseal dysplasia--Algerian type. Report of five cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A new, dominantly inherited, severe form of spondylometaphyseal dysplasia in five members of an Algerian family is reported.
    explanation: Dominant transmission in the family that defines the entity.
  - reference: PMID:38162154
    reference_title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylometaphyseal dysplasia Algerian type (MIM no.: 184253) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the COL2A1 gene (MIM no.: 120140).
    explanation: >-
      States the mode of inheritance together with the gene and the OMIM
      identifier this entry is keyed to.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population estimate exists. The published series is one Algerian family
    with five affected members, a sporadic Polish boy, a sporadic Japanese boy and
    a fourth sporadic case reported in 2023, so the denominator for any rate is
    unknown. This is
    also why no phenotype in this entry carries a frequency band.
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SMD-A is an autosomal dominant disorder, and the phenotypic definition is derived from 5 affected sibs in an Algerian family and a sporadic case of a Polish boy
    explanation: The size of the case base from which the entity was defined.
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Afterwards, however, no additional report has emerged to date."
    explanation: >-
      Records that a quarter of a century passed with no further published case,
      which is the reason no rate can be given.
pathophysiology:
- name: Heterozygous COL2A1 Glycine Substitution
  biological_scale: MOLECULAR
  description: >-
    A single heterozygous missense change replacing an obligatory glycine of the
    Gly-X-Y repeat in the triple-helical domain of the pro-alpha-1(II) collagen
    chain. Both molecularly solved patients carry one: Gly861Val in exon 39 and
    Gly1092Asp in exon 47.
  genes:
  - preferred_term: COL2A1
    term:
      id: hgnc:2200
      label: COL2A1
  downstream:
  - target: Disrupted Type II Collagen Triple-Helix Assembly
    causal_link_type: DIRECT
    description: >-
      Glycine is the only residue small enough for the interior position of the
      collagen triple helix, so substituting a bulkier side chain obstructs
      helix formation.
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation was assumed to substitute valine for a glycine in the triple helical domain (Gly861Val).
    explanation: >-
      The first COL2A1 allele found in this phenotype, and the reason the
      disorder is classed as a type II collagenopathy at all.
  - reference: PMID:38162154
    reference_title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366-13C > A in intron 21.
    explanation: >-
      The second reported allele, an independent glycine substitution in the same
      domain.
- name: Disrupted Type II Collagen Triple-Helix Assembly
  biological_scale: MOLECULAR
  description: >-
    The mutant pro-alpha-1(II) chain interferes with assembly of the type II
    procollagen triple helix. Glycine substitutions of this class are the
    recognised pathogenic mechanism across the type II collagenopathies and are
    shared with spondyloepimetaphyseal dysplasia Strudwick type and with
    hypochondrogenesis / spondyloepiphyseal dysplasia congenita.
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: DECREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  downstream:
  - target: Abnormal Cartilage Extracellular Matrix
    causal_link_type: DIRECT
    description: >-
      Type II collagen is the principal fibrillar collagen of hyaline cartilage,
      so a defective helix yields a defective cartilage matrix.
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      It is well known that single nucleotide transitions that change an obligatory glycine residue in the Gly-X-Y triplet repeats to another bulkier amino acid are pathogenic.
    explanation: >-
      States the mechanism of this allele class. Graded indirect because it is
      the paper's framing of established collagen biochemistry rather than an
      experiment on this patient's protein; no functional study of either allele
      has been published.
- name: Abnormal Cartilage Extracellular Matrix
  biological_scale: TISSUE
  description: >-
    A structurally defective type II collagen network in hyaline cartilage. The
    consequences track the tissues in which type II collagen is the dominant
    structural protein: the growth plates of the long bones, the cartilaginous
    vertebral bodies and pelvis, and the vitreous humor.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: DECREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  downstream:
  - target: Metaphyseal Growth Plate Dysplasia
    causal_link_type: DIRECT
  - target: Vertebral Body Growth Failure
    causal_link_type: DIRECT
  - target: Pelvic and Proximal Femoral Dysplasia
    causal_link_type: DIRECT
  - target: Abnormal Vitreous Collagen
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      COL2A1mutations create a multiplicity of clinical entities collectively termed type II collagenopathy.
    explanation: >-
      Places the disorder in the allelic series whose shared substrate is
      cartilage type II collagen. Quoted as it appears in the cached full text,
      where the gene symbol has been run together with the following word;
      the sentence reads "COL2A1 mutations create a multiplicity of clinical
      entities collectively termed type II collagenopathy."
- name: Metaphyseal Growth Plate Dysplasia
  biological_scale: TISSUE
  description: >-
    Disordered endochondral ossification at the metaphyses of the long bones,
    most severe at the hip and knee and only minimally affecting the short tubular
    bones of the hands and feet. Radiologically it appears as irregular
    radiolucencies intermingled with radiodensities, partial fragmentation, and
    metaphyseal corner fractures, and mechanically it produces the severe valgus
    deformity that names the entity in the skeletal dysplasia nosology.
  biological_processes:
  - preferred_term: endochondral ossification
    modifier: DECREASED
    term:
      id: GO:0001958
      label: endochondral ossification
  downstream:
  - target: Metaphyseal Dysplasia
    causal_link_type: DIRECT
  - target: Metaphyseal Irregularity
    causal_link_type: DIRECT
  - target: Metaphyseal Corner Fracture
    causal_link_type: DIRECT
  - target: Genu Valgum
    causal_link_type: DIRECT
  - target: Wrist Deformity
    causal_link_type: DIRECT
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The metaphyseal changes are most conspicuous in the hip and knee, and are associated with coxa vara and severe genu valgum.
    explanation: >-
      Locates the metaphyseal lesion and links it to the two deformities it
      produces.
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The metaphyses of the long bones manifested irregular radiolucencies intermingled with radiodensities and were in part fragmented.
    explanation: The radiological appearance of the metaphyseal lesion in a solved patient.
- name: Vertebral Body Growth Failure
  biological_scale: TISSUE
  description: >-
    Reduced and disordered growth of the cartilaginous vertebral bodies, giving
    moderate platyspondyly with a characteristic dorsal flattening. The short
    trunk of this disorder follows from it, as do the progressive spinal
    deformities.
  biological_processes:
  - preferred_term: bone development
    modifier: DECREASED
    term:
      id: GO:0060348
      label: bone development
  downstream:
  - target: Platyspondyly
    causal_link_type: DIRECT
  - target: Disproportionate Short-Trunk Short Stature
    causal_link_type: DIRECT
  - target: Kyphoscoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Lumbar Hyperlordosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiological hallmarks of SMD-A include moderate platyspondyly particularly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches and generalized metaphyseal dysplasia of the long bones.
    explanation: >-
      The spinal component of the radiological definition of the entity.
- name: Pelvic and Proximal Femoral Dysplasia
  biological_scale: TISSUE
  description: >-
    Short, broad ilia with narrow greater sciatic notches, irregular acetabula,
    and a short varus femoral neck. The proximal femoral epiphyses may be mottled
    early and then improve with age, which is the observation that undermined the
    "normal epiphyses" criterion once used to separate this entity from
    spondyloepimetaphyseal dysplasia Strudwick type.
  downstream:
  - target: Hypoplastic Ilia
    causal_link_type: DIRECT
  - target: Narrow Greater Sciatic Notch
    causal_link_type: DIRECT
  - target: Coxa Vara
    causal_link_type: DIRECT
  - target: Delayed Proximal Femoral Epiphyseal Ossification
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ilia were broad and short with narrow greater sciatic notches. The iliac crests and acetabula appeared irregular. The proximal femoral epiphyses were mottled together with horizontal clefts. Coxa vara and short femoral necks were noted.
    explanation: >-
      The pelvic and proximal femoral findings in the molecularly solved Japanese
      patient.
- name: Abnormal Vitreous Collagen
  biological_scale: TISSUE
  description: >-
    Type II collagen is also the structural collagen of the vitreous humor, which
    is why an otherwise skeletal disorder carries an ocular component. Myopia was
    part of the original clinical definition and was present in the solved patient.
  downstream:
  - target: Myopia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Myopia is consistently reported in this disorder and in the type II
      collagenopathies generally, but no study cited here traces the refractive
      error to a measured vitreous or scleral collagen abnormality in these
      patients, so the step is recorded as indirect.
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myopia may be a syndromic component."
    explanation: Myopia in the clinical definition of the entity.
  - reference: PMID:30696995
    reference_title: "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Myopia is a common feature of type II collagen disorders"
    explanation: >-
      The ocular involvement of the disorder class. Graded indirect and OTHER
      because it is an expert-consensus statement about type II collagen
      disorders as a group, not about this entity.
phenotypes:
- category: Growth
  name: Disproportionate Short-Trunk Short Stature
  description: >-
    A short trunk is one of the two defining clinical features of the entity.
  phenotype_term:
    preferred_term: Disproportionate short-trunk short stature
    term:
      id: HP:0003521
      label: Disproportionate short-trunk short stature
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with SMD-A manifest with short trunk and severe genu valgum."
    explanation: The clinical definition of the entity.
- category: Growth
  name: Short Stature
  description: >-
    Severe short stature. The molecularly solved Japanese boy was 87.6 cm at age
    7, which is 7.2 standard deviations below the mean.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At age 7, he was referred to us because of short stature and severe deformity of the legs.
    explanation: The presenting complaint of the first solved patient.
  - reference: PMID:3368247
    reference_title: "A new type of spondylo-metaphyseal dysplasia--Algerian type. Report of five cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet.
    explanation: >-
      Short stature, written as dwarfism in the 1988 idiom, in the index Algerian
      family.
- category: Skeletal
  name: Genu Valgum
  description: >-
    Severe knock-knee deformity, the feature the skeletal dysplasia nosology uses
    to name this entity ("SMD with severe genu valgum"). It was strikingly
    asymmetric in the Japanese patient and required bilateral femoral osteotomy.
  phenotype_term:
    preferred_term: Genu valgum
    severity: SEVERE
    term:
      id: HP:0002857
      label: Genu valgum
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with SMD-A manifest with short trunk and severe genu valgum."
    explanation: The clinical definition of the entity.
  - reference: PMID:38162154
    reference_title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum
    explanation: Severe genu valgum in the second molecularly solved patient.
- category: Skeletal
  name: Metaphyseal Dysplasia
  description: >-
    Generalised metaphyseal dysplasia of the long bones, most severe at hip and
    knee, with the short tubular bones of the hands and feet only mildly affected.
  phenotype_term:
    preferred_term: Metaphyseal dysplasia
    term:
      id: HP:0100255
      label: Metaphyseal dysplasia
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiological hallmarks of SMD-A include moderate platyspondyly particularly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches and generalized metaphyseal dysplasia of the long bones.
    explanation: The radiological definition of the entity.
- category: Skeletal
  name: Metaphyseal Irregularity
  phenotype_term:
    preferred_term: Metaphyseal irregularity
    term:
      id: HP:0003025
      label: Metaphyseal irregularity
  evidence:
  - reference: PMID:38162154
    reference_title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures.
    explanation: Radiological findings in the second solved patient.
- category: Skeletal
  name: Metaphyseal Corner Fracture
  description: >-
    Reported in the second molecularly solved patient. Corner fractures are the
    defining radiological sign of a different spondylometaphyseal dysplasia, the
    corner fracture type, so their presence here is worth recording explicitly.
  phenotype_term:
    preferred_term: Corner fracture of metaphysis
    term:
      id: HP:0003908
      label: Corner fracture of metaphysis
  evidence:
  - reference: PMID:38162154
    reference_title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures.
    explanation: The finding in that patient.
- category: Skeletal
  name: Wrist Deformity
  description: >-
    Wrist deformity was part of the original description of the Algerian family.
    Bound to the generic wrist-abnormality term because the 1988 report does not
    say which deformity, and the specific HPO wrist terms name particular
    entities such as Madelung deformity that the source does not support.
  phenotype_term:
    preferred_term: Wrist deformity
    term:
      id: HP:0003019
      label: Abnormality of the wrist
  evidence:
  - reference: PMID:3368247
    reference_title: "A new type of spondylo-metaphyseal dysplasia--Algerian type. Report of five cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet.
    explanation: Wrist deformity in the index Algerian family.
- category: Skeletal
  name: Platyspondyly
  description: >-
    Moderate platyspondyly, characteristically with flattening of the dorsal part
    of the vertebral body.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The radiological hallmarks of SMD-A include moderate platyspondyly particularly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches and generalized metaphyseal dysplasia of the long bones.
    explanation: The spinal radiological hallmark of the entity.
- category: Skeletal
  name: Kyphoscoliosis
  description: >-
    Progressive kyphoscoliosis in the index family. The second solved patient had
    severe dorsolumbar scoliosis; the first had only minimal scoliosis at age 7.
  phenotype_term:
    preferred_term: Kyphoscoliosis
    clinical_course: PROGRESSIVE
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:3368247
    reference_title: "A new type of spondylo-metaphyseal dysplasia--Algerian type. Report of five cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet.
    explanation: Progressive kyphoscoliosis in the index Algerian family.
- category: Skeletal
  name: Lumbar Hyperlordosis
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  evidence:
  - reference: PMID:38162154
    reference_title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum
    explanation: Lumbar hyperlordosis in the second solved patient.
- category: Skeletal
  name: Hypoplastic Ilia
  phenotype_term:
    preferred_term: Hypoplastic ilia
    term:
      id: HP:0000946
      label: Hypoplastic ilia
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ilia were broad and short with narrow greater sciatic notches."
    explanation: Pelvic finding in the first solved patient.
- category: Skeletal
  name: Narrow Greater Sciatic Notch
  phenotype_term:
    preferred_term: Narrow greater sciatic notch
    term:
      id: HP:0003375
      label: Narrow greater sciatic notch
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ilia were broad and short with narrow greater sciatic notches."
    explanation: Pelvic finding in the first solved patient, and part of the radiological definition.
- category: Skeletal
  name: Coxa Vara
  phenotype_term:
    preferred_term: Coxa vara
    term:
      id: HP:0002812
      label: Coxa vara
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The metaphyseal changes are most conspicuous in the hip and knee, and are associated with coxa vara and severe genu valgum.
    explanation: Coxa vara as a consequence of the hip metaphyseal lesion.
- category: Skeletal
  name: Delayed Proximal Femoral Epiphyseal Ossification
  description: >-
    Mottled proximal femoral epiphyses with horizontal clefts in the first solved
    patient, which then improved with age after femoral osteotomy. The
    nosological importance of this finding is that "normal epiphyses" had been
    the criterion separating this entity from spondyloepimetaphyseal dysplasia
    Strudwick type.
  phenotype_term:
    preferred_term: Delayed epiphyseal ossification
    term:
      id: HP:0002663
      label: Delayed epiphyseal ossification
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proximal femoral epiphyses were mottled together with horizontal clefts.
    explanation: The epiphyseal finding in the first solved patient.
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thereafter, ossification of the proximal femoral epiphyses has somewhat progressed
    explanation: >-
      The improvement with age, which is what makes "normal epiphyses" an
      unreliable discriminator against Strudwick type.
- category: Ophthalmologic
  name: Myopia
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:3368247
    reference_title: "A new type of spondylo-metaphyseal dysplasia--Algerian type. Report of five cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is characterised by a unique clinical and radiological set of features: dwarfism, genu valgum deformity, progressive kypho-scoliosis, wrist deformity, myopia and severe metaphyseal dysplasia, with moderate spinal changes and minimal changes in the hands and feet.
    explanation: Myopia in the index Algerian family.
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmologic examination showed myopia. He had a hearing impairment with bilateral ear canal stenosis.
    explanation: >-
      Myopia in the first solved patient. The quote runs on into the hearing
      finding because the myopia sentence alone is too short to be a usable
      snippet; the hearing impairment is not curated as a phenotype here, since
      it is a single-patient finding that the entity's clinical definition does
      not include.
- category: Craniofacial
  name: Cleft Soft Palate
  description: >-
    Reported in the first molecularly solved patient, together with micrognathia
    and feeding difficulty in infancy, and surgically corrected at age one. It is
    not part of the clinical definition of the entity and was not reported in the
    index Algerian family, but palatal clefting is a recognised feature of the
    type II collagenopathies generally.
  notes: >-
    Deliberately not wired to a pathophysiology node. Palatal clefting in a type
    II collagenopathy is plausibly a consequence of the same cartilage matrix
    defect, but none of the sources cited here says so for this disorder, and no
    node in this entry covers craniofacial development.
  phenotype_term:
    preferred_term: Cleft soft palate
    term:
      id: HP:0000185
      label: Cleft soft palate
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A cleft of the soft palate and micrognathia were noted."
    explanation: Reported at birth in the first solved patient.
  - reference: PMID:30696995
    reference_title: "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      stature, radiographic spondyloepiphyseal dysplasia, palate abnormalities, myopia,
    explanation: >-
      Palate abnormalities among the features of the type II collagen disorders
      as a class. Graded indirect and OTHER because it is expert consensus about
      the group, not about this entity.
genetic:
- name: COL2A1
  gene_term:
    preferred_term: COL2A1
    term:
      id: hgnc:2200
      label: COL2A1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Two alleles have been reported, both heterozygous glycine substitutions in
    the triple-helical domain: c.2582G>T p.Gly861Val in exon 39, and c.3275G>A
    p.Gly1092Asp in exon 47. The second patient additionally carried an intronic
    variant of uncertain significance, c.1366-13C>A, which the authors raised as
    a possible modifier of severity rather than as a second causal allele; this
    entry does not treat it as causal. No functional study of either allele has
    been published, so the dominant-negative mechanism usually invoked for
    glycine substitutions in this gene is an inference from the allele class
    here, not a measurement.
  evidence:
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a 7-year-old Japanese boy with a heterozygous missense mutation in COL2A1, 2582G>T (Gly861Val), whose phenotype matched that of SMD-A.
    explanation: The first COL2A1 allele reported in this phenotype.
  - reference: PMID:38162154
    reference_title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366-13C > A in intron 21.
    explanation: >-
      The second reported allele, plus the intronic variant of uncertain
      significance this entry declines to treat as causal.
diagnosis:
- name: Molecular testing of COL2A1
  description: >-
    Sequencing COL2A1 confirms the diagnosis and separates the entity from the
    non-collagen spondylometaphyseal dysplasias, notably the TRPV4-related
    Kozlowski type. The type II collagen disorder best-practice guideline
    recommends molecular confirmation whenever the clinical or radiographic
    picture suggests the group.
  evidence:
  - reference: PMID:30696995
    reference_title: "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      In patients with clinical or radiographic features of a type II collagen disorder, molecular testing should be done to confirm diagnosis, allowing accurate recurrence risk counseling, prenatal diagnosis, and appropriate treatment options
    explanation: >-
      The consensus recommendation for the disorder class. Graded indirect and
      OTHER because it is expert consensus about the group.
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The entire coding regions ofCOL2A1, along with flanking intronic regions, were amplified by PCR using previously described primer sets
    explanation: >-
      The method by which the first case was solved. Quoted as it appears in the
      cached full text, where the gene symbol has been run together with the
      preceding word.
treatments:
- name: Realignment Osteotomy for Severe Genu Valgum
  description: >-
    The severe valgus deformity is the main surgical problem. Guided growth while
    growth remains, and realignment osteotomy otherwise, are the recommended
    interventions for severe genu valgum in type II collagen disorders; the first
    molecularly solved patient underwent bilateral valgus proximal femoral
    osteotomy at age 8.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:30696995
    reference_title: "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      Guided growth techniques (if sufficient growth remains) and realignment osteotomies are effective in the treatment of severe genu valgum in children with type II collagen disorders
    explanation: >-
      The consensus recommendation. Graded indirect and OTHER: it is expert
      consensus about type II collagen disorders as a group, and no trial exists
      for this entity.
  - reference: PMID:23653587
    reference_title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He underwent a bilateral valgus proximal femora osteotomy at age 8."
    explanation: The operation actually performed in a patient with this disorder.
- name: Ophthalmologic Surveillance
  description: >-
    Because myopia is part of this phenotype and the type II collagen disorders
    carry an increased risk of retinal detachment, routine ophthalmologic review
    is recommended.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:30696995
    reference_title: "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      Routine evaluation and surveillance by an ophthalmologist is necessary because the risk of retinal detachment and severe myopia are increased in type II collagen disorders
    explanation: >-
      The consensus surveillance recommendation. Graded indirect and OTHER for
      the same reason as the other treatment records: it addresses the class.
  notes: >-
    Retinal detachment itself is not curated as a phenotype of this entity. No
    source cited here reports it in an SMD-A patient; the risk is asserted for
    the type II collagen disorders as a group, and importing it would claim more
    than the evidence supports.
- name: Spinal Deformity Monitoring
  description: >-
    Progressive kyphoscoliosis occurs in this disorder and in type II collagen
    disorders generally, and is recommended to be monitored clinically and
    radiographically.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:30696995
    reference_title: "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      Progressive kyphoscoliosis can occur in children with type II collagen disorders and should be clinically and radiographically monitored
    explanation: >-
      The consensus surveillance recommendation, graded indirect and OTHER
      because it addresses the disorder class.
references:
- reference: PMID:3368247
  title: "A new type of spondylo-metaphyseal dysplasia--Algerian type. Report of five cases."
- reference: PMID:23653587
  title: "COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type."
- reference: PMID:38162154
  title: "A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1."
- reference: PMID:30696995
  title: "Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders."
- reference: PMID:31021589
  title: "Type II Collagen Disorders Overview."
  tags:
  - GeneReviews
notes: >-
  Eight things about this entry are deliberate.

  First, **it is a standalone Disease entry rather than a subtype of another.**
  MONDO, OMIM (184253) and Orphanet (93316) all keep the concept distinct;
  dismech already curates five spondylometaphyseal dysplasias by eponym
  (Kozlowski, corner fracture, Megarbane, with cone-rod dystrophy, with corneal
  dystrophy); and the closest precedent for a COL2A1 eponym is multiple
  epiphyseal dysplasia Beighton type, curated standalone in #10987 with the type
  II collagenopathy spectrum argued in its own notes.

  Second, **the strongest argument against that decision is recorded rather than
  buried.** The 2013 report that supplied the first COL2A1 allele concluded that
  it is rational to lump this entity with spondyloepimetaphyseal dysplasia
  Strudwick type, which dismech curates separately as
  `Spondyloepimetaphyseal_Dysplasia_Strudwick_Type`. Its argument is that the
  two share dorsal vertebral flattening, iliac hypoplasia, extensive metaphyseal
  dysplasia and near-normal short tubular bones, and that the one discriminator,
  normal proximal femoral epiphyses, failed in their own patient whose mottled
  femoral heads improved with age. That improvement is curated here as the
  `Delayed Proximal Femoral Epiphyseal Ossification` phenotype precisely because
  it is the nosologically load-bearing observation. Anyone revisiting the
  lump/split call should start there.

  Third, **the eponym in the MONDO label is a 1988 attribution, not a
  historical fact this entry endorses.** Kozlowski's group proposed that a 1963
  case reported by Schmidt might be the same disorder; the modern literature
  writes the entity as Algerian type, and the 1963 paper is not cited here
  because it has no PubMed record with quotable content. "Schmidt type" is also
  ambiguous outside skeletal dysplasia, where Schmidt syndrome names autoimmune
  polyglandular syndrome type II, so anything sourced by this entry's name alone
  needs the OMIM number or COL2A1 attached.

  Fourth, **no phenotype carries a `frequency` band.** The entire literature is
  one Algerian family of five, a Polish boy, a Japanese boy and a fourth sporadic
  case reported in 2023.
  Several phenotypes here rest on a single patient and say so in their
  `explanation`; a frequency band computed from that would be fiction.

  Fifth, **every treatment and surveillance record is class-level and graded
  that way.** No management study addresses this entity. What exists is the
  Skeletal Dysplasia Management Consortium's best-practice guideline for type II
  collagen disorders, so all three records carry `evidence_source: OTHER`
  (expert consensus, not a study) and `directness: INDIRECT`, and each says so
  in its own explanation. Retinal detachment is deliberately not curated as a
  phenotype for the same reason: the risk is asserted for the class and no
  source reports it in a patient with this disorder.

  Sixth, **the dominant-negative mechanism is not asserted as measured.** No
  functional study of Gly861Val or Gly1092Asp exists. The triple-helix node is
  supported by the 2013 paper's statement of the general allele-class mechanism
  and is graded `directness: INDIRECT` for that reason, and the `genetic` record
  says explicitly that the mechanism is inferred from the allele class.

  Seventh, **one phenotype is deliberately unwired.** `Cleft Soft Palate` has no
  incoming edge and its own `notes` says why: no node in this entry covers
  craniofacial development and no cited source connects the palate to the
  cartilage matrix defect in this disorder. Every other phenotype is the target
  of exactly one pathophysiology node.

  Eighth, **cervical-spine surveillance is deliberately not a treatment
  record.** The type II collagen best-practice guideline (`PMID:30696995`) that
  supplies the other management records stratifies this recommendation: routine
  cervical-spine imaging is advised for the more severe phenotypes, which it
  names as SEDC and Kniest dysplasia, and not for the class as a whole. This
  disorder is not among those named, and the one patient in `PMID:23653587`
  whose cervical spine was assessed had no C1/C2 instability.

  Two follow-ups left out of this pull request on purpose. Adding the entry to
  the `Type_2_Collagenopathies` grouping is a natural next step and belongs in
  its own PR so the grouping change can be reviewed on its own, exactly as the
  multiple epiphyseal dysplasia Beighton type entry left it. And
  `PMID:31021589`, the GeneReviews *Type II Collagen Disorders Overview*, is
  listed in `references` with a GeneReviews tag but carries no evidence item:
  the cached record is the chapter's scope statement only, with no clinical or
  management text to quote.
📚

References & Deep Research

References

5
PMID:3368247
A new type of spondylo-metaphyseal dysplasia--Algerian type. Report of five cases.
No top-level findings curated for this source.
PMID:23653587
COL2A1 Mutation in Spondylometaphyseal Dysplasia Algerian Type.
No top-level findings curated for this source.
PMID:38162154
A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1.
No top-level findings curated for this source.
PMID:30696995
Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders.
No top-level findings curated for this source.
PMID:31021589
Type II Collagen Disorders Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Spondylometaphyseal Dysplasia, Schmidt Type (MONDO:0008478, COL2A1) · 2026-09-09T18:41:49Z · View source

New standalone entry for MONDO:0008478, resolved through its cross-references to OMIM 184253 and ORPHA 93316. The gene is COL2A1, confirmed by the stub's MONDO genes block and independently by the two molecularly solved case reports (PMID:23653587 Gly861Val, PMID:38162154 Gly1092Asp). Decided DISEASE rather than SUBTYPE or GROUPING: MONDO, OMIM and Orphanet all keep the concept distinct, dismech curates five other spondylometaphyseal dysplasias by eponym, and the closest COL2A1 precedent is Multiple_Epiphyseal_Dysplasia_Beighton_Type curated standalone in #10987. The strongest counter-argument, the 2013 paper's conclusion that this entity should be lumped with spondyloepimetaphyseal dysplasia Strudwick type, is recorded in notes rather than acted on, and the nosologically load-bearing observation behind it (proximal femoral epiphyseal ossification that improved with age) is curated as its own phenotype. Seven pathophysiology nodes, sixteen phenotypes, all wired except Cleft Soft Palate which is deliberately unwired with its reason in its own notes. No frequency bands anywhere: the literature is one Algerian family of five plus three sporadic cases. All treatment and surveillance records are class-level from the type II collagen disorders best-practice guideline PMID:30696995 and are graded evidence_source OTHER with directness INDIRECT. Deep research: the first falcon run used a disambiguated disease_name inlining OMIM 184253, ORPHA 93316, COL2A1 and explicit exclusions for Schmidt syndrome and the TRPV4-related Kozlowski type; it returned the right disease. Validated with just validate, validate-terms, count-verified-snippets 43/43, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-folded-hyphens, validate-disorders and the whole-KB snippet checks.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 36 citations 2026-09-09T11:39:03.579127

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Spondylometaphyseal dysplasia Algerian type (SMD-A), also called spondylometaphyseal dysplasia Schmidt type and SMD with severe genu valgum, OMIM 184253, ORPHA 93316 - an autosomal dominant type II collagenopathy caused by heterozygous COL2A1 glycine substitutions, not Schmidt syndrome (autoimmune polyglandular syndrome type II) and not the TRPV4-related SMD Kozlowski type
  • MONDO ID: MONDO:0008478 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Spondylometaphyseal dysplasia Algerian type (SMD-A), also called spondylometaphyseal dysplasia Schmidt type and SMD with severe genu valgum, OMIM 184253, ORPHA 93316 - an autosomal dominant type II collagenopathy caused by heterozygous COL2A1 glycine substitutions, not Schmidt syndrome (autoimmune polyglandular syndrome type II) and not the TRPV4-related SMD Kozlowski type covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Spondylometaphyseal dysplasia, Algerian type (SMD-A): research report

Executive summary

Spondylometaphyseal dysplasia, Algerian type (SMD-A) is an exceptionally rare, nonlethal, autosomal-dominant skeletal dysplasia and type II collagenopathy. Its characteristic combination is disproportionate short stature with a short trunk, severe bilateral genu valgum, moderate platyspondyly—especially posterior/dorsal vertebral flattening—short ilia with narrow greater sciatic notches, and generalized metaphyseal dysplasia of the long bones. The disorder was delineated in five members of an Algerian family in 1988; a phenotypically concordant 7-year-old Japanese boy reported in 2013 carried heterozygous COL2A1 NM_001844.4:c.2582G>T, p.(Gly861Val), linking SMD-A to defective type II collagen. The disease literature remains limited to very small case reports, so prevalence, penetrance, phenotype frequencies, natural history, surgical outcomes, and life expectancy cannot be estimated reliably. (zhang2020integratedanalysisof pages 21-24, zhang2020integratedanalysisof pages 10-14)

The strongest evidence is summarized below.

Evidence domain Direct SMD-A finding Evidence type/publication Confidence and limitations
Original delineation SMD-A was introduced after evaluation of five affected individuals from an Algerian family. Human case series: Kozlowski et al., Pediatric Radiology (1988), DOI: 10.1007/BF02390399 (zhang2020integratedanalysisof pages 21-24) Moderate: Foundational disease-specific evidence, but only five related cases; detailed individual-level data were unavailable in the retrieved text.
Defining phenotype Core findings are short trunk and severe genu valgum, with moderate platyspondyly—especially dorsal vertebral flattening—short ilia, narrow greater sciatic notches, and generalized metaphyseal dysplasia of the long bones. Disease-specific synthesis of the original phenotype: Zhang et al., Clinical Genetics (2020), DOI: 10.1111/cge.13680 (zhang2020integratedanalysisof pages 10-14) Moderate: The clinicoradiographic pattern is characteristic, but frequencies, penetrance, and longitudinal progression cannot be estimated from the very small cohort.
Molecular etiology A 7-year-old Japanese boy with an SMD-A-matching phenotype carried heterozygous COL2A1 NM_001844.4:c.2582G>T, p.(Gly861Val), supporting classification as an autosomal-dominant type II collagenopathy. Human molecular case report: Matsubayashi et al., Molecular Syndromology (2013), 4:148–151 (barathouari2016mutationupdatefor pages 7-8, zhang2020integratedanalysisof pages 10-14) Moderate: Disease-specific genotype–phenotype evidence, but based on one molecularly characterized case; no SMD-A-specific functional assay was reported, and the 2020 review described the classification as supportive rather than definitive.
Overlapping phenotype context Six patients with a related COL2A1 phenotype shared disproportionate short stature, platyspondyly, shortened long bones, epiphyseal and hip dysplasia, metaphyseal dappling and corner-fracture lesions, and genu varum or valgum. Reported substitutions were Gly154Arg in two patients, Gly181Arg, Gly922Arg, Gly861Val, and Gly546Ser. Human comparative case synthesis: Chen et al., BMC Pediatrics (2017), DOI: 10.1186/s12887-017-0930-9 (chen2017recurrentc.g1636a(p.g546s) pages 3-5, chen2017recurrentc.g1636a(p.g546s) pages 5-6) Low for strict SMD-A assignment; moderate for phenotypic overlap: The authors classified this pattern as an SEMD-Strudwick variant; corner-fracture and dappling findings should not automatically be equated with classic SMD-A.
Broader COL2A1 evidence Across 663 probands, investigators catalogued 460 distinct COL2A1 variants and 21 disorders; 488 of 663 variants (73.6%) were substitutions, 439 of 539 coding-region variants lay in the triple-helical domain, and 140 substitutions replaced glycine. Aggregated literature and LOVD analysis: Zhang et al., Clinical Genetics (2020), DOI: 10.1111/cge.13680 (zhang2020integratedanalysisof pages 6-10, zhang2020integratedanalysisof pages 1-6) High for the broader type II collagenopathy spectrum, not SMD-A prevalence: Database ascertainment and phenotype-label uncertainty limit genotype–phenotype inference; these statistics are not SMD-A-specific.
Glycine-substitution mechanism Glycine substitutions in Gly-X-Y repeats commonly destabilize the collagen-II triple helix and are generally interpreted as dominant-negative structural variants; glycine replacement accounted for 142 of 415 (34%) catalogued variants. Mutation review and database synthesis: Barat-Houari et al., Human Mutation (published online October 7, 2015; issue 2016), DOI: 10.1002/humu.22915 (barathouari2016mutationupdatefor pages 2-4, barathouari2016mutationupdatefor pages 1-2) High as a general collagen-II model; inferred for p.Gly861Val: Variant position does not reliably predict phenotype, and genetic, epigenetic, or environmental modifiers remain possible.
Contemporary mechanistic model A human isogenic iPSC-cartilage model of another dominant COL2A1 glycine substitution, p.Gly1170Ser, showed slow procollagen-II folding and secretion with intracellular ER accumulation but no coupled unfolded-protein response. Human in-vitro preprint, version posted March 9, 2024: Yammine et al., bioRxiv, DOI: 10.1101/2023.10.19.562780 (yammine2023erprocollagenstorage pages 1-5) Indirect and hypothesis-generating only: This is a different variant and phenotype, and the cited version was not peer reviewed. It does not establish ER storage or absent UPR activation in p.Gly861Val SMD-A; reviews emphasize mutation-, collagen-, and cell-specific responses (bateman2022collagenmisfoldingmutations pages 14-15, bateman2022collagenmisfoldingmutations pages 1-2).

Table: Evidence tiers supporting the clinical definition and COL2A1 association of SMD-A, while distinguishing direct disease observations from overlapping phenotypes and indirect mechanistic models.

1. Disease information

Definition and classification

SMD-A is a Mendelian chondrodysplasia affecting vertebral bodies and long-bone metaphyses. It belongs to the COL2A1/type II collagenopathy spectrum, in which defective cartilage extracellular matrix impairs endochondral bone growth. The original publication was Kozlowski et al., “A new type of spondylo-metaphyseal dysplasia—Algerian type,” Pediatric Radiology, published April 1988, DOI: https://doi.org/10.1007/BF02390399; it described five cases. Molecular support came from Matsubayashi et al., “COL2A1 mutation in spondylometaphyseal dysplasia Algerian type,” Molecular Syndromology 4:148–151 (2013), DOI: https://doi.org/10.1159/000346644. (zhang2020integratedanalysisof pages 21-24, barathouari2016mutationupdatefor pages 7-8, zhang2020integratedanalysisof pages 10-14)

Identifiers and names

  • OMIM phenotype: 184253.
  • Orphanet: ORPHA:93316.
  • MONDO: MONDO:0008478, as supplied in the target specification; this should be revalidated against the current MONDO release before automated ingestion.
  • Gene: COL2A1, OMIM 120140/108300 in historical literature; HGNC symbol COL2A1.
  • Synonyms: spondylometaphyseal dysplasia, Algerian type; SMD Algerian type; SMD-A; spondylometaphyseal dysplasia with severe genu valgum; and historically Schmidt type.
  • No disease-specific ICD-10, ICD-11, or MeSH code was established in the retrieved evidence. Coding generally falls under broader osteochondrodysplasia/skeletal-dysplasia categories; local coding systems should not substitute “Schmidt syndrome.”

Critical disambiguation: this is not autoimmune polyglandular syndrome type II (“Schmidt syndrome”), and it is not TRPV4-related SMD Kozlowski type. It should also not be conflated automatically with FN1-related SMD corner-fracture/Sutcliffe type or COL2A1-related SEMD Strudwick type.

The evidence is principally aggregated disease-level literature derived from individual pedigrees and case reports, not EHR-scale or registry data. The 2020 COL2A1 synthesis reviewed 170 publications, 663 independent probands, 1,678 affected individuals, 460 distinct variants, and 21 COL2A1-associated disorders, but only one molecularly characterized case was assigned specifically to SMD-A. (zhang2020integratedanalysisof pages 10-14, zhang2020integratedanalysisof pages 1-6)

2. Etiology

Causal factor

The demonstrated cause is a constitutional heterozygous missense alteration in COL2A1, specifically c.2582G>T, p.(Gly861Val), in the molecularly characterized Japanese case. This replaces an invariant glycine in the Gly-X-Y repeat of the collagen-II triple-helical domain. Type II procollagen is a homotrimer of three α1(II) chains and is the major fibrillar collagen of cartilage; after secretion and propeptide cleavage, molecules assemble into a cross-linked extracellular fibrillar network. (zhang2020integratedanalysisof pages 10-14, zhang2020integratedanalysisof pages 1-6)

Glycine substitutions are a major pathogenic class: a 2016 mutation review found them in 142/415 variants (34%), while a later dataset found 140 glycine substitutions among 488 substitutions and 439/539 coding-region variants in the triple-helical domain. Such substitutions generally act through a dominant-negative structural mechanism, destabilizing helix folding and/or fibril assembly rather than simple haploinsufficiency. (barathouari2016mutationupdatefor pages 2-4, barathouari2016mutationupdatefor pages 1-2, zhang2020integratedanalysisof pages 6-10)

Risk, protective, and modifying factors

  • Genetic risk: carrying a pathogenic heterozygous COL2A1 allele is the primary risk. An affected heterozygous individual ordinarily has a 50% transmission probability per conception.
  • Family history: relevant because of dominant inheritance, although de novo COL2A1 variants occur elsewhere in the collagenopathy spectrum.
  • Modifiers: none are validated for SMD-A. Broader COL2A1 studies show marked inter- and intrafamilial variability and suggest unidentified genetic, epigenetic, age-dependent, or environmental modifiers. This remains hypothesis-level evidence. (chen2017recurrentc.g1636a(p.g546s) pages 5-6, barathouari2016mutationupdatefor pages 5-6)
  • Environmental risk or protective factors: none are known to cause or prevent SMD-A. Mechanical loading may influence symptoms and progression of deformity or secondary osteoarthritis, but it does not cause the germline disorder.
  • Gene–environment interaction: not studied directly.
  • Protective alleles, diet, supplements, toxins, infections, occupational exposures, smoking, or alcohol effects: no SMD-A-specific evidence.

3. Phenotypes

The cardinal phenotype is based on a handful of patients; therefore, “characteristic” does not mean that a population frequency is known.

Phenotype Characteristics Suggested HPO term
Disproportionate short stature/short trunk Pediatric developmental manifestation; chronic and likely lifelong Short stature, HP:0004322; Disproportionate short stature; Short trunk
Severe genu valgum Cardinal, usually bilateral lower-limb angular deformity; may impair gait and knee mechanics Genu valgum, HP:0002857
Platyspondyly Moderate, with characteristic dorsal/posterior vertebral flattening Platyspondyly, HP:0000926
Generalized metaphyseal dysplasia Long-bone metaphyseal irregularity/remodeling defect Metaphyseal dysplasia, HP:0000944
Short ilia and narrow greater sciatic notches Pelvic radiographic hallmark Short ilium; Abnormality of the greater sciatic notch
Short-trunk skeletal dysplasia Combined axial and appendicular growth disturbance Abnormality of the vertebral column; Abnormality of long-bone morphology
Possible myopia/hearing loss in overlapping COL2A1 cases Not established as cardinal or frequent in strict SMD-A Myopia, HP:0000545; Sensorineural hearing impairment, HP:0000407

The 2020 review describes SMD-A as presenting with “short trunk, severe genu valgum,” and the radiographic hallmarks listed above. The 2013 molecular case was diagnosed at age seven, supporting childhood recognition. (zhang2020integratedanalysisof pages 10-14)

A related six-patient COL2A1 series with metaphyseal “dappling” and “corner-fracture” lesions reported disproportionate short stature, platyspondyly, short long bones, femoral-head/neck and hip dysplasia, and genu varum/valgum in all six tabulated patients. However, those authors classified the phenotype as an SEMD-Strudwick variant; these frequencies must not be imported as SMD-A frequencies. (chen2017recurrentc.g1636a(p.g546s) pages 3-5, chen2017recurrentc.g1636a(p.g546s) pages 5-6)

Quality of life: no SMD-A-specific EQ-5D, SF-36, PROMIS, pain, mobility, educational, or employment study exists in the retrieved literature. Severe knee malalignment, short stature, gait disturbance, pain, reduced mobility, and later degenerative joint disease are plausible functional burdens, but quantitative estimates are unavailable.

4. Genetic and molecular information

  • Gene: COL2A1, encoding collagen α1(II); 54 coding exons were described in the 2020 analysis.
  • Disease-associated variant: NM_001844.4:c.2582G>T, p.(Gly861Val), heterozygous missense; germline/constitutional in the reported child. (zhang2020integratedanalysisof pages 10-14)
  • Protein domain: triple-helical Gly-X-Y repeat.
  • Functional class: inferred dominant-negative structural allele. No p.Gly861Val-specific secretion, thermal-stability, fibrillogenesis, cartilage histology, or animal functional assay was retrieved.
  • ACMG/AMP status: the human phenotype, invariant glycine substitution, dominant mechanism, and rarity support pathogenicity, but an up-to-date ClinVar assertion and criterion-level ACMG classification were not available in the retrieved documents and should be checked directly before database deposition.
  • Population frequency: no allele count was available from gnomAD, TOPMed, ExAC, or 1000 Genomes in the retrieved evidence. A causal ultra-rare dominant skeletal-dysplasia allele is expected to be absent or exceptionally rare, but this must not be recorded as a measured frequency without a current database query.
  • Somatic variants: not etiologic. Somatic and germline mosaicism occur elsewhere in COL2A1 disease, but neither was demonstrated in SMD-A. (barathouari2016mutationupdatefor pages 5-6, barathouari2016mutationupdatefor pages 6-7)
  • Modifier genes/epigenetics/chromosomal abnormalities: none established. SMD-A is not known to result from aneuploidy, translocation, repeat expansion, mitochondrial mutation, or a recurrent copy-number abnormality.

The broader genotype–phenotype relationship is weak. The 2020 abstract states: “a well-defined genotype-phenotype correlation has not been established,” and the 2017 report similarly notes that identical COL2A1 mutations can produce different metaphyseal phenotypes. (chen2017recurrentc.g1636a(p.g546s) pages 1-3, zhang2020integratedanalysisof pages 1-6)

5. Environmental information

SMD-A is not an infectious, toxic, nutritional, radiation-induced, occupational, or lifestyle disease. No pathogen, toxin, pollutant, dietary deficiency, smoking exposure, alcohol exposure, or medication has been shown to initiate it. Exercise, body weight, and joint loading could modify pain or mechanical complications but are downstream management considerations, not etiologic factors. No vaccine or anti-infective intervention is relevant beyond routine preventive care.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous COL2A1 c.2582G>T lesion leads to p.Gly861Val substitution at an obligatory glycine in the α1(II) triple helix. (zhang2020integratedanalysisof pages 10-14)
  2. Incorporation of mutant α1(II) chains into homotrimeric procollagen is inferred to lead to delayed or abnormal triple-helix folding and reduced molecular stability; this has not been demonstrated directly for p.Gly861Val. (barathouari2016mutationupdatefor pages 2-4, barathouari2016mutationupdatefor pages 1-2)
  3. Abnormal procollagen-II is inferred to result in one or both of two branches: (A) defective secretion/ER retention and proteostasis disturbance; (B) secretion of structurally abnormal collagen that disrupts extracellular fibrillogenesis. Branch B has stronger general support for dominant glycine substitutions, but neither branch has been tested in SMD-A cartilage. (bateman2022collagenmisfoldingmutations pages 14-15, bateman2022collagenmisfoldingmutations pages 1-2)
  4. Qualitatively or structurally defective collagen-II matrix leads to impaired cartilage tensile architecture, growth-plate organization, and chondrocyte differentiation/signaling during endochondral ossification. Broader COL2A1 studies report sparse matrix, irregular/short collagen fibrils, and altered hypertrophic differentiation markers. (zhang2020integratedanalysisof pages 14-18)
  5. Growth-plate dysfunction results in generalized metaphyseal dysplasia and abnormal longitudinal/remodeling growth of long bones.
  6. Abnormal endochondral growth at vertebral and pelvic sites results in platyspondyly, short trunk, short ilia, and narrow sciatic notches.
  7. Disordered growth and load transmission across the lower extremities result in severe genu valgum and likely gait limitation, with a plausible downstream risk of pain and early degenerative joint disease.

Important expert caveat: ER stress must not be asserted as proven. A 2022 authoritative review concluded that evidence for a canonical cytotoxic unfolded-protein response in collagen types other than collagen X is incomplete and mutation- and cell-type-specific. It states that “while it is tempting to implicate UPR activation,” the evidence is mixed. (bateman2022collagenmisfoldingmutations pages 14-15, bateman2022collagenmisfoldingmutations pages 1-2)

A 2024 human iPSC-cartilage preprint involving a different variant, p.Gly1170Ser, found that mutant procollagen-II was slow to fold and secrete and accumulated intracellularly, but “this accumulation is not recognized by the unfolded protein response.” This is an important contemporary model of collagen-II proteostasis, not direct SMD-A evidence. (yammine2023erprocollagenstorage pages 1-5)

Suggested annotations: GO: collagen fibril organization; extracellular-matrix organization; cartilage development; chondrocyte differentiation; endochondral ossification; skeletal-system development; protein folding in ER; response to ER stress. Cell types: growth-plate chondrocyte, proliferative chondrocyte, prehypertrophic chondrocyte, hypertrophic chondrocyte, articular chondrocyte, and osteoblast. Cellular components: collagen-containing extracellular matrix, collagen trimer, endoplasmic-reticulum lumen, Golgi apparatus, and extracellular fibril.

No SMD-A-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or multi-omics study was identified.

7. Anatomical structures affected

Primary structures: vertebral bodies, ilia/pelvis, long-bone metaphyses, growth plates, and knee alignment. The dominant tissue is hyaline cartilage—especially growth-plate cartilage—and its collagen-II extracellular matrix. Type II collagen is also present in articular cartilage, intervertebral discs, and vitreous, but ocular disease is not established as a defining SMD-A feature. (zhang2020integratedanalysisof pages 1-6)

Suggested UBERON labels include vertebral body, vertebral column, ilium, greater sciatic notch, femur, tibia, humerus, long-bone metaphysis, epiphyseal growth plate, articular cartilage, knee joint, and intervertebral disc. Suggested GO cellular components include collagen-containing extracellular matrix, collagen type-II trimer, ER lumen, and collagen fibril. Genu valgum is expected to be bilateral; no characteristic unilateral or asymmetric distribution is established.

8. Temporal development

SMD-A is congenital in genetic origin, with skeletal manifestations becoming clinically/radiographically evident during growth. The molecularly confirmed case was recognized at seven years. The course is chronic and lifelong rather than episodic or remitting. Deformity may become more apparent as growth and weight-bearing proceed, but no prospective natural-history cohort defines progression rate, stages, or critical intervention windows. (zhang2020integratedanalysisof pages 10-14)

The practical period of greatest vulnerability is childhood growth, when angular deformity may progress and growth-modulation surgery—if indicated—remains possible. This is orthopedic inference, not a measured SMD-A treatment effect. There is no spontaneous or pharmacologic remission.

9. Inheritance and population

  • Inheritance: autosomal dominant.
  • Recurrence: 50% per pregnancy for an affected heterozygous parent, assuming ordinary Mendelian segregation.
  • Penetrance: not quantified; apparently high in the original family, but the sample is too small to claim complete penetrance.
  • Expressivity: likely variable across COL2A1 disease, but strict SMD-A variability is poorly measured.
  • Anticipation: no evidence.
  • Founder effect: the original Algerian pedigree does not by itself prove a founder allele. No founder haplotype is established.
  • Consanguinity: not etiologically important for a dominant disorder.
  • Carrier frequency: unknown and not meaningfully estimable.
  • Sex ratio: unknown; no sex bias can be inferred from a few cases.
  • Prevalence/incidence: no population estimate. It should be described as ultra-rare, not assigned a numerical prevalence.
  • Geography: first reported in Algeria, followed by a molecularly concordant Japanese case; therefore, it is not known to be geographically restricted. (zhang2020integratedanalysisof pages 21-24, zhang2020integratedanalysisof pages 10-14)

10. Diagnostics

Clinical and imaging diagnosis

Initial evaluation should combine pedigree, growth proportions, limb alignment, gait, joint range of motion, and a skeletal survey. The key radiographic constellation is severe genu valgum plus moderate dorsal platyspondyly, generalized long-bone metaphyseal dysplasia, short ilia, and narrow greater sciatic notches. Detailed clinical and radiographic assessment remains essential because COL2A1 phenotypes overlap extensively. (zhang2020integratedanalysisof pages 10-14, zhang2020integratedanalysisof pages 1-6)

Recommended real-world assessments include standing long-leg radiographs for mechanical-axis deviation; spine and pelvis radiographs; targeted cervical-spine imaging before anesthesia or if instability/neurologic symptoms are suspected; and MRI when cartilage, spinal cord, or joint complications require clarification. There is no diagnostic serum enzyme, metabolite, inflammatory marker, biopsy signature, electrophysiologic test, or liquid-biopsy biomarker.

Genetic testing

  1. Use a skeletal-dysplasia/type II collagenopathy multigene panel including COL2A1, TRPV4, FN1, and phenotype-directed differential genes; ensure coding exons and splice junctions are covered.
  2. If the phenotype is classic, sequence and deletion/duplication analysis of COL2A1 is reasonable.
  3. Confirm candidate variants by an orthogonal method and test parents/affected relatives for segregation.
  4. WES or WGS is useful when panel testing is negative or phenotype overlap is substantial. A 2017 COL2A1 family illustrates successful WES followed by Sanger confirmation and segregation testing. (chen2017recurrentc.g1636a(p.g546s) pages 3-5)
  5. RNA analysis may clarify suspected splice variants. CMA, karyotype, FISH, mitochondrial sequencing, and repeat-expansion assays are not first-line tests for classic SMD-A.

Differential diagnosis

  • TRPV4-related SMD Kozlowski type: distinguish genetically and by its own radiographic spectrum.
  • FN1-related SMD corner-fracture/Sutcliffe type: corner-fracture-like metaphyseal lesions with relative epiphyseal sparing; COL2A1 cases can phenotypically overlap. (zhang2020integratedanalysisof pages 10-14)
  • COL2A1 SEMD Strudwick type: dappled metaphyses, scoliosis, pectus carinatum, disproportionate short stature; overlap is substantial. (zhang2020integratedanalysisof pages 10-14)
  • SEDC, Kniest dysplasia, and other type II collagenopathies: assess epiphyseal disease, ocular/hearing features, cleft palate, joint enlargement, and molecular findings.
  • Metaphyseal dysplasia and other genu-valgum skeletal dysplasias: distinguish by vertebral/pelvic pattern and gene testing.
  • Autoimmune Schmidt syndrome: unrelated endocrine-autoimmune condition, not a skeletal dysplasia.

No universally accepted SMD-A diagnostic criteria, newborn screening, or population screening program exists. Cascade testing is appropriate after identifying a familial pathogenic variant.

11. Outcome and prognosis

SMD-A is considered nonlethal, but no survival curve, mortality rate, or disease-specific life-expectancy estimate exists. Available reports do not establish cardiopulmonary, renal, hepatic, neurologic, or immune-system failure. Expected morbidity centers on short stature, progressive lower-limb malalignment, gait impairment, joint pain, restricted mobility, secondary osteoarthritis, and possible need for corrective orthopedic procedures. These complications are biologically and clinically plausible but lack SMD-A-specific rates.

No validated prognostic biomarker or prediction model exists. Potential clinical prognostic factors include baseline mechanical-axis deviation, remaining growth, hip/spine involvement, pain, joint degeneration, and functional status. Molecular position alone is not a reliable severity predictor because COL2A1 genotype–phenotype correlation is weak. (chen2017recurrentc.g1636a(p.g546s) pages 5-6, barathouari2016mutationupdatefor pages 5-6)

12. Treatment

There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, cell therapy, or SMD-A-specific clinical trial in the retrieved evidence. No response-rate or adverse-event series exists.

Current care is multidisciplinary and supportive:

  • pediatric skeletal-dysplasia/genetics follow-up;
  • pediatric orthopedic surveillance of genu valgum, hips, spine, gait, and mechanical axis;
  • physical therapy emphasizing safe mobility, muscle strength, balance, and preservation of range of motion;
  • occupational therapy and school/work accommodations where required;
  • weight management and low-impact activity to reduce excessive joint load without restricting healthy participation;
  • standard age-appropriate analgesia for pain, individualized to comorbidity and age;
  • hearing and ophthalmologic assessment at baseline because other COL2A1 disorders can involve these organs, although their frequency in strict SMD-A is unknown;
  • corrective surgery—guided growth/hemiepiphysiodesis during growth or osteotomy for established deformity—when progressive malalignment, pain, gait dysfunction, or joint overload warrants it. SMD-A-specific outcome data are absent.

Suggested NCIT intervention labels include Genetic Counseling; Physical Therapy; Occupational Therapy; Pain Management; Hemiepiphysiodesis; Corrective Osteotomy; and Orthopedic Surgery. Exact NCIT codes should be resolved against the current ontology release.

The 2024 iPSC-cartilage work provides a platform for future testing of collagen folding, quality-control, and secretion therapies, but it studied another COL2A1 allele and is not a clinical implementation. (yammine2023erprocollagenstorage pages 1-5)

13. Prevention

Primary prevention by lifestyle change, vaccination, or medication is not possible for a germline dominant disorder. Secondary/tertiary prevention includes early molecular diagnosis, growth-period orthopedic surveillance, timely management of angular deformity, preservation of mobility, and monitoring for joint degeneration.

After molecular confirmation, genetic counseling should cover dominant transmission, variable expression, cascade testing, prenatal diagnosis, and preimplantation genetic testing for the known familial allele. Broader COL2A1 guidance supports antenatal or preimplantation testing and presymptomatic testing of at-risk relatives once the causal variant is identified. (barathouari2016mutationupdatefor pages 5-6)

Population newborn screening and universal carrier screening are not justified because the condition is ultra-rare, dominant, and lacks an established newborn-screening intervention. Germline mosaicism cannot be excluded absolutely after an apparently de novo case, although it has not been documented for SMD-A.

14. Other species and natural disease

No naturally occurring animal disease specifically homologous to human SMD-A or carrying orthologous p.Gly861Val was identified. COL2A1 is evolutionarily conserved across vertebrates and collagen-II disorders occur in experimental and naturally occurring contexts, but these should not be labeled SMD-A without variant and phenotype concordance. There is no infectious transmission, zoonotic potential, or cross-species contagion.

Relevant comparative taxa include Mus musculus (NCBI Taxon 10090) and Danio rerio (7955), both useful for endochondral-bone and cartilage biology. No breed-specific VBO annotation is justified from current evidence.

15. Model organisms and experimental systems

No SMD-A-specific knock-in mouse, zebrafish, organoid, or patient-derived iPSC line was identified. Broader COL2A1-mutant mice show dilated rough ER/Golgi, fewer and thinner matrix fibrils, poor matrix organization, and altered growth-plate differentiation, but heterozygous mice may under-recapitulate human disease whereas homozygous animals may be excessively severe. (yammine2023erprocollagenstorage pages 1-5, zhang2020integratedanalysisof pages 14-18)

The most relevant recent development is isogenic human iPSC-derived cartilage. In the p.Gly1170Ser model, RNA sequencing, interactomics, microscopy, and biochemical assays demonstrated slow folding/secretion and ER storage without canonical UPR activation. Its strengths are human genotype, chondrocyte context, expandable tissue-like matrix, and suitability for drug screening; its limitations are a different allele/phenotype and, for the cited March 9, 2024 version, preprint status. (yammine2023erprocollagenstorage pages 1-5)

A high-value future SMD-A model would introduce c.2582G>T into an isogenic human iPSC line, differentiate it into growth-plate and articular chondrocytes, and measure triple-helix folding, secretion, collagen-II fibril architecture, matrix mechanics, ER proteostasis, chondrocyte-zone differentiation, and response to allele-selective silencing or proteostasis modulators.

Evidence limitations and knowledge-base recommendation

The disease assignment is credible but rests on five original familial cases plus one molecularly characterized phenocopy/concordant case. The most defensible knowledge-base entry is therefore: “autosomal-dominant COL2A1-related spondylometaphyseal dysplasia characterized by severe genu valgum,” with p.Gly861Val recorded as disease-associated and its dominant-negative mechanism marked inferred, not experimentally demonstrated. Frequencies, penetrance, natural history, prognosis, treatment outcomes, environmental modifiers, and molecular profiling should be entered as unknown, rather than extrapolated numerically from other type II collagenopathies. (zhang2020integratedanalysisof pages 21-24, zhang2020integratedanalysisof pages 10-14)

Key source dates and URLs

  • Kozlowski K, et al. Pediatric Radiology. April 1988. DOI: https://doi.org/10.1007/BF02390399.
  • Matsubayashi S, et al. Molecular Syndromology. 2013;4:148–151. DOI: https://doi.org/10.1159/000346644.
  • Barat-Houari M, et al. Published online October 7, 2015; Human Mutation 2016;37:7–15. DOI: https://doi.org/10.1002/humu.22915. (barathouari2016mutationupdatefor pages 1-2)
  • Chen J, et al. BMC Pediatrics. July 2017;17:175. DOI: https://doi.org/10.1186/s12887-017-0930-9. (chen2017recurrentc.g1636a(p.g546s) pages 1-3)
  • Zhang B, et al. Clinical Genetics. 2020;97:383–395. DOI: https://doi.org/10.1111/cge.13680. (zhang2020integratedanalysisof pages 1-6)
  • Bateman JF, et al. Connective Tissue Research. May 2022;63:210–227. DOI: https://doi.org/10.1080/03008207.2022.2036735. (bateman2022collagenmisfoldingmutations pages 1-2)
  • Yammine KM, et al. bioRxiv version posted March 9, 2024. DOI: https://doi.org/10.1101/2023.10.19.562780. (yammine2023erprocollagenstorage pages 1-5)

References

  1. (zhang2020integratedanalysisof pages 21-24): Boyan Zhang, Yue Zhang, Naichao Wu, Jianing Li, He Liu, and Jincheng Wang. Integrated analysis of col2a1 variant data and classification of type ii collagenopathies. Clinical Genetics, 97:383-395, Dec 2020. URL: https://doi.org/10.1111/cge.13680, doi:10.1111/cge.13680. This article has 63 citations and is from a peer-reviewed journal.

  2. (zhang2020integratedanalysisof pages 10-14): Boyan Zhang, Yue Zhang, Naichao Wu, Jianing Li, He Liu, and Jincheng Wang. Integrated analysis of col2a1 variant data and classification of type ii collagenopathies. Clinical Genetics, 97:383-395, Dec 2020. URL: https://doi.org/10.1111/cge.13680, doi:10.1111/cge.13680. This article has 63 citations and is from a peer-reviewed journal.

  3. (barathouari2016mutationupdatefor pages 7-8): Mouna Barat-Houari, Guillaume Sarrabay, Vincent Gatinois, Aurélie Fabre, Bruno Dumont, David Genevieve, and Isabelle Touitou. Mutation update for col2a1 gene variants associated with type ii collagenopathies. Human Mutation, 37:7-15, Jan 2016. URL: https://doi.org/10.1002/humu.22915, doi:10.1002/humu.22915. This article has 179 citations and is from a domain leading peer-reviewed journal.

  4. (chen2017recurrentc.g1636a(p.g546s) pages 3-5): Jing Chen, Xiaomin Ma, Yulin Zhou, Guimei Li, and Qiwei Guo. Recurrent c.g1636a (p.g546s) mutation of col2a1 in a chinese family with skeletal dysplasia and different metaphyseal changes: a case report. BMC Pediatrics, Jul 2017. URL: https://doi.org/10.1186/s12887-017-0930-9, doi:10.1186/s12887-017-0930-9. This article has 6 citations and is from a peer-reviewed journal.

  5. (chen2017recurrentc.g1636a(p.g546s) pages 5-6): Jing Chen, Xiaomin Ma, Yulin Zhou, Guimei Li, and Qiwei Guo. Recurrent c.g1636a (p.g546s) mutation of col2a1 in a chinese family with skeletal dysplasia and different metaphyseal changes: a case report. BMC Pediatrics, Jul 2017. URL: https://doi.org/10.1186/s12887-017-0930-9, doi:10.1186/s12887-017-0930-9. This article has 6 citations and is from a peer-reviewed journal.

  6. (zhang2020integratedanalysisof pages 6-10): Boyan Zhang, Yue Zhang, Naichao Wu, Jianing Li, He Liu, and Jincheng Wang. Integrated analysis of col2a1 variant data and classification of type ii collagenopathies. Clinical Genetics, 97:383-395, Dec 2020. URL: https://doi.org/10.1111/cge.13680, doi:10.1111/cge.13680. This article has 63 citations and is from a peer-reviewed journal.

  7. (zhang2020integratedanalysisof pages 1-6): Boyan Zhang, Yue Zhang, Naichao Wu, Jianing Li, He Liu, and Jincheng Wang. Integrated analysis of col2a1 variant data and classification of type ii collagenopathies. Clinical Genetics, 97:383-395, Dec 2020. URL: https://doi.org/10.1111/cge.13680, doi:10.1111/cge.13680. This article has 63 citations and is from a peer-reviewed journal.

  8. (barathouari2016mutationupdatefor pages 2-4): Mouna Barat-Houari, Guillaume Sarrabay, Vincent Gatinois, Aurélie Fabre, Bruno Dumont, David Genevieve, and Isabelle Touitou. Mutation update for col2a1 gene variants associated with type ii collagenopathies. Human Mutation, 37:7-15, Jan 2016. URL: https://doi.org/10.1002/humu.22915, doi:10.1002/humu.22915. This article has 179 citations and is from a domain leading peer-reviewed journal.

  9. (barathouari2016mutationupdatefor pages 1-2): Mouna Barat-Houari, Guillaume Sarrabay, Vincent Gatinois, Aurélie Fabre, Bruno Dumont, David Genevieve, and Isabelle Touitou. Mutation update for col2a1 gene variants associated with type ii collagenopathies. Human Mutation, 37:7-15, Jan 2016. URL: https://doi.org/10.1002/humu.22915, doi:10.1002/humu.22915. This article has 179 citations and is from a domain leading peer-reviewed journal.

  10. (yammine2023erprocollagenstorage pages 1-5): Kathryn M. Yammine, Sophia Mirda Abularach, Seo-yeon Kim, Agata A. Bikovtseva, Jinia Lilianty, Vincent L. Butty, Richard P. Schiavoni, John F. Bateman, Shireen R. Lamandé, and Matthew D. Shoulders. Er procollagen storage defect without coupled unfolded protein response drives precocious arthritis. Oct 2024. URL: https://doi.org/10.1101/2023.10.19.562780, doi:10.1101/2023.10.19.562780. This article has 5 citations.

  11. (bateman2022collagenmisfoldingmutations pages 14-15): John F. Bateman, Matthew D. Shoulders, and Shireen R. Lamandé. Collagen misfolding mutations: the contribution of the unfolded protein response to the molecular pathology. Connective Tissue Research, 63:210-227, Feb 2022. URL: https://doi.org/10.1080/03008207.2022.2036735, doi:10.1080/03008207.2022.2036735. This article has 38 citations and is from a peer-reviewed journal.

  12. (bateman2022collagenmisfoldingmutations pages 1-2): John F. Bateman, Matthew D. Shoulders, and Shireen R. Lamandé. Collagen misfolding mutations: the contribution of the unfolded protein response to the molecular pathology. Connective Tissue Research, 63:210-227, Feb 2022. URL: https://doi.org/10.1080/03008207.2022.2036735, doi:10.1080/03008207.2022.2036735. This article has 38 citations and is from a peer-reviewed journal.

  13. (barathouari2016mutationupdatefor pages 5-6): Mouna Barat-Houari, Guillaume Sarrabay, Vincent Gatinois, Aurélie Fabre, Bruno Dumont, David Genevieve, and Isabelle Touitou. Mutation update for col2a1 gene variants associated with type ii collagenopathies. Human Mutation, 37:7-15, Jan 2016. URL: https://doi.org/10.1002/humu.22915, doi:10.1002/humu.22915. This article has 179 citations and is from a domain leading peer-reviewed journal.

  14. (barathouari2016mutationupdatefor pages 6-7): Mouna Barat-Houari, Guillaume Sarrabay, Vincent Gatinois, Aurélie Fabre, Bruno Dumont, David Genevieve, and Isabelle Touitou. Mutation update for col2a1 gene variants associated with type ii collagenopathies. Human Mutation, 37:7-15, Jan 2016. URL: https://doi.org/10.1002/humu.22915, doi:10.1002/humu.22915. This article has 179 citations and is from a domain leading peer-reviewed journal.

  15. (chen2017recurrentc.g1636a(p.g546s) pages 1-3): Jing Chen, Xiaomin Ma, Yulin Zhou, Guimei Li, and Qiwei Guo. Recurrent c.g1636a (p.g546s) mutation of col2a1 in a chinese family with skeletal dysplasia and different metaphyseal changes: a case report. BMC Pediatrics, Jul 2017. URL: https://doi.org/10.1186/s12887-017-0930-9, doi:10.1186/s12887-017-0930-9. This article has 6 citations and is from a peer-reviewed journal.

  16. (zhang2020integratedanalysisof pages 14-18): Boyan Zhang, Yue Zhang, Naichao Wu, Jianing Li, He Liu, and Jincheng Wang. Integrated analysis of col2a1 variant data and classification of type ii collagenopathies. Clinical Genetics, 97:383-395, Dec 2020. URL: https://doi.org/10.1111/cge.13680, doi:10.1111/cge.13680. This article has 63 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 3
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 8
Resolved 7
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0008478 (3 mentions) - the report calls it "if available"; MONDO calls it spondylometaphyseal dysplasia, Schmidt type

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.