ACAN-Related Short Stature Spectrum

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Classifications

ISDS Skeletal Nosology

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Mappings

MONDO

MONDO:0012019 spondyloepiphyseal dysplasia, Kimberley type Not Yet Curated

The skeletal-dysplasia end of the spectrum modeled here, curated as the SEDK subtype. narrowMatch rather than exactMatch because this entry also covers the SSOAOD presentations.

MONDO:0100462 short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans Not Yet Curated

The short-stature and joint-disease end of the spectrum modeled here, curated as the SSOAOD subtype and subsuming familial osteochondritis dissecans. narrowMatch rather than exactMatch because this entry also covers SED Kimberley type.

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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant transmission is supported by cosegregation in multiple kindreds. Growth and joint manifestations vary with age and between carriers. Cosegregation in ascertained families does not establish complete penetrance across all pathogenic variants.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Identified ACAN variants showed perfect cosegregation with phenotype."

The segregation result underpinning the dominant assignment.

PMID:27870580 SUPPORT DIRECT Human Clinical

"No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints."

Supports describing penetrance per-feature: the joint arm varies independently of the allele class.

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Subtypes

2

Spondyloepiphyseal dysplasia, Kimberley type MONDO:0012019

ACAN hgnc:319 Autosomal dominant inheritance

The overt skeletal-dysplasia presentation: short stature with vertebral and epiphyseal change and premature degenerative arthropathy, recognized as a dysplasia on radiographs rather than as isolated short stature. Delineated in one multigenerational South African kindred mapped to 15q26.1, in which the causal allele is a single-base-pair insertion in the variable repeat region of ACAN exon 12 - the first ACAN variant shown to cause a human disorder.

Show evidence (2 references)

PMID:16080123 SUPPORT DIRECT Human Clinical

"The autosomal dominant SED type Kimberley (SEDK) is associated with premature degenerative arthropathy and has been previously mapped in a multigenerational family to a novel locus on 15q26.1."

Establishes SEDK as a dominant entity with joint disease and locates it to the ACAN interval, which is what makes it a member of this spectrum rather than a separate disease.

PMID:16080123 SUPPORT DIRECT Human Clinical

"This is the first identification of an AGC1 mutation causing a human disorder."

Records SEDK as the founding member of the ACAN allelic series, which is why this subtype carries the historical name rather than the spectrum.

Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans MONDO:0100462

ACAN hgnc:319 Autosomal dominant inheritance

The commoner presentation, and the one reached through an endocrine rather than a genetics clinic: proportionate or mildly disproportionate short stature with a normal endocrine workup, often an advanced bone age, and early growth cessation. Its "with or without" clause carries familial osteochondritis dissecans, which was described separately in a Swedish five-generation family and is now placed under the same OMIM entity; Stattin et al. label their families "fOCD/SSOAOD" for exactly that reason.

Show evidence (2 references)

PMID:24762113 SUPPORT DIRECT Human Clinical

"Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age."

Delineates the subtype as a mild dysplasia presenting as short stature with advanced bone age, which is what distinguishes it from SEDK.

PMID:24762113 SUPPORT DIRECT Human Clinical

"Our patients have short stature, variable, mild facial dysmorphism, and brachydactyly, but do not exhibit the vertebral body deformities detected in SEDK and SEMD."

The authors' own contrast with SEDK, which is the clinical basis for keeping the two as separate subtypes inside one entry rather than merging them.

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Discussions and Knowledge Gaps

5

Is one spectrum entry with two subtypes the right granularity for the dominant ACAN disorders, or should SED Kimberley type and SSOAOD be separate entries?

OPEN QUESTION acan_spectrum_lumping

Attached to

has_subtypes#SEDK has_subtypes#SSOAOD disease#ACAN-Related Short Stature Spectrum

SED Kimberley type, SSOAOD and familial osteochondritis dissecans form an overlapping ACAN allelic spectrum. The 2022 functional study discusses familial OCD as a potential subgroup of SSOAOD while leaving open whether its mechanism merits a separate entity. This entry retains the existing dominant-spectrum scope and subtype distinctions. The separate biallelic SEMD entry is not absorbed; enrichment of joint disease-associated variants in G3 does not imply that every dominant variant has the same molecular effect.

Do the G3 C-type lectin missense alleles act simply by reducing functional aggrecan dose, or by a distinct mechanism that the haploinsufficiency model does not capture?

CONTROVERSY acan_haploinsufficiency_vs_g3

Attached to

pathophysiology#Aggrecan Deficiency in the Cartilage Extracellular Matrix pathophysiology#Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan pathophysiology#Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum

Functional haploinsufficiency is a proposed explanation for growth impairment, whereas selected G3 variants have experimentally separable secretion and ligand-binding defects. The 2017 cohort found no simple variant-class association with joint complaints; the 2024 Dutch cohort found an association with height. These observations do not establish molecular equivalence across all variants. The contribution of ER retention, reduced export and altered extracellular interactions to each clinical presentation remains unresolved.

How do assay context and allele-specific secretion influence the amount and function of aggrecan in patient cartilage?

CONTROVERSY acan_secretion_versus_presence

Attached to

pathophysiology#Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan pathophysiology#Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum pathophysiology#Reduced Secretion of G3-Domain Variant Aggrecan

The 2010 study detected variant protein in patient cartilage and found similar total proteoglycan in a patient extract and pooled osteoarthritic control extracts. The 2016 differentiated-cell study found ER retention and extracellular depletion. The 2022 p.V2455M explant pilot measured less variant than wild-type protein in tissue and medium. These are distinct measurements in different systems, not proof of either normal secretion or complete failure across all tissues. Splice construct and differentiation state may influence results; their contributions have not been isolated in a matched comparison.

Show evidence (1 reference)

PMID:20137779 SUPPORT DIRECT In Vitro

"Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue."

Mass spectrometry of purified patient-cartilage aggrecan establishes the presence of variant protein. It does not quantify secretion or establish normal extracellular abundance.

Does growth hormone, with or without bone age suppression, improve adult height in this condition?

KNOWLEDGE GAP acan_growth_promoting_therapy_evidence

Attached to

treatments#Recombinant Human Growth Hormone treatments#Pubertal Suppression with a GnRH Analogue pathophysiology#Premature Epiphyseal Fusion treatments#Aromatase Inhibition with Letrozole

Prospective and retrospective studies support improved childhood growth, but the magnitude of an adult-height benefit and the added value of pubertal suppression remain uncertain. The 2024 three-year prospective trial was single-arm, and its authors caution against treating early growth response or predicted adult height as attained adult height. Later family follow-up likewise leaves long-term benefit unresolved. Some adult or near-adult outcomes exist, so the uncertainty is comparative effectiveness, not complete absence of adult-height observations.

Does the premature hypertrophic maturation seen in aggrecan-null animals actually occur in the growth plate of a human heterozygote?

HUMAN MODEL MISMATCH acan_heterozygous_growth_plate_evidence

Attached to

pathophysiology#Premature Epiphyseal Fusion phenotypes#Accelerated skeletal maturation

Premature hypertrophic maturation is inferred from aggrecan-null animal growth plates and human radiographic observations. Null animal disease and heterozygous human disease differ substantially in dosage and severity. Direct measurement of maturation timing in an appropriate heterozygous model or human growth-plate system would test this proposed intermediate; the cited human studies do not establish it directly.

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Pathophysiology

8

Heterozygous ACAN Variants

Heterozygous pathogenic ACAN variants include truncating, splice-site and missense alleles distributed across the gene. Missense variants associated with familial osteochondritis dissecans are enriched in the G3 domain, but neither all missense variants nor all familial osteochondritis dissecans variants are restricted to that domain. Variant class, domain and experimental system must be distinguished when interpreting functional effects.

ACAN hgnc:319

Downstream

Aggrecan Deficiency in the Cartilage Extracellular Matrix The route taken by the truncating alleles: one functional copy of the gene supplies the matrix.

Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan Studied G3 missense variants alter ligand affinity.

Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum Patient-derived cells carrying p.V2303M show ER aggrecan accumulation.

Reduced Secretion of G3-Domain Variant Aggrecan G3 missense variant expression constructs show reduced secretion.

Show evidence (4 references)

PMID:16080123 SUPPORT DIRECT Human Clinical

"We screened AGC1 for mutations and identified a single-base-pair insertion, within the variable repeat region of exon 12 in affected individuals from the family with SEDK, that introduces a frameshift of 212 amino acids, including 22 cysteine residues, followed by a premature stop codon."

The founding truncating allele, given in the detail that establishes it as a protein-truncating rather than a missense lesion.

PMID:33471655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Approximately half of these mutations can lead to protein truncation."

Quantifies the split between the truncating and non-truncating allele classes across the reported series, which is why this node branches rather than asserting one mechanism.

PMID:35338222 SUPPORT DIRECT Human Clinical

"Mapping these and other ACAN variants linked to hereditary skeletal disorders showed a clustering of osteochondritis dissecans-linked variants to the G3 domain."

The enrichment concerns osteochondritis dissecans-associated variants, not every missense allele in the ACAN spectrum.

+ 1 more reference

Aggrecan Deficiency in the Cartilage Extracellular Matrix

Reduced functional aggrecan availability is a proposed convergence mechanism for impaired cartilage growth. Similar growth impairment across allele classes in the 2017 cohort supported functional haploinsufficiency, but did not demonstrate identical molecular effects. The 2024 Dutch cohort found shorter stature among subjects with truncating than non-truncating variants. Secretion and ligand-binding defects remain experimentally distinguishable in G3 missense disease.

chondrocyte CL:0000138

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

cartilage tissue UBERON:0002418

Downstream

Impaired Growth Plate Chondrogenesis Growth-plate cartilage is where longitudinal bone growth is produced, so a matrix deficit there limits elongation.

Articular and Intervertebral Disc Matrix Insufficiency The same protein is the major proteoglycan of articular cartilage and of the intervertebral disc, which is why one gene dose produces a joint arm as well as a growth arm.

Show evidence (4 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Therefore, it is likely that the impairment of growth plate chondrogenesis is due to functional haploinsufficiency of aggrecan, rather than different mutation-specific mechanisms (25)."

The authors' own statement of the convergent mechanism this node asserts. Marked DIRECT because it states the claim, and note it is offered as a likelihood rather than a demonstration - the acan_haploinsufficiency_vs_g3 discussion records what is not settled by it.

PMID:27870580 SUPPORT INDIRECT Human Clinical

"Taken together, these findings suggest that different disease-causing heterozygous ACAN variants impair growth plate chondrogenesis similarly, which, in turn, suggests a common mechanism."

The clinical observation the dosage inference rests on - similar growth impairment across different variant types. Marked INDIRECT because the common mechanism is inferred from phenotypic similarity, not measured.

PMID:35338222 SUPPORT INDIRECT BACKGROUND Other

"The large proteoglycan aggrecan is vital for skeletal development and cartilage function, creating a swelling pressure in the tissue that provides resistance to compression and load dissipation over the joint surface"

States the biophysical function that a reduced aggrecan dose degrades, which is why this node is the pivot of the entry. Graded quote_role BACKGROUND because the sentence opens the paper's introduction and restates established cartilage biology rather than reporting this study's own result; evidence_source OTHER because the restated claim is textbook matrix biology with no single study design behind it.

+ 1 more reference

Reduced Secretion of G3-Domain Variant Aggrecan

Selected G3 variants are secreted less efficiently in recombinant expression assays, with severity depending on the splice construct. In the 2022 pilot explant experiment, a patient carrying p.V2455M had less variant than wild-type aggrecan in both cartilage and conditioned medium. This is a within-patient allelic comparison, not a measurement in cartilage from each of the three newly described families.

protein secretion GO:0009306 ↓ DECREASED

Downstream

Aggrecan Deficiency in the Cartilage Extracellular Matrix Reduced export decreases the amount of variant aggrecan available to the extracellular matrix.

Show evidence (3 references)

PMID:35338222 SUPPORT DIRECT In Vitro

"Functional studies showed that neither recombinant variant proteins, nor full-length variant aggrecan proteoglycan from heterozygous patient cartilage, were secreted to the same level as wild-type aggrecan."

Supports decreased secretion in recombinant constructs and in the patient explant experiment, with experimental scope specified by the full-text evidence below.

PMID:35338222 SUPPORT DIRECT In Vitro

"In a pilot experiment, we cultured cartilage explants from an fOCD patient heterozygous for the p.V2455M variant, obtained at arthroplasty for advanced osteoarthritis."

Identifies the patient allele and the pilot explant design; the full-length experiment did not sample all three new variant families.

PMID:35338222 SUPPORT DIRECT In Vitro

"The variant protein was, however, only present at low levels, both in the tissue explant (Fig. 6a) and the culture medium (Fig. 6b)."

Variant-specific mass spectrometry found reduced variant protein relative to wild type in the heterozygous patient explant and medium.

Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan

Studied G3 C-type lectin variants alter extracellular ligand binding. The 2010 p.V2303M experiments found weakened or absent interactions depending on ligand and splice construct. The 2022 assays showed pronounced impairment of fibulin-1 and tenascin-C binding, with residual tenascin-R binding in all variants tested. Tenascin-R is a CNS ligand in that study, so its assay result is not evidence that it is the relevant cartilage ligand.

TNC hgnc:5318 FBLN1 hgnc:3600

Downstream

Articular and Intervertebral Disc Matrix Insufficiency Impaired interactions with cartilage ligands may compromise matrix organization and stability; the tissue consequence is inferred from biochemical binding experiments.

Show evidence (4 references)

PMID:20137779 SUPPORT DIRECT In Vitro

"Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein."

The 2010 assays demonstrate impaired ligand interactions for p.V2303M; the full text distinguishes weakened affinity from complete loss across constructs.

PMID:35338222 SUPPORT DIRECT In Vitro

"The variant proteins also showed decreased binding to known cartilage extracellular matrix ligands."

The 2022 experiments extend impaired ligand binding to additional G3 variants; the effect varies by ligand and construct.

PMID:35338222 SUPPORT DIRECT In Vitro

"Interaction with the brain ligand tenascin-R was affected to a lesser degree, with retained binding of all the variants tested."

The full-text binding experiments qualify the abstract-level loss-of-binding summary: tenascin-R interaction is reduced, not universally abolished.

+ 1 more reference

Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum

Established only in patient-derived cells, and only for the p.V2303M familial-osteochondritis-dissecans allele. Chondrocytes differentiated from patient bone-marrow mesenchymal stromal cells and from patient iPSC lines accumulate large amounts of aggrecan inside the endoplasmic reticulum while the surrounding matrix is depleted of it - the authors' term is chondrocyte aggrecanosis. The pellets these cells form are rich in glycosaminoglycan and still structurally poor, which is the cellular-level version of the whole entry's point that the defect is in matrix assembly rather than in bulk synthesis.

chondrocyte CL:0000138

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED

Experimental models

Patient BM-MSC and iPSC-derived chondrocyte model of familial osteochondritis dissecans IPSC DERIVED MODEL Patient-derived chondrocyte models supply the evidence for intracellular retention of this variant; they do not establish the same intracellular fate for other ACAN alleles.

Downstream

Reduced Secretion of G3-Domain Variant Aggrecan Intracellular retention is a candidate contributor to impaired export; retention and extracellular depletion were observed together in patient-derived cells, without a causal rescue experiment.

Show evidence (3 references)

PMID:27388238 SUPPORT DIRECT In Vitro

"Second, it was evident that large amounts of aggrecan accumulated within the endoplasmic reticulum of chondrocytes differentiated from both BM-MSCs and iPSCs."

The direct observation of intracellular retention that this node names, made independently in two patient-derived chondrocyte systems.

PMID:27388238 SUPPORT DIRECT In Vitro

"In turn, there was a marked absence of aggrecan in the extracellular matrix."

Links the retention to the matrix deficit, which is the causal edge below.

PMID:27388238 SUPPORT INDIRECT In Vitro

"First, patient chondrogenic pellets had poor structural integrity but were rich in glycosaminoglycan."

Separates the assembly defect from a synthesis defect - the cells are making glycosaminoglycan, and the tissue they build is still weak. Marked INDIRECT because it is a property of the engineered pellet rather than of the retained protein itself.

Impaired Growth Plate Chondrogenesis

Longitudinal bone growth is produced at the growth plate by chondrocyte proliferation, hypertrophy and matrix production, then replacement of that cartilage by bone. Aggrecan is a critical component of the matrix the plate is built from, so a reduced dose degrades the template and the mechanical environment the chondrocytes work in at the same time. This is the growth arm of the spectrum, and it is the same lesion as the joint arm one tissue over.

chondrocyte CL:0000138

growth plate cartilage development GO:0003417 ⚠ ABNORMAL endochondral ossification GO:0001958 ⚠ ABNORMAL

epiphyseal plate UBERON:0002516

Downstream

Premature Epiphyseal Fusion Altered maturation is proposed from aggrecan-null animal growth plates and human radiographic observations; it has not been directly demonstrated in heterozygous human growth plates.

Short stature Reduced elongation at the growth plates of the long bones and vertebrae.

Disproportionate short stature Limb and spine plates are not affected to the same degree, which is what makes a minority of patients disproportionate rather than uniformly small.

Spondyloepiphyseal dysplasia Where the plate involvement is severe enough to be radiographically evident in the vertebrae and epiphyses, the presentation is the SEDK end of the spectrum.

Brachydactyly The short tubular bones of the hand grow from the same kind of plate and are affected disproportionately.

Accelerated skeletal maturation Altered growth-plate maturation is the proposed link to advanced radiographic bone age; accelerated bone age can occur before complete fusion.

Show evidence (2 references)

PMID:24762113 SUPPORT DIRECT BACKGROUND Other

"Aggrecan is a critical proteoglycan component of the cartilage matrix, both in articular and growth plate cartilage, thus accounting for the dual phenotypic effects on both these types of cartilage."

The authors' own account of why one gene produces two organ-level arms, which is the branch structure this entry uses.

PMID:24762113 SUPPORT INDIRECT BACKGROUND Model Organism

"Consistent with this explanation, homozygous mutations in ACAN in both mice and chicks severely disrupt growth plate function and impair bone elongation (18, 19)."

The animal evidence that growth-plate failure is the route from aggrecan loss to short bones. Graded MODEL_ORGANISM because the evidence described is murine and avian, and quote_role BACKGROUND because this paper is a human exome study restating work it did not perform. Marked INDIRECT because the animals are homozygous nulls and the human disease is heterozygous.

Premature Epiphyseal Fusion

Premature growth-plate closure limits remaining longitudinal growth. Early fusion and growth cessation are observed clinically. Premature hypertrophic maturation has been proposed as an upstream mechanism from aggrecan-null chick studies; that cellular mechanism is not directly demonstrated in human heterozygotes.

hypertrophic chondrocyte CL:0000743

epiphyseal plate UBERON:0002516

Downstream

Short stature Early closure truncates the growing period, so adult height falls further below the mean than childhood height did.

Show evidence (4 references)

PMID:24762113 SUPPORT INDIRECT BACKGROUND Model Organism

"In chicks, there is evidence for abnormal Indian hedgehog, fibroblast growth factor, and bone morphogenetic protein signaling, leading to premature hypertrophic chondrocyte maturation (18)."

The signalling evidence behind premature hypertrophy. Graded MODEL_ORGANISM for the avian source and quote_role BACKGROUND because the citing paper is a human study restating it; INDIRECT because the chick model is an aggrecan null.

PMID:24762113 SUPPORT INDIRECT BACKGROUND Model Organism

"Because hypertrophic differentiation induces vascular invasion and ossification of growth cartilage (3), these findings provide a likely explanation for the advanced bone age, premature growth cessation, and early epiphyseal fusion observed in the current study."

Joins premature hypertrophy to the three clinical features this node feeds, and is explicitly offered by its authors as a likely explanation rather than a demonstrated one - which is why the link is INDIRECT and the node is not treated as settled.

PMID:27870580 SUPPORT DIRECT Human Clinical

"This relative advancement of BA appears to reflect decreased remaining growth potential as evidenced by the history of early growth cessation in subjects"

The human-cohort statement that the advanced bone age indexes lost growth potential, which is what makes it a readout of this node and not an independent phenotype.

+ 1 more reference

Articular and Intervertebral Disc Matrix Insufficiency

The joint arm. Aggrecan is the major proteoglycan of articular cartilage and of the intervertebral disc, and a matrix built with less of it - or with aggrecan that cannot bind its network partners - carries load badly for decades. This node substitutes an intrinsic matrix lesion for the mechanical overload that opens the osteoarthritis module, which is the substitution that module's own notes name for ACAN defects, and then hands off to the module's conserved chondrocyte-to-matrix-degradation chain.

articular chondrocyte CL:1001607

extracellular matrix organization GO:0030198 ⚠ ABNORMAL

articular cartilage of joint UBERON:0010996 intervertebral disk UBERON:0001066

Downstream

Premature osteoarthritis Through the conserved chondrocyte-stress and matrix-degradation chain of the osteoarthritis module this node conforms to; the intervening decades of loading are omitted.

Osteochondritis dissecans A weakened osteochondral junction allows fragments of articular cartilage and subchondral bone to separate from the joint surface.

Intervertebral disk degeneration Reduced functional aggrecan may compromise disc matrix hydration and load-bearing function.

Show evidence (3 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage."

The cohort observation and the authors' localisation of it to the two cartilages this node names.

PMID:27870580 SUPPORT INDIRECT BACKGROUND Other

"This finding is consistent with aggrecan being the major proteoglycan component of the intervertebral disc and loss of aggrecan being an important pathogenic mechanism for degenerative disc disease (21)."

Supplies the disc-specific mechanism. Graded quote_role BACKGROUND and evidence_source OTHER because the sentence cites established disc biology from another source rather than reporting this cohort's own measurement.

PMID:20137779 SUPPORT DIRECT Human Clinical

"Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo."

Connects the G3 binding lesion to articular cartilage failure in patients, which is the second inbound route to this node.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Head and Neck 2

Midface retrusion HP:0011800

Show evidence (2 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"the mutations were associated with mild midface hypoplasia and flat nasal bridge (8 of 20 families"

Records the facial finding and its frequency. The quote is cut mid-clause because the source's sentence continues into a supplemental-figure reference, which carries no claim.

PMID:36387899 SUPPORT INDIRECT Human Clinical

"The prevalence of dysmorphic features in the Chinese populations is significantly lower than that in the Western populations."

Supports treating the facial features as ascertainment-dependent. Marked INDIRECT because it is a statement about dysmorphic features in general rather than about midface hypoplasia specifically.

Frontal bossing HP:0002007

Deliberately left with no causal inlink. The entry models no craniofacial mechanism node, aggrecan's role in the facial skeleton not being worked out in these families, so any edge drawn to this phenotype would assert a mechanism the entry does not have. The same applies to Midface retrusion.

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"young children in 2 families were noted to have frontal bossing (families 16 and 18)"

Records the finding, its age dependence and its rarity in the cohort.

Limbs 1

Brachydactyly HP:0001156

Show evidence (3 references)

PMID:29464738 SUPPORT DIRECT Human Clinical

"Interestingly, brachydactyly was observed in all probands."

All 16 probands had brachydactyly, but the series included ten VUS; it is not an estimate of penetrance among confirmed pathogenic-variant carriers.

PMID:27870580 SUPPORT DIRECT Human Clinical

"Brachydactyly was reported in 5 of 20 families."

The lower figure from the larger cohort, quoted alongside the first so the discrepancy is visible rather than averaged away.

PMID:29464738 SUPPORT DIRECT Human Clinical

"A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS)."

Qualifies the diagnostic certainty of the 16-proband denominator.

Musculoskeletal 5

Accelerated skeletal maturation FREQUENT HP:0005616

Show evidence (5 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years)."

Quantifies the advancement and its range, including the zero lower bound that makes it non-obligate.

PMID:27870580 SUPPORT DIRECT Human Clinical

"Children in 6 families (families 1, 4, 12, 15, 18, and 20) had markedly advanced skeletal maturation (BA, 3 to 4 years advanced); however, the children in the other 14 families had normal or modestly advanced BA"

Supports the stated variable expression and the warning that advanced bone age is not required. Thresholds and ascertainment differ between studies, so these observations are not pooled into one prevalence estimate.

PMID:36387899 SUPPORT DIRECT Human Clinical

"Meanwhile, only 24.24% of aggrecan-deficient Chinese children showed significantly advanced bone age (BA)."

Supports the stated variable expression and the warning that advanced bone age is not required. Thresholds and ascertainment differ between studies, so these observations are not pooled into one prevalence estimate.

+ 2 more references

Spondyloepiphyseal dysplasia HP:0002655

Show evidence (2 references)

PMID:29464738 SUPPORT DIRECT Human Clinical

"ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia."

Places overt spondyloepiphyseal dysplasia within the heterozygous ACAN phenotype, which is what this phenotype records.

PMID:16080123 SUPPORT DIRECT Human Clinical

"The autosomal dominant SED type Kimberley (SEDK) is associated with premature degenerative arthropathy and has been previously mapped in a multigenerational family to a novel locus on 15q26.1."

Establishes SEDK as a dominant entity with joint disease and locates it to the ACAN interval, which is what makes it a member of this spectrum rather than a separate disease.

Premature osteoarthritis HP:0003088

Show evidence (2 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families)."

Gives family-level counts of both joint features in the 2017 cohort.

PMID:16080123 SUPPORT DIRECT Human Clinical

"The autosomal dominant SED type Kimberley (SEDK) is associated with premature degenerative arthropathy and has been previously mapped in a multigenerational family to a novel locus on 15q26.1."

Records the same feature in the founding SEDK kindred, which is what makes it common to both subtypes rather than specific to one.

Osteochondritis dissecans HP:0010886

Show evidence (2 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"In some families (families 3, 5, and 6), the ACAN mutations were associated with osteochondritis dissecans (OD) (4, 13, 20)."

Identifies three affected families; this establishes occurrence but does not quantify the fraction of individual carriers with OCD.

PMID:24762113 SUPPORT DIRECT Human Clinical

"In addition, she has a history of persistent pain in both knees and a knee x-ray and magnetic resonance imaging detected multiple osteochondral lesions along the weight-bearing parts of the medial femoral condyles consistent with osteochondritis dissecans."

An individual case with the imaging findings and their anatomical distribution, which is what makes the lesion recognizable clinically.

Intervertebral disk degeneration HP:0008419

Sequelae: Back pain

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"In our cohort, the affected individuals of several families also reported early-onset intervertebral disc disease that often caused neurologic symptoms and required surgical intervention."

Records the disc involvement and its clinical severity in the cohort.

Constitutional 1

Back pain HP:0003418

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Back pain was also a common complaint in affected adult individuals of 11 families"

Gives the family-level frequency of the symptom in adults.

Growth 2

Short stature HP:0004322

Show evidence (4 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Heterozygous ACAN mutations cause short stature with bone age acceleration and premature growth cessation and are frequently associated with early-onset osteoarthritis and degenerative disc disease."

The cohort's one-sentence statement of the phenotype, establishing short stature as the defining feature of the spectrum.

PMID:27870580 SUPPORT DIRECT Human Clinical

"Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6)."

Provides the childhood distribution, including individuals above the usual short-stature cutoff; it does not establish complete penetrance.

PMID:24762113 SUPPORT DIRECT Human Clinical

"We identified three novel loss-of-function variants mutations in ACAN in three families, all with the rare combination of short stature, advanced bone age, and premature growth cessation."

An independent set of families showing the same triad, which is what makes the combination characteristic rather than a feature of one cohort. Quoted verbatim including the source's "variants mutations" duplication.

+ 1 more reference

Disproportionate short stature HP:0003498

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly."

Establishes the spectrum of body proportions without quantifying the proportion of patients with disproportion.

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Genetic Associations

1

ACAN

Gene: ACAN hgnc:319 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Identified ACAN variants showed perfect cosegregation with phenotype."

The segregation evidence across 20 families, which is what establishes causation rather than association for this gene.

PMID:29464738 SUPPORT DIRECT Human Clinical

"Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type."

Enumerates the allelic series and its two inheritance modes, which is the basis for this entry's scope statement.

PMID:33471655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Approximately half of these mutations can lead to protein truncation."

Quantifies the truncating class, which is the basis for the two-class description above.

+ 1 more reference

💊

Medical Actions

5

Recombinant Human Growth Hormone

Action: Pharmacotherapy NCIT:C15986

Agent: somatropin NCIT:C837

Platform: Protein replacement

Growth hormone has shown improved childhood growth in retrospective cohorts and in an open-label, single-arm prospective study of ten children followed for three years. The prospective median height gain was +1.21 SDS. These results do not establish the size of an adult-height benefit against an untreated control group. Older children entering puberty showed an attenuated response; IGF-I elevations frequently prompted dose reduction.

Mechanism Target:

MODULATES Impaired Growth Plate Chondrogenesis — Growth hormone acts on the growth plate to increase chondrocyte proliferation and matrix production. It does not restore aggrecan, so the effect is a partial compensation at the affected node rather than a correction of the lesion - which is consistent with the modest observed response.

Show evidence (1 reference)

PMID:27870580 SUPPORT INDIRECT Human Clinical

"Both of these observations suggest a modest response to GH, with a magnitude similar to that seen with GH treatment of idiopathic short stature (32, 33)."

Supports a partial, non-specific effect at the growth plate. Marked INDIRECT because the inference from a height gain to an action on this node is not measured in these patients.

Show evidence (10 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"During GH treatment, the height SDS increased on average by +0.4, +0.7, and +1.0 SDS during the first year, the first 2 years, and the first 3 years of treatment, respectively"

The quantified growth response in the treated subset of the 2017 cohort.

PMID:36387899 SUPPORT DIRECT Human Clinical

"Promising therapeutic benefits were seen in the patients who received growth-promoting treatment, with an increase in growth velocity from 4.52 ± 1.00 cm/year to 8.03 ± 1.16 cm/year."

The 2022 cohort reports improved growth velocity in a small treated series that includes variants classified as uncertain; it is supportive observational evidence, not a controlled pathogenic-variant-only trial.

PMID:27870580 SUPPORT DIRECT Human Clinical

"However, to rigorously assess the efficacy and safety of GHs for the treatment of children with short stature due to ACAN mutations, a randomized controlled trial would be required."

The 2017 authors explicitly limit the certainty of their observational treatment findings; this is compatible with, rather than a refutation of, the qualified treatment claim.

+ 7 more references

Pubertal Suppression with a GnRH Analogue

Action: Pharmacotherapy NCIT:C15986

Agent: gonadotropin-releasing hormone analogue NCIT:C1910

Platform: Peptide

GnRH analogues have been combined with growth hormone to delay pubertal skeletal maturation. The 2017 cohort had paired radiographs in only two treated individuals, with arrested bone-age progression during observation. This surrogate response does not establish improvement in final adult height.

Mechanism Target:

INHIBITS Premature Epiphyseal Fusion — Suppression of gonadotropins and gonadal sex steroids may delay pubertal growth-plate maturation and fusion. This does not correct the ACAN defect, and advanced bone age before puberty is not necessarily estrogen dependent.

Show evidence (1 reference)

PMID:24762113 SUPPORT INDIRECT Human Clinical

"However, the fact that affected females seem to experience sudden growth cessation early in puberty taken together with the finding that GnRH analog treatment essentially froze bone age progression in the proband of Family 3 suggest an important role for estrogen."

The reasoning that links the treatment to this node through estrogen. Marked INDIRECT because the estrogen role is inferred from the treatment response and the sex difference rather than measured.

Show evidence (2 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"During treatment, BA progression was halted (0 years of progression/chronological year) during 9 and 22 months of gonadotropin-releasing hormone analog treatment, respectively."

The measured effect on the surrogate endpoint, in the two patients with paired radiographs.

PMID:27870580 SUPPORT INDIRECT Human Clinical

"Moreover, no adverse events or serious side effects from the treatments, including no new or worsened joint pain, were recorded for any of the patients."

The safety observation, and specifically that the joint arm did not worsen - a reasonable prior concern when suppressing sex steroids in a cartilage disease. Marked INDIRECT because absence of recorded events in a retrospective cohort is weak evidence of safety.

Aromatase Inhibition with Letrozole

Action: Pharmacotherapy NCIT:C15986

Agent: letrozole CHEBI:6413

Platform: Small molecule

One male in the 2017 cohort received growth hormone plus letrozole, with halted bone-age progression during treatment. This single-patient, combined-treatment observation does not establish efficacy or safety for routine use.

Mechanism Target:

INHIBITS Premature Epiphyseal Fusion — Aromatase inhibition reduces estrogen synthesis and may delay skeletal maturation; the disease-specific support is the observed bone-age response during combined treatment.

Show evidence (1 reference)

PMID:27870580 SUPPORT INDIRECT Human Clinical

"During letrozole treatment, BA progression was halted (Fig. 6)."

Documents the surrogate endpoint in the individual receiving combined GH and letrozole; no controlled adult-height effect is established.

Show evidence (2 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"In addition, 1 male patient had received treatment with GH and an aromatase inhibitor (letrozole; family 1) for 11 months."

Records the aromatase-inhibitor arm and its n, which is one.

PMID:27870580 SUPPORT DIRECT Human Clinical

"During letrozole treatment, BA progression was halted (Fig. 6)."

Documents the surrogate endpoint in the individual receiving combined GH and letrozole; no controlled adult-height effect is established.

Orthopaedic Management of Joint and Disc Disease

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

The joint arm needs its own follow-up, and it is what most affected adults present with: early osteoarthritis, degenerative disc disease that in several families required surgery, and osteochondritis dissecans lesions. Nothing here is disease-specific - it is standard orthopaedic care - but recording it makes the point that a diagnosis reached in an endocrine clinic for short stature carries a lifelong musculoskeletal consequence.

Mechanism Target:

BYPASSES Intervertebral disk degeneration — Decompressive or stabilising surgery addresses the consequence of the degenerated disc; it does nothing to the matrix defect. Targeted at the phenotype because that is where the operation acts.

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"In our cohort, the affected individuals of several families also reported early-onset intervertebral disc disease that often caused neurologic symptoms and required surgical intervention."

Ties the surgical action to this specific phenotype node - the disc disease is what was operated on. It documents the indication, not a mechanistic effect, which is why the link is BYPASSES.

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"In our cohort, the affected individuals of several families also reported early-onset intervertebral disc disease that often caused neurologic symptoms and required surgical intervention."

Documents that surgical management was actually required, rather than recommending it.

Genetic Counselling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling should explain dominant transmission, variable growth and joint manifestations, and the difference between a pathogenic variant and a VUS. Perfect cosegregation within an ascertained family should not be presented as universal complete penetrance.

Show evidence (1 reference)

PMID:27870580 SUPPORT INDIRECT Human Clinical

"Identified ACAN variants showed perfect cosegregation with phenotype."

Family segregation supports counselling about dominant transmission; the study did not measure counselling outcomes or population-wide penetrance.

🔬

Diagnosis

2

Bone Age Radiograph (Variable bone age advancement; normal bone age does not exclude the disorder)

A hand and wrist radiograph estimates skeletal maturation; the 2017 study used the Greulich and Pyle method. Markedly advanced bone age can be a diagnostic clue, but normal bone age does not exclude ACAN-related disease. Height predictions require caution in a skeletal growth disorder.

radiographic bone age assessment NCIT:C137876

Bound to NCIT:C137876 Bone Radiography, the imaging action this test performs. NCIT does carry the exact method the description names - NCIT:C181502 Greulich and Pyle Bone Age Estimation, returned by `runoak -i ols:ncit search "l~bone age"` - but it is not bindable here on positive grounds rather than absent ones: its ancestors are C81307 Estimation Method and C16847 Technique, with no path to NCIT:C25218 Clinical Intervention or Procedure, which is the TreatmentActionTerm root. It names the reading method, not the clinical action. C137876 is reachable from that root via C128940 Radiographic Examination, C16502 Diagnostic Imaging Testing, C17369 Imaging Procedure and C18020 Diagnostic Procedure, so the binding keeps the radiograph and leaves the bone-age reading to preferred_term. An earlier note here recorded a search for "Bone Age Determination" returning nothing and concluded no term existed; that query was too narrow, and the broader one above returns both terms.

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"BA was assessed according to the method of Greulich and Pyle (12) by a single reader of the films, who was kept unaware of the age and identification of the individuals."

Records the method and its blinding, which is what makes the cohort's bone age figures comparable across families.

ACAN Sequencing (Heterozygous ACAN variant in all confirmed patients)

A pathogenic or likely pathogenic heterozygous ACAN variant interpreted with the phenotype and segregation supports molecular diagnosis. Published approaches include candidate-gene Sanger sequencing, targeted panels and exome sequencing. Neither a normal skeletal survey nor absence of advanced bone age excludes the disorder. A VUS alone does not establish the diagnosis.

ACAN sequence analysis NCIT:C153598

A variant-of-unknown-significance rate high enough to matter: 10 of 16 variants in one series were VUS, and the probands carrying them differed from the pathogenic-variant probands in bone age and in coxa valga frequency. A reported ACAN variant is not by itself a diagnosis.

Show evidence (3 references)

PMID:24762113 SUPPORT DIRECT Human Clinical

"We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation."

Records the method that identified the gene in the short-stature presentation.

PMID:29464738 SUPPORT DIRECT Human Clinical

"ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia."

States the clinical indication for testing, which is what this diagnosis entry is for.

PMID:38232712 SUPPORT DIRECT Human Clinical

"genetic testing for ACAN deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement."

The registry study supports considering ACAN analysis beyond the stereotypical dysmorphic or advanced-bone-age presentation.

📈

Progression

3

Childhood

Growth impairment may become more conspicuous from childhood to adulthood. The 2017 cohort reported median childhood height -2.0 SDS; endocrine evaluation was normal in most probands, and bone age could be normal or advanced.

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6)."

Gives the childhood figure that the adult figure is compared against.

Puberty and growth cessation

Early growth cessation and reduced pubertal growth spurts can occur despite normally timed puberty. Bone-age-based adult-height prediction may overestimate attained height in this disorder.

Show evidence (2 references)

PMID:27870580 SUPPORT DIRECT Human Clinical

"This relative advancement of BA appears to reflect decreased remaining growth potential as evidenced by the history of early growth cessation in subjects"

Ties the advanced bone age to lost growth potential at this phase.

PMID:24762113 SUPPORT DIRECT Human Clinical

"Interestingly, our subjects seemed to undergo growth cessation even earlier than their advanced bone ages would suggest, highlighting the inherent inaccuracy of height prediction by bone age assessment in children with underlying genetic growth disorders."

The specific practical warning about height prediction, which is a management-relevant property of this phase and not a general caveat.

Adult course

Adult morbidity can include early osteoarthritis, disc degeneration, back pain and osteochondritis dissecans requiring orthopaedic management. The cited cohorts do not establish a population survival estimate.

Show evidence (1 reference)

PMID:27870580 SUPPORT DIRECT Human Clinical

"Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage."

Records the adult morbidity that dominates this phase.

📊

Prevalence

1

Worldwide

Cases In Literature

The 2020 review reported more than 200 genetically diagnosed individuals. This is a historical literature count, not a current count or a measured population prevalence. The cited studies do not establish population prevalence.

Show evidence (2 references)

PMID:33471655 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In the literature, more than 200 affected individuals have been diagnosed genetically with a similar condition"

The reported case count behind the CASES_IN_LITERATURE measure.

PMID:27870580 SUPPORT INDIRECT Human Clinical

"heterozygous ACAN mutations might be relatively common in families with autosomal dominant short stature with accelerated skeletal maturation and early growth cessation"

Supports the under-ascertainment caveat. Marked INDIRECT because it is the authors' expectation about a selected clinical group, not a measured frequency in any population.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from ACAN-Related Short Stature Spectrum:

Idiopathic short stature

Overlapping Features Not a mimic so much as the label these patients carry until someone sequences them. What should prompt the test is short stature with a normal endocrine workup plus any of brachydactyly, an advanced bone age, a family history of early growth cessation, or a family history of early-onset osteoarthritis.

Spondyloepimetaphyseal dysplasia, aggrecan type

Overlapping Features The biallelic form of the same gene, with severe short stature and a combined spondylo-epi-metaphyseal radiographic picture. Recessive rather than dominant, and curated as its own dismech entry. It is the reason this entry states its heterozygous scope explicitly.

SHOX deficiency disorders

Overlapping Features The other common monogenic cause of mildly disproportionate short stature reached through an endocrine clinic, and the one ACAN is most often tested alongside. Distinguished by Madelung deformity and mesomelia, and by a bone age that is not advanced.

Spondyloepiphyseal dysplasia congenita

Overlapping Features COL2A1-related spondyloepiphyseal dysplasia is a differential for the SEDK presentation. Congenital skeletal findings and associated ocular or hearing abnormalities can help distinguish it; absence of these findings alone is not diagnostic.

Sporadic osteochondritis dissecans

Overlapping Features Far commoner than the familial form and usually attributed to repetitive joint loading in an athletic adolescent. Short stature in the patient or the family, or lesions in several joints, is what should raise the familial possibility.

🔬

Clinical Trials

1

NCT03288103 PHASE_II COMPLETED

Registered phase 1/phase 2, open-label, single-arm pilot of growth hormone in children with ACAN deficiency, extended from one to three treatment years. The single-valued phase field records phase II; the registry lists both phase I and phase II. Phase and completed status were checked against the ClinicalTrials.gov record during this review.

Show evidence (2 references)

clinicaltrials:NCT03288103 SUPPORT Other

"This is an open-label, single-arm prospective pilot study to study the effects of a single dose regimen of daily growth hormone medication (Norditropin) on pre-pubertal children with Aggrecan deficiency."

The registry summary establishes the disease, intervention and uncontrolled prospective design.

PMID:39502477 SUPPORT DIRECT Human Clinical

"Ten treatment-naïve prepubertal patients with genetically confirmed ACAN deficiency were treated with rhGH for 3 years in an open-label, single-arm prospective study."

Establishes the prospective interventional design and absence of a randomized comparison.

🧫

Experimental Models

1

Patient BM-MSC and iPSC-derived chondrocyte model of familial osteochondritis dissecans IPSC_DERIVED_MODEL

Chondrocytes differentiated from bone-marrow mesenchymal stromal cells and, independently, from iPSC lines of patients heterozygous for the G3 C-type lectin missense allele. The two routes were run in parallel and agreed, which is what makes the intracellular retention finding more than an artefact of one differentiation protocol.

Organism

human NCBITaxon:9606

Cell source

Patient bone marrow mesenchymal stromal cells and patient fibroblast-derived iPSC lines

Publication

PMID:27388238

Pathograph links

Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum recapitulates fidelity: moderate observes: cellular Patient-derived chondrocyte models supply the evidence for intracellular retention of this variant; they do not establish the same intracellular fate for other ACAN alleles.

Limitations: One allele, one family. Differentiated stromal and iPSC-derived chondrocytes are not native growth-plate or articular chondrocytes, and the pellet cultures have no mechanical loading, no vasculature and no growth-plate zonal architecture - so nothing about the growth arm of the disease can be read off this model. Fidelity is MODERATE rather than HIGH because the retention has not been confirmed in patient cartilage in situ, and because the same allele was earlier shown by mass spectrometry to yield aggrecan that is present in patient cartilage.

Readouts

Intracellular aggrecan localisation in differentiated chondrocytes

Direction: INCREASED

Interpretation: Accumulation within the endoplasmic reticulum, seen in both BM-MSC- and iPSC-derived chondrocytes.

Show evidence (1 reference)

PMID:27388238 SUPPORT DIRECT In Vitro

"Second, it was evident that large amounts of aggrecan accumulated within the endoplasmic reticulum of chondrocytes differentiated from both BM-MSCs and iPSCs."

The measurement this readout records, in both derivation routes.

Extracellular matrix aggrecan content

Direction: DECREASED

Interpretation: The matrix counterpart of the intracellular accumulation.

Show evidence (1 reference)

PMID:27388238 SUPPORT DIRECT In Vitro

"In turn, there was a marked absence of aggrecan in the extracellular matrix."

Records the depletion of matrix aggrecan alongside the intracellular accumulation.

Show evidence (1 reference)

PMID:27388238 SUPPORT DIRECT In Vitro

"The results suggest that FOCD is a chondrocyte aggrecanosis with associated matrix dysregulation."

The authors' own summary of what the model shows, which is the claim the link above carries.

Show evidence (2 references)

PMID:27388238 SUPPORT DIRECT In Vitro

"It is associated with a heterozygous mutation in the ACAN gene, resulting in a Val-Met replacement in the C-type lectin domain of aggrecan."

Establishes that the cells carry the disease allele of this spectrum, which is what makes the model informative for these nodes at all.

PMID:27388238 SUPPORT DIRECT In Vitro

"The results suggest that FOCD is a chondrocyte aggrecanosis with associated matrix dysregulation."

The authors' own summary of what the model shows, which is the claim the link above carries.

{ }

Source YAML

click to show

name: ACAN-Related Short Stature Spectrum
creation_date: "2026-09-20T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: ACAN-related short stature spectrum
  term:
    id: MONDO:1060149
    label: ACAN-related short stature spectrum
parents:
- hereditary disease
- Skeletal Dysplasia
synonyms:
- aggrecanopathy
- aggrecan deficiency
- spondyloepiphyseal dysplasia, Kimberley type
- SEDK
- short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans
- SSOAOD
- familial osteochondritis dissecans
- fOCD
description: >-
  An autosomal dominant spectrum caused by heterozygous pathogenic ACAN variants.
  Aggrecan supports both growth-plate and articular cartilage, accounting for variable
  short stature, altered skeletal maturation, early growth cessation, premature
  osteoarthritis, osteochondritis dissecans and disc degeneration. Truncating alleles
  can reduce functional aggrecan dosage. Missense alleles occur in several domains;
  familial osteochondritis dissecans-associated variants are enriched in the G3 C-type
  lectin repeat, where studied alleles impair secretion and extracellular ligand
  interactions. The entry covers heterozygous presentations historically called SED
  Kimberley type, SSOAOD and familial osteochondritis dissecans. Biallelic
  spondyloepimetaphyseal dysplasia aggrecan type is curated separately.
notes: >-
  SCOPE NOTE (deliberate; read before changing disease_term or has_subtypes).
  MONDO:1060149 has exactly three children: MONDO:0012019 (SED Kimberley type),
  MONDO:0100462 (SSOAOD) and MONDO:0013014 (SEMD aggrecan type). The first two are the
  dominant forms curated here as has_subtypes. The third is recessive and is already a
  full dismech entry (kb/disorders/Spondyloepimetaphyseal_Dysplasia_Aggrecan_Type.yaml,
  MONDO:0013014), which states its own scope as "relating the others rather than
  absorbing them". This entry returns the complement: the spectrum term is used as the
  anchor because it is the only MONDO class that names the dominant spectrum at all, and
  the recessive extreme is recorded as a differential diagnosis and in the genetic notes
  rather than duplicated as a third subtype. The two entries therefore cover the parent
  term and one of its children respectively, and share no disease_term.

  VARIANT NOMENCLATURE HAZARD. The G3-domain missense variants in this spectrum have
  been renumbered. The familial osteochondritis dissecans allele published as p.V2303M
  (NM_013227.2) is p.V2455M under RefSeq NM_001369268.1; the SSOAOD allele published as
  p.L2355P is p.L2393P; and the recessive SEMD allele published as p.D2267N is p.D2419N.
  Stattin et al. (PMID:35338222) give the mapping table. Both numbering systems are in
  current use, so a variant matched by residue number alone can be assigned to the wrong
  allele - and two of the three renumbered alleles belong to different diseases in this
  same gene. Quote each source's own notation rather than normalizing it.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012019
      label: spondyloepiphyseal dysplasia, Kimberley type
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO (OMIM:608361)
    mapping_justification: >-
      The skeletal-dysplasia end of the spectrum modeled here, curated as the
      SEDK subtype. narrowMatch rather than exactMatch because this entry also
      covers the SSOAOD presentations.
  - term:
      id: MONDO:0100462
      label: short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO (OMIM:165800)
    mapping_justification: >-
      The short-stature and joint-disease end of the spectrum modeled here,
      curated as the SSOAOD subtype and subsuming familial osteochondritis
      dissecans. narrowMatch rather than exactMatch because this entry also
      covers SED Kimberley type.
classifications:
  isds_skeletal_category:
  - classification_value: proteoglycan_core_protein_disorders
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (11th edition;
      Unger et al., PMID:36779427), group 7 "Proteoglycan core protein
      disorders". In the 2019 revision (PMID:31633310) the ACAN disorders sat in
      a separate "Aggrecan group", which lists "SED, Kimberley type" and "Short
      stature and advanced bone age" as distinct Table 1 rows; this entry lumps
      them, for the reasons given in the acan_spectrum_lumping discussion.
    evidence:
    - reference: PMID:36779427
      reference_title: "Nosology of genetic skeletal disorders: 2023 revision."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the previous “Perlecan group” and “Aggrecan group” were incorporated into
        the new group of “Proteoglycan core protein disorders”
      explanation: >-
        Supports the group's identity and its provenance from the merged 2019
        aggrecan group. Graded OTHER because the source is a consensus
        nosology paper rather than a primary study.
has_subtypes:
- name: SEDK
  display_name: Spondyloepiphyseal dysplasia, Kimberley type
  subtype_term:
    preferred_term: spondyloepiphyseal dysplasia, Kimberley type
    term:
      id: MONDO:0012019
      label: spondyloepiphyseal dysplasia, Kimberley type
  description: >-
    The overt skeletal-dysplasia presentation: short stature with vertebral and
    epiphyseal change and premature degenerative arthropathy, recognized as a
    dysplasia on radiographs rather than as isolated short stature. Delineated in
    one multigenerational South African kindred mapped to 15q26.1, in which the
    causal allele is a single-base-pair insertion in the variable repeat region
    of ACAN exon 12 - the first ACAN variant shown to cause a human disorder.
  genes:
  - preferred_term: ACAN
    term:
      id: hgnc:319
      label: ACAN
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:16080123
    reference_title: >-
      A mutation in the variable repeat region of the aggrecan gene (AGC1) causes
      a form of spondyloepiphyseal dysplasia associated with severe, premature
      osteoarthritis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The autosomal dominant SED type Kimberley (SEDK) is associated with
      premature degenerative arthropathy and has been previously mapped in a
      multigenerational family to a novel locus on 15q26.1.
    explanation: >-
      Establishes SEDK as a dominant entity with joint disease and locates it to
      the ACAN interval, which is what makes it a member of this spectrum rather
      than a separate disease.
  - reference: PMID:16080123
    reference_title: >-
      A mutation in the variable repeat region of the aggrecan gene (AGC1) causes
      a form of spondyloepiphyseal dysplasia associated with severe, premature
      osteoarthritis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first identification of an AGC1 mutation causing a human
      disorder.
    explanation: >-
      Records SEDK as the founding member of the ACAN allelic series, which is why
      this subtype carries the historical name rather than the spectrum.
- name: SSOAOD
  display_name: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans
  subtype_term:
    preferred_term: short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans
    term:
      id: MONDO:0100462
      label: short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans
  description: >-
    The commoner presentation, and the one reached through an endocrine rather than a
    genetics clinic: proportionate or mildly disproportionate short stature with a
    normal endocrine workup, often an advanced bone age, and early growth cessation. Its
    "with or without" clause carries familial osteochondritis dissecans, which was
    described separately in a Swedish five-generation family and is now placed under the
    same OMIM entity; Stattin et al. label their families "fOCD/SSOAOD" for exactly that
    reason.
  genes:
  - preferred_term: ACAN
    term:
      id: hgnc:319
      label: ACAN
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study demonstrates that heterozygous mutations in ACAN can cause a mild
      skeletal dysplasia, which presents clinically as short stature with advanced
      bone age.
    explanation: >-
      Delineates the subtype as a mild dysplasia presenting as short stature with
      advanced bone age, which is what distinguishes it from SEDK.
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients have short stature, variable, mild facial dysmorphism, and
      brachydactyly, but do not exhibit the vertebral body deformities detected in
      SEDK and SEMD.
    explanation: >-
      The authors' own contrast with SEDK, which is the clinical basis for keeping
      the two as separate subtypes inside one entry rather than merging them.
pathophysiology:
- name: Heterozygous ACAN Variants
  description: >-
    Heterozygous pathogenic ACAN variants include truncating, splice-site and missense
    alleles distributed across the gene. Missense variants associated with familial
    osteochondritis dissecans are enriched in the G3 domain, but neither all missense
    variants nor all familial osteochondritis dissecans variants are restricted to that
    domain. Variant class, domain and experimental system must be distinguished when
    interpreting functional effects.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ACAN
    term:
      id: hgnc:319
      label: ACAN
  evidence:
  - reference: PMID:16080123
    reference_title: >-
      A mutation in the variable repeat region of the aggrecan gene (AGC1) causes
      a form of spondyloepiphyseal dysplasia associated with severe, premature
      osteoarthritis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We screened AGC1 for mutations and identified a single-base-pair insertion,
      within the variable repeat region of exon 12 in affected individuals from
      the family with SEDK, that introduces a frameshift of 212 amino acids,
      including 22 cysteine residues, followed by a premature stop codon.
    explanation: >-
      The founding truncating allele, given in the detail that establishes it as a
      protein-truncating rather than a missense lesion.
  - reference: PMID:33471655
    reference_title: >-
      Growth-Promoting Therapies May Be Useful In Short Stature Patients With
      Nonspecific Skeletal Abnormalities Caused By Acan Heterozygous Mutations:
      Six Chinese Cases And Literature Review.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately half of these mutations can lead to protein truncation.
    explanation: >-
      Quantifies the split between the truncating and non-truncating allele
      classes across the reported series, which is why this node branches rather
      than asserting one mechanism.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mapping these and other ACAN variants linked to hereditary skeletal
      disorders showed a clustering of osteochondritis dissecans-linked variants
      to the G3 domain.
    explanation: >-
      The enrichment concerns osteochondritis dissecans-associated variants, not every
      missense allele in the ACAN spectrum.
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, an additional fOCD missense ACAN variant has been reported
      affecting the aggrecan G1 globular domain
    explanation: >-
      The full-text discussion explicitly records a familial OCD variant outside G3, so
      clustering is not an absolute domain restriction.
    quote_role: BACKGROUND
  downstream:
  - target: Aggrecan Deficiency in the Cartilage Extracellular Matrix
    causal_link_type: DIRECT
    description: >-
      The route taken by the truncating alleles: one functional copy of the gene
      supplies the matrix.
  - target: Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan
    causal_link_type: DIRECT
    description: >-
      Studied G3 missense variants alter ligand affinity.
    evidence:
    - reference: PMID:20137779
      reference_title: >-
        A missense mutation in the aggrecan C-type lectin domain disrupts extracellular
        matrix interactions and causes dominant familial osteochondritis dissecans.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Binding studies with recombinant mutated and wild-type G3 proteins showed loss
        of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein.
      explanation: >-
        The 2010 assays demonstrate impaired ligand interactions for p.V2303M; the full
        text distinguishes weakened affinity from complete loss across constructs.
  - target: Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum
    causal_link_type: DIRECT
    description: >-
      Patient-derived cells carrying p.V2303M show ER aggrecan accumulation.
    evidence:
    - reference: PMID:27388238
      reference_title: >-
        Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
        Cells of Patients With Familial Osteochondritis Dissecans Exhibit an Endoplasmic
        Reticulum Stress Response and Defective Matrix Assembly.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Second, it was evident that large amounts of aggrecan accumulated within the
        endoplasmic reticulum of chondrocytes differentiated from both BM-MSCs and
        iPSCs.
      explanation: >-
        The direct observation of intracellular retention that this node names, made
        independently in two patient-derived chondrocyte systems.
  - target: Reduced Secretion of G3-Domain Variant Aggrecan
    causal_link_type: DIRECT
    description: >-
      G3 missense variant expression constructs show reduced secretion.
    evidence:
    - reference: PMID:35338222
      reference_title: >-
        Novel missense ACAN gene variants linked to familial osteochondritis dissecans
        cluster in the C-terminal globular domain of aggrecan.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Functional studies showed that neither recombinant variant proteins, nor
        full-length variant aggrecan proteoglycan from heterozygous patient cartilage,
        were secreted to the same level as wild-type aggrecan.
      explanation: >-
        Supports decreased secretion in recombinant constructs and in the patient
        explant experiment, with experimental scope specified by the full-text evidence
        below.
  notes: >-
    The variant numbering in the cited sources is not uniform - see the
    nomenclature hazard recorded in the entry notes. Each snippet quotes its own
    source's notation rather than a normalized form.
- name: Aggrecan Deficiency in the Cartilage Extracellular Matrix
  description: >-
    Reduced functional aggrecan availability is a proposed convergence mechanism for
    impaired cartilage growth. Similar growth impairment across allele classes in the
    2017 cohort supported functional haploinsufficiency, but did not demonstrate
    identical molecular effects. The 2024 Dutch cohort found shorter stature among
    subjects with truncating than non-truncating variants. Secretion and ligand-binding
    defects remain experimentally distinguishable in G3 missense disease.
  role: mechanism
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: cartilage tissue
    term:
      id: UBERON:0002418
      label: cartilage tissue
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, it is likely that the impairment of growth plate chondrogenesis
      is due to functional haploinsufficiency of aggrecan, rather than different
      mutation-specific mechanisms (25).
    explanation: >-
      The authors' own statement of the convergent mechanism this node asserts.
      Marked DIRECT because it states the claim, and note it is offered as a
      likelihood rather than a demonstration - the acan_haploinsufficiency_vs_g3
      discussion records what is not settled by it.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Taken together, these findings suggest that different disease-causing
      heterozygous ACAN variants impair growth plate chondrogenesis similarly,
      which, in turn, suggests a common mechanism.
    explanation: >-
      The clinical observation the dosage inference rests on - similar growth
      impairment across different variant types. Marked INDIRECT because the
      common mechanism is inferred from phenotypic similarity, not measured.
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      The large proteoglycan aggrecan is vital for skeletal development and
      cartilage function, creating a swelling pressure in the tissue that provides
      resistance to compression and load dissipation over the joint surface
    explanation: >-
      States the biophysical function that a reduced aggrecan dose degrades, which
      is why this node is the pivot of the entry. Graded quote_role BACKGROUND
      because the sentence opens the paper's introduction and restates established
      cartilage biology rather than reporting this study's own result;
      evidence_source OTHER because the restated claim is textbook matrix biology
      with no single study design behind it.
  - reference: PMID:38232712
    reference_title: "Clinical Characteristics of Pathogenic ACAN Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subjects with a truncating ACAN variant had a shorter height SDS compared to
      subjects with a non-truncating variant (-2.8 SDS and -2.1 SDS, respectively, p =
      0.002).
    explanation: >-
      A later cohort identifies an allele-class association with height; the earlier
      absence of a correlation cannot establish universal molecular equivalence.
  downstream:
  - target: Impaired Growth Plate Chondrogenesis
    causal_link_type: DIRECT
    description: >-
      Growth-plate cartilage is where longitudinal bone growth is produced, so a
      matrix deficit there limits elongation.
  - target: Articular and Intervertebral Disc Matrix Insufficiency
    causal_link_type: DIRECT
    description: >-
      The same protein is the major proteoglycan of articular cartilage and of the
      intervertebral disc, which is why one gene dose produces a joint arm as well
      as a growth arm.
- name: Reduced Secretion of G3-Domain Variant Aggrecan
  description: >-
    Selected G3 variants are secreted less efficiently in recombinant expression assays,
    with severity depending on the splice construct. In the 2022 pilot explant
    experiment, a patient carrying p.V2455M had less variant than wild-type aggrecan in
    both cartilage and conditioned medium. This is a within-patient allelic comparison,
    not a measurement in cartilage from each of the three newly described families.
  role: mechanism
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: protein secretion
    modifier: DECREASED
    term:
      id: GO:0009306
      label: protein secretion
  evidence:
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies showed that neither recombinant variant proteins, nor
      full-length variant aggrecan proteoglycan from heterozygous patient
      cartilage, were secreted to the same level as wild-type aggrecan.
    explanation: >-
      Supports decreased secretion in recombinant constructs and in the patient explant
      experiment, with experimental scope specified by the full-text evidence below.
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      In a pilot experiment, we cultured cartilage explants from an fOCD patient
      heterozygous for the p.V2455M variant, obtained at arthroplasty for advanced
      osteoarthritis.
    explanation: >-
      Identifies the patient allele and the pilot explant design; the full-length
      experiment did not sample all three new variant families.
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The variant protein was, however, only present at low levels, both in the tissue
      explant (Fig. 6a) and the culture medium (Fig. 6b).
    explanation: >-
      Variant-specific mass spectrometry found reduced variant protein relative to wild
      type in the heterozygous patient explant and medium.
  downstream:
  - target: Aggrecan Deficiency in the Cartilage Extracellular Matrix
    causal_link_type: DIRECT
    description: >-
      Reduced export decreases the amount of variant aggrecan available to the
      extracellular matrix.
- name: Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan
  description: >-
    Studied G3 C-type lectin variants alter extracellular ligand binding. The 2010
    p.V2303M experiments found weakened or absent interactions depending on ligand and
    splice construct. The 2022 assays showed pronounced impairment of fibulin-1 and
    tenascin-C binding, with residual tenascin-R binding in all variants tested.
    Tenascin-R is a CNS ligand in that study, so its assay result is not evidence that
    it is the relevant cartilage ligand.
  role: mechanism
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TNC
    term:
      id: hgnc:5318
      label: TNC
  - preferred_term: FBLN1
    term:
      id: hgnc:3600
      label: FBLN1
  evidence:
  - reference: PMID:20137779
    reference_title: >-
      A missense mutation in the aggrecan C-type lectin domain disrupts
      extracellular matrix interactions and causes dominant familial
      osteochondritis dissecans.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Binding studies with recombinant mutated and wild-type G3 proteins showed
      loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M
      protein.
    explanation: >-
      The 2010 assays demonstrate impaired ligand interactions for p.V2303M; the full
      text distinguishes weakened affinity from complete loss across constructs.
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The variant proteins also showed decreased binding to known cartilage
      extracellular matrix ligands.
    explanation: >-
      The 2022 experiments extend impaired ligand binding to additional G3 variants; the
      effect varies by ligand and construct.
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Interaction with the brain ligand tenascin-R was affected to a lesser degree, with
      retained binding of all the variants tested.
    explanation: >-
      The full-text binding experiments qualify the abstract-level loss-of-binding
      summary: tenascin-R interaction is reduced, not universally abolished.
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Note pronounced loss of binding of fOCD variants to fibulin-1 and tenascin-C
      (a,b).
    explanation: >-
      Figure 7 identifies the cartilage ligands with the pronounced binding defect.
  downstream:
  - target: Articular and Intervertebral Disc Matrix Insufficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired interactions with cartilage ligands may compromise matrix organization
      and stability; the tissue consequence is inferred from biochemical binding
      experiments.
- name: Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum
  description: >-
    Established only in patient-derived cells, and only for the p.V2303M
    familial-osteochondritis-dissecans allele. Chondrocytes differentiated from
    patient bone-marrow mesenchymal stromal cells and from patient iPSC lines
    accumulate large amounts of aggrecan inside the endoplasmic reticulum while
    the surrounding matrix is depleted of it - the authors' term is chondrocyte
    aggrecanosis. The pellets these cells form are rich in glycosaminoglycan and
    still structurally poor, which is the cellular-level version of the whole
    entry's point that the defect is in matrix assembly rather than in bulk
    synthesis.
  role: mechanism
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  evidence:
  - reference: PMID:27388238
    reference_title: >-
      Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
      Cells of Patients With Familial Osteochondritis Dissecans Exhibit an
      Endoplasmic Reticulum Stress Response and Defective Matrix Assembly.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Second, it was evident that large amounts of aggrecan accumulated within the
      endoplasmic reticulum of chondrocytes differentiated from both BM-MSCs and
      iPSCs.
    explanation: >-
      The direct observation of intracellular retention that this node names, made
      independently in two patient-derived chondrocyte systems.
  - reference: PMID:27388238
    reference_title: >-
      Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
      Cells of Patients With Familial Osteochondritis Dissecans Exhibit an
      Endoplasmic Reticulum Stress Response and Defective Matrix Assembly.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      In turn, there was a marked absence of aggrecan in the extracellular matrix.
    explanation: >-
      Links the retention to the matrix deficit, which is the causal edge below.
  - reference: PMID:27388238
    reference_title: >-
      Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
      Cells of Patients With Familial Osteochondritis Dissecans Exhibit an
      Endoplasmic Reticulum Stress Response and Defective Matrix Assembly.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      First, patient chondrogenic pellets had poor structural integrity but were
      rich in glycosaminoglycan.
    explanation: >-
      Separates the assembly defect from a synthesis defect - the cells are making
      glycosaminoglycan, and the tissue they build is still weak. Marked INDIRECT
      because it is a property of the engineered pellet rather than of the retained
      protein itself.
  downstream:
  - target: Reduced Secretion of G3-Domain Variant Aggrecan
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Intracellular retention is a candidate contributor to impaired export; retention
      and extracellular depletion were observed together in patient-derived cells,
      without a causal rescue experiment.
    evidence:
    - reference: PMID:27388238
      reference_title: >-
        Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
        Cells of Patients With Familial Osteochondritis Dissecans Exhibit an Endoplasmic
        Reticulum Stress Response and Defective Matrix Assembly.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Second, it was evident that large amounts of aggrecan accumulated within the
        endoplasmic reticulum of chondrocytes differentiated from both BM-MSCs and
        iPSCs.
      explanation: >-
        The direct observation of intracellular retention that this node names, made
        independently in two patient-derived chondrocyte systems.
  notes: >-
    Observed in differentiated patient BM-MSC and iPSC-derived chondrocytes carrying
    p.V2303M. The relationship to reduced secretion is mechanistic interpretation of
    co-occurring cellular abnormalities, not proof that reduced secretion causes ER
    retention. Native growth-plate localization has not been established by these
    experiments.
- name: Impaired Growth Plate Chondrogenesis
  description: >-
    Longitudinal bone growth is produced at the growth plate by chondrocyte
    proliferation, hypertrophy and matrix production, then replacement of that
    cartilage by bone. Aggrecan is a critical component of the matrix the plate is
    built from, so a reduced dose degrades the template and the mechanical
    environment the chondrocytes work in at the same time. This is the growth arm
    of the spectrum, and it is the same lesion as the joint arm one tissue over.
  role: mechanism
  biological_scale: TISSUE
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: growth plate cartilage development
    modifier: ABNORMAL
    term:
      id: GO:0003417
      label: growth plate cartilage development
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  locations:
  - preferred_term: epiphyseal plate
    term:
      id: UBERON:0002516
      label: epiphyseal plate
  evidence:
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      Aggrecan is a critical proteoglycan component of the cartilage matrix, both
      in articular and growth plate cartilage, thus accounting for the dual
      phenotypic effects on both these types of cartilage.
    explanation: >-
      The authors' own account of why one gene produces two organ-level arms,
      which is the branch structure this entry uses.
    quote_role: BACKGROUND
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      Consistent with this explanation, homozygous mutations in ACAN in both mice
      and chicks severely disrupt growth plate function and impair bone elongation
      (18, 19).
    explanation: >-
      The animal evidence that growth-plate failure is the route from aggrecan loss
      to short bones. Graded MODEL_ORGANISM because the evidence described is
      murine and avian, and quote_role BACKGROUND because this paper is a human
      exome study restating work it did not perform. Marked INDIRECT because the
      animals are homozygous nulls and the human disease is heterozygous.
  downstream:
  - target: Premature Epiphyseal Fusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered maturation is proposed from aggrecan-null animal growth plates and human
      radiographic observations; it has not been directly demonstrated in heterozygous
      human growth plates.
  - target: Short stature
    causal_link_type: DIRECT
    description: >-
      Reduced elongation at the growth plates of the long bones and vertebrae.
  - target: Disproportionate short stature
    causal_link_type: DIRECT
    description: >-
      Limb and spine plates are not affected to the same degree, which is what
      makes a minority of patients disproportionate rather than uniformly small.
  - target: Spondyloepiphyseal dysplasia
    causal_link_type: DIRECT
    description: >-
      Where the plate involvement is severe enough to be radiographically evident
      in the vertebrae and epiphyses, the presentation is the SEDK end of the
      spectrum.
  - target: Brachydactyly
    causal_link_type: DIRECT
    description: >-
      The short tubular bones of the hand grow from the same kind of plate and are
      affected disproportionately.
  - target: Accelerated skeletal maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered growth-plate maturation is the proposed link to advanced radiographic bone
      age; accelerated bone age can occur before complete fusion.
- name: Premature Epiphyseal Fusion
  description: >-
    Premature growth-plate closure limits remaining longitudinal growth. Early fusion
    and growth cessation are observed clinically. Premature hypertrophic maturation has
    been proposed as an upstream mechanism from aggrecan-null chick studies; that
    cellular mechanism is not directly demonstrated in human heterozygotes.
  role: mechanism
  biological_scale: TISSUE
  cell_types:
  - preferred_term: hypertrophic chondrocyte
    term:
      id: CL:0000743
      label: hypertrophic chondrocyte
  locations:
  - preferred_term: epiphyseal plate
    term:
      id: UBERON:0002516
      label: epiphyseal plate
  evidence:
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      In chicks, there is evidence for abnormal Indian hedgehog, fibroblast growth
      factor, and bone morphogenetic protein signaling, leading to premature
      hypertrophic chondrocyte maturation (18).
    explanation: >-
      The signalling evidence behind premature hypertrophy. Graded MODEL_ORGANISM
      for the avian source and quote_role BACKGROUND because the citing paper is a
      human study restating it; INDIRECT because the chick model is an aggrecan
      null.
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      Because hypertrophic differentiation induces vascular invasion and
      ossification of growth cartilage (3), these findings provide a likely
      explanation for the advanced bone age, premature growth cessation, and early
      epiphyseal fusion observed in the current study.
    explanation: >-
      Joins premature hypertrophy to the three clinical features this node feeds,
      and is explicitly offered by its authors as a likely explanation rather than
      a demonstrated one - which is why the link is INDIRECT and the node is not
      treated as settled.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This relative advancement of BA appears to reflect decreased remaining
      growth potential as evidenced by the history of early growth cessation in
      subjects
    explanation: >-
      The human-cohort statement that the advanced bone age indexes lost growth
      potential, which is what makes it a readout of this node and not an
      independent phenotype.
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 15 years of age a bone age x-ray revealed that all growth plates were fused.
    explanation: >-
      Documents epiphyseal fusion in an affected woman whose growth had ceased early;
      this is human evidence for the tissue endpoint.
  downstream:
  - target: Short stature
    causal_link_type: DIRECT
    description: >-
      Early closure truncates the growing period, so adult height falls further
      below the mean than childhood height did.
- name: Articular and Intervertebral Disc Matrix Insufficiency
  conforms_to: "osteoarthritis_cartilage_degradation#Mechanical Overload and Chondrocyte Stress"
  description: >-
    The joint arm. Aggrecan is the major proteoglycan of articular cartilage and
    of the intervertebral disc, and a matrix built with less of it - or with
    aggrecan that cannot bind its network partners - carries load badly for
    decades. This node substitutes an intrinsic matrix lesion for the mechanical
    overload that opens the osteoarthritis module, which is the substitution that
    module's own notes name for ACAN defects, and then hands off to the module's
    conserved chondrocyte-to-matrix-degradation chain.
  role: mechanism
  biological_scale: TISSUE
  cell_types:
  - preferred_term: articular chondrocyte
    term:
      id: CL:1001607
      label: articular chondrocyte
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: articular cartilage of joint
    term:
      id: UBERON:0010996
      label: articular cartilage of joint
  - preferred_term: intervertebral disk
    term:
      id: UBERON:0001066
      label: intervertebral disk
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many affected individuals developed early-onset osteoarthritis and
      degenerative disc disease, suggesting dysfunction of the articular cartilage
      and intervertebral disc cartilage.
    explanation: >-
      The cohort observation and the authors' localisation of it to the two
      cartilages this node names.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      This finding is consistent with aggrecan being the major proteoglycan
      component of the intervertebral disc and loss of aggrecan being an important
      pathogenic mechanism for degenerative disc disease (21).
    explanation: >-
      Supplies the disc-specific mechanism. Graded quote_role BACKGROUND and
      evidence_source OTHER because the sentence cites established disc biology
      from another source rather than reporting this cohort's own measurement.
  - reference: PMID:20137779
    reference_title: >-
      A missense mutation in the aggrecan C-type lectin domain disrupts
      extracellular matrix interactions and causes dominant familial
      osteochondritis dissecans.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results provide a molecular mechanism for the etiology of familial
      osteochondritis dissecans and show the importance of the aggrecan C-type
      lectin interactions for cartilage function in vivo.
    explanation: >-
      Connects the G3 binding lesion to articular cartilage failure in patients,
      which is the second inbound route to this node.
  downstream:
  - target: Premature osteoarthritis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Through the conserved chondrocyte-stress and matrix-degradation chain of the
      osteoarthritis module this node conforms to; the intervening decades of
      loading are omitted.
  - target: Osteochondritis dissecans
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A weakened osteochondral junction allows fragments of articular cartilage and
      subchondral bone to separate from the joint surface.
  - target: Intervertebral disk degeneration
    causal_link_type: DIRECT
    description: >-
      Reduced functional aggrecan may compromise disc matrix hydration and load-bearing
      function.
phenotypes:
- name: Short stature
  category: Growth
  description: >-
    Growth impairment is variable and often becomes more pronounced with age. The 2017
    cohort abstract reports median childhood height -2.0 SDS and median adult height
    -2.8 SDS, with some mutation-positive individuals in the low-normal range. Short
    stature is therefore not an obligate finding at every age.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous ACAN mutations cause short stature with bone age acceleration
      and premature growth cessation and are frequently associated with
      early-onset osteoarthritis and degenerative disc disease.
    explanation: >-
      The cohort's one-sentence statement of the phenotype, establishing short
      stature as the defining feature of the spectrum.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to
      -0.6).
    explanation: >-
      Provides the childhood distribution, including individuals above the usual
      short-stature cutoff; it does not establish complete penetrance.
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three novel loss-of-function variants mutations in ACAN in
      three families, all with the rare combination of short stature, advanced
      bone age, and premature growth cessation.
    explanation: >-
      An independent set of families showing the same triad, which is what makes
      the combination characteristic rather than a feature of one cohort. Quoted
      verbatim including the source's "variants mutations" duplication.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9
    explanation: >-
      The adult height distribution from the abstract. Quoting the numerical clause
      without its surrounding brackets preserves the source text while avoiding bracket
      stripping by the validator.
- name: Disproportionate short stature
  category: Growth
  description: >-
    Body disproportion is variable and often mild. The spectrum includes proportionate
    short stature and more recognizable skeletal dysplasia; its frequency cannot be
    inferred from a statement that both presentations occur.
  phenotype_term:
    preferred_term: Disproportionate short stature
    term:
      id: HP:0003498
      label: Disproportionate short stature
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous ACAN mutations result in a phenotypic spectrum ranging from
      mild and proportionate short stature to a mild skeletal dysplasia with
      disproportionate short stature and brachydactyly.
    explanation: >-
      Establishes the spectrum of body proportions without quantifying the proportion of
      patients with disproportion.
- name: Accelerated skeletal maturation
  category: Skeletal
  description: >-
    Bone age may be markedly advanced, modestly advanced or normal. In the 2017 cohort,
    20 of 31 assessed children had bone age more than 12 months ahead of chronological
    age. The six families with marked advancement are a different denominator and
    severity threshold. Normal bone age does not exclude ACAN-related disease.
  phenotype_term:
    preferred_term: Accelerated skeletal maturation
    term:
      id: HP:0005616
      label: Accelerated skeletal maturation
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most children with ACAN mutations had advanced bone age (bone age -
      chronologic age; median, +1.3 years; range, +0.0 to +3.7 years).
    explanation: >-
      Quantifies the advancement and its range, including the zero lower bound
      that makes it non-obligate.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children in 6 families (families 1, 4, 12, 15, 18, and 20) had markedly
      advanced skeletal maturation (BA, 3 to 4 years advanced); however, the
      children in the other 14 families had normal or modestly advanced BA
    explanation: >-
      Supports the stated variable expression and the warning that advanced bone age is
      not required. Thresholds and ascertainment differ between studies, so these
      observations are not pooled into one prevalence estimate.
  - reference: PMID:36387899
    reference_title: >-
      Description of the molecular and phenotypic spectrum in Chinese patients
      with aggrecan deficiency: Novel ACAN heterozygous variants in eight Chinese
      children and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Meanwhile, only 24.24% of aggrecan-deficient Chinese children showed
      significantly advanced bone age (BA).
    explanation: >-
      Supports the stated variable expression and the warning that advanced bone age is
      not required. Thresholds and ascertainment differ between studies, so these
      observations are not pooled into one prevalence estimate.
  - reference: PMID:29464738
    reference_title: >-
      Heterozygous aggrecan variants are associated with short stature and
      brachydactyly: Description of 16 probands and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is also important to note that advanced BA and osteoarticular
      complications are not obligatory conditions for
      aggrecanopathies/aggrecan-associated dysplasias.
    explanation: >-
      Supports the stated variable expression and the warning that advanced bone age is
      not required. Thresholds and ascertainment differ between studies, so these
      observations are not pooled into one prevalence estimate.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 31 children with heterozygous ACAN mutations, 20 presented with a BA that was
      >12 months advanced, and no child had delayed BA
    explanation: >-
      20/31 assessed children had bone age advancement over 12 months, supporting
      FREQUENT in this cohort; family counts and marked advancement are not substituted
      for this patient-level denominator.
  frequency: FREQUENT
- name: Brachydactyly
  category: Skeletal
  description: >-
    Reported in 5 of 20 families in the 2017 cohort. The 2018 series found brachydactyly
    in all 16 probands, but ten carried variants of uncertain significance. These
    family-level and mixed-classification observations establish occurrence without a
    general patient-level frequency.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:29464738
    reference_title: >-
      Heterozygous aggrecan variants are associated with short stature and
      brachydactyly: Description of 16 probands and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, brachydactyly was observed in all probands.
    explanation: >-
      All 16 probands had brachydactyly, but the series included ten VUS; it is not an
      estimate of penetrance among confirmed pathogenic-variant carriers.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brachydactyly was reported in 5 of 20 families.
    explanation: >-
      The lower figure from the larger cohort, quoted alongside the first so the
      discrepancy is visible rather than averaged away.
  - reference: PMID:29464738
    reference_title: >-
      Heterozygous aggrecan variants are associated with short stature and
      brachydactyly: Description of 16 probands and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 16 ACAN variants were located throughout the gene, six pathogenic
      mutations and 10 variants of unknown significance (VUS).
    explanation: >-
      Qualifies the diagnostic certainty of the 16-proband denominator.
- name: Spondyloepiphyseal dysplasia
  category: Skeletal
  description: >-
    Vertebral and epiphyseal dysplasia evident on radiographs, which is the SEDK
    end of the spectrum. Explicitly absent in the families curated as SSOAOD,
    whose authors contrast their patients with SEDK on exactly this point.
  subtype: SEDK
  phenotype_term:
    preferred_term: Spondyloepiphyseal dysplasia
    term:
      id: HP:0002655
      label: Spondyloepiphyseal dysplasia
  evidence:
  - reference: PMID:29464738
    reference_title: >-
      Heterozygous aggrecan variants are associated with short stature and
      brachydactyly: Description of 16 probands and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ACAN should be considered as a candidate gene in patients with short stature
      and minor skeletal defects, particularly those with brachydactyly, and in
      patients with spondyloepiphyseal dysplasia.
    explanation: >-
      Places overt spondyloepiphyseal dysplasia within the heterozygous ACAN
      phenotype, which is what this phenotype records.
  - reference: PMID:16080123
    reference_title: >-
      A mutation in the variable repeat region of the aggrecan gene (AGC1) causes
      a form of spondyloepiphyseal dysplasia associated with severe, premature
      osteoarthritis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The autosomal dominant SED type Kimberley (SEDK) is associated with
      premature degenerative arthropathy and has been previously mapped in a
      multigenerational family to a novel locus on 15q26.1.
    explanation: >-
      Establishes SEDK as a dominant entity with joint disease and locates it to
      the ACAN interval, which is what makes it a member of this spectrum rather
      than a separate disease.
- name: Premature osteoarthritis
  category: Skeletal
  description: >-
    Early-onset degenerative joint disease was reported in 12 of 20 families in the 2017
    cohort. The presence or absence of joint complaints did not show a simple
    association with variant class in that cohort. Family counts describe affected
    kindreds and are not patient-level prevalence.
  phenotype_term:
    preferred_term: Premature osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition was frequently associated with early-onset osteoarthritis (12
      families) and intervertebral disc disease (9 families).
    explanation: >-
      Gives family-level counts of both joint features in the 2017 cohort.
  - reference: PMID:16080123
    reference_title: >-
      A mutation in the variable repeat region of the aggrecan gene (AGC1) causes
      a form of spondyloepiphyseal dysplasia associated with severe, premature
      osteoarthritis.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The autosomal dominant SED type Kimberley (SEDK) is associated with
      premature degenerative arthropathy and has been previously mapped in a
      multigenerational family to a novel locus on 15q26.1.
    explanation: >-
      Records the same feature in the founding SEDK kindred, which is what makes
      it common to both subtypes rather than specific to one.
- name: Osteochondritis dissecans
  category: Skeletal
  description: >-
    Articular cartilage and underlying subchondral bone fragments separate from the
    joint surface. The 2017 cohort recorded the phenotype in three families; those
    family counts do not give patient-level penetrance. The later prospective growth
    study detected clinically silent lesions on imaging.
  phenotype_term:
    preferred_term: Osteochondritis dissecans
    term:
      id: HP:0010886
      label: Osteochondritis dissecans
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In some families (families 3, 5, and 6), the ACAN mutations were associated
      with osteochondritis dissecans (OD) (4, 13, 20).
    explanation: >-
      Identifies three affected families; this establishes occurrence but does not
      quantify the fraction of individual carriers with OCD.
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, she has a history of persistent pain in both knees and a knee
      x-ray and magnetic resonance imaging detected multiple osteochondral lesions
      along the weight-bearing parts of the medial femoral condyles consistent
      with osteochondritis dissecans.
    explanation: >-
      An individual case with the imaging findings and their anatomical
      distribution, which is what makes the lesion recognizable clinically.
- name: Intervertebral disk degeneration
  category: Skeletal
  description: >-
    Early-onset disc disease was recorded in 9 of 20 families in the 2017 cohort. Some
    affected individuals developed neurological symptoms and required surgery.
    Family-level ascertainment does not establish individual penetrance.
  phenotype_term:
    preferred_term: Intervertebral disk degeneration
    term:
      id: HP:0008419
      label: Intervertebral disk degeneration
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort, the affected individuals of several families also reported
      early-onset intervertebral disc disease that often caused neurologic
      symptoms and required surgical intervention.
    explanation: >-
      Records the disc involvement and its clinical severity in the cohort.
  sequelae:
  - target: Back pain
    causal_link_type: DIRECT
    description: >-
      The symptom the disc degeneration presents with in adults.
- name: Back pain
  category: Neurological
  description: >-
    Back pain was reported among affected adults in 11 of 20 families in the 2017
    cohort, in association with confirmed or suspected disc disease. This is a
    family-level observation, not a measured patient prevalence or proof that every
    episode has the same cause.
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Back pain was also a common complaint in affected adult individuals of 11
      families
    explanation: >-
      Gives the family-level frequency of the symptom in adults.
- name: Midface retrusion
  category: Craniofacial
  description: >-
    Mild midface hypoplasia and a flat nasal bridge were recorded in 8 of 20 families.
    This observation is not a patient-level frequency estimate. Reported dysmorphic
    features vary across cohorts.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the mutations were associated with mild midface hypoplasia and flat nasal
      bridge (8 of 20 families
    explanation: >-
      Records the facial finding and its frequency. The quote is cut mid-clause
      because the source's sentence continues into a supplemental-figure
      reference, which carries no claim.
  - reference: PMID:36387899
    reference_title: >-
      Description of the molecular and phenotypic spectrum in Chinese patients
      with aggrecan deficiency: Novel ACAN heterozygous variants in eight Chinese
      children and a review of the literature.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of dysmorphic features in the Chinese populations is
      significantly lower than that in the Western populations.
    explanation: >-
      Supports treating the facial features as ascertainment-dependent. Marked
      INDIRECT because it is a statement about dysmorphic features in general
      rather than about midface hypoplasia specifically.
- name: Frontal bossing
  category: Craniofacial
  description: >-
    Frontal bossing was noted in young children from two families in the 2017 cohort;
    the individual-level frequency was not reported.
  notes: >-
    Deliberately left with no causal inlink. The entry models no craniofacial
    mechanism node, aggrecan's role in the facial skeleton not being worked out
    in these families, so any edge drawn to this phenotype would assert a
    mechanism the entry does not have. The same applies to Midface retrusion.
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      young children in 2 families were noted to have frontal bossing (families 16
      and 18)
    explanation: >-
      Records the finding, its age dependence and its rarity in the cohort.
genetic:
- name: ACAN
  gene_term:
    preferred_term: ACAN
    term:
      id: hgnc:319
      label: ACAN
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Pathogenic ACAN variants include truncating, splice-site and missense alleles across
    the gene. Studied G3 missense variants can affect secretion and ligand interactions,
    but this does not establish a single mechanism for all missense variants. The
    biallelic SEMD aggrecan-type disorder is curated separately and is not equated with
    lethal aggrecan-null animal models. Domain location alone does not establish
    inheritance mode, severity or pathogenicity.
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identified ACAN variants showed perfect cosegregation with phenotype.
    explanation: >-
      The segregation evidence across 20 families, which is what establishes
      causation rather than association for this gene.
  - reference: PMID:29464738
    reference_title: >-
      Heterozygous aggrecan variants are associated with short stature and
      brachydactyly: Description of 16 probands and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the aggrecan gene (ACAN) have been identified in two autosomal
      dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type
      (SEDK), and osteochondritis dissecans, as well as in a severe recessive
      dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type.
    explanation: >-
      Enumerates the allelic series and its two inheritance modes, which is the
      basis for this entry's scope statement.
  - reference: PMID:33471655
    reference_title: >-
      Growth-Promoting Therapies May Be Useful In Short Stature Patients With
      Nonspecific Skeletal Abnormalities Caused By Acan Heterozygous Mutations:
      Six Chinese Cases And Literature Review.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately half of these mutations can lead to protein truncation.
    explanation: >-
      Quantifies the truncating class, which is the basis for the two-class
      description above.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:35338222
    reference_title: >-
      Novel missense ACAN gene variants linked to familial osteochondritis
      dissecans cluster in the C-terminal globular domain of aggrecan.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We previously reported a missense ACAN variant linked to familial
      osteochondritis dissecans, with short stature and early onset osteoarthritis,
      and now describe three novel ACAN gene variants from additional families with
      this disorder.
    explanation: >-
      Establishes that the osteochondritis-dissecans presentation is not a single
      private allele, which is what makes the G3 clustering a finding rather than
      a coincidence.
inheritance:
- name: Autosomal dominant
  description: >-
    Autosomal dominant transmission is supported by cosegregation in multiple kindreds.
    Growth and joint manifestations vary with age and between carriers. Cosegregation in
    ascertained families does not establish complete penetrance across all pathogenic
    variants.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identified ACAN variants showed perfect cosegregation with phenotype.
    explanation: >-
      The segregation result underpinning the dominant assignment.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No apparent genotype-phenotype correlation was found between the type of
      ACAN mutation and the presence of joint complaints.
    explanation: >-
      Supports describing penetrance per-feature: the joint arm varies
      independently of the allele class.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The 2020 review reported more than 200 genetically diagnosed individuals. This is a
    historical literature count, not a current count or a measured population
    prevalence. The cited studies do not establish population prevalence.
  evidence:
  - reference: PMID:33471655
    reference_title: >-
      Growth-Promoting Therapies May Be Useful In Short Stature Patients With
      Nonspecific Skeletal Abnormalities Caused By Acan Heterozygous Mutations:
      Six Chinese Cases And Literature Review.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the literature, more than 200 affected individuals have been diagnosed
      genetically with a similar condition
    explanation: >-
      The reported case count behind the CASES_IN_LITERATURE measure.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      heterozygous ACAN mutations might be relatively common in families with
      autosomal dominant short stature with accelerated skeletal maturation and
      early growth cessation
    explanation: >-
      Supports the under-ascertainment caveat. Marked INDIRECT because it is the
      authors' expectation about a selected clinical group, not a measured
      frequency in any population.
progression:
- phase: Childhood
  notes: >-
    Growth impairment may become more conspicuous from childhood to adulthood. The 2017
    cohort reported median childhood height -2.0 SDS; endocrine evaluation was normal in
    most probands, and bone age could be normal or advanced.
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to
      -0.6).
    explanation: >-
      Gives the childhood figure that the adult figure is compared against.
- phase: Puberty and growth cessation
  notes: >-
    Early growth cessation and reduced pubertal growth spurts can occur despite normally
    timed puberty. Bone-age-based adult-height prediction may overestimate attained
    height in this disorder.
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This relative advancement of BA appears to reflect decreased remaining
      growth potential as evidenced by the history of early growth cessation in
      subjects
    explanation: >-
      Ties the advanced bone age to lost growth potential at this phase.
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, our subjects seemed to undergo growth cessation even earlier
      than their advanced bone ages would suggest, highlighting the inherent
      inaccuracy of height prediction by bone age assessment in children with
      underlying genetic growth disorders.
    explanation: >-
      The specific practical warning about height prediction, which is a
      management-relevant property of this phase and not a general caveat.
- phase: Adult course
  notes: >-
    Adult morbidity can include early osteoarthritis, disc degeneration, back pain and
    osteochondritis dissecans requiring orthopaedic management. The cited cohorts do not
    establish a population survival estimate.
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many affected individuals developed early-onset osteoarthritis and
      degenerative disc disease, suggesting dysfunction of the articular cartilage
      and intervertebral disc cartilage.
    explanation: >-
      Records the adult morbidity that dominates this phase.
diagnosis:
- name: Bone Age Radiograph
  description: >-
    A hand and wrist radiograph estimates skeletal maturation; the 2017 study used the
    Greulich and Pyle method. Markedly advanced bone age can be a diagnostic clue, but
    normal bone age does not exclude ACAN-related disease. Height predictions require
    caution in a skeletal growth disorder.
  diagnosis_term:
    preferred_term: radiographic bone age assessment
    term:
      id: NCIT:C137876
      label: Bone Radiography
  presence: Variable bone age advancement; normal bone age does not exclude the disorder
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BA was assessed according to the method of Greulich and Pyle (12) by a
      single reader of the films, who was kept unaware of the age and
      identification of the individuals.
    explanation: >-
      Records the method and its blinding, which is what makes the cohort's bone
      age figures comparable across families.
  notes: >-
    Bound to NCIT:C137876 Bone Radiography, the imaging action this test
    performs. NCIT does carry the exact method the description names -
    NCIT:C181502 Greulich and Pyle Bone Age Estimation, returned by
    `runoak -i ols:ncit search "l~bone age"` - but it is not bindable here on
    positive grounds rather than absent ones: its ancestors are C81307
    Estimation Method and C16847 Technique, with no path to NCIT:C25218
    Clinical Intervention or Procedure, which is the TreatmentActionTerm root.
    It names the reading method, not the clinical action. C137876 is reachable
    from that root via C128940 Radiographic Examination, C16502 Diagnostic
    Imaging Testing, C17369 Imaging Procedure and C18020 Diagnostic Procedure,
    so the binding keeps the radiograph and leaves the bone-age reading to
    preferred_term. An earlier note here recorded a search for "Bone Age
    Determination" returning nothing and concluded no term existed; that query
    was too narrow, and the broader one above returns both terms.
- name: ACAN Sequencing
  description: >-
    A pathogenic or likely pathogenic heterozygous ACAN variant interpreted with the
    phenotype and segregation supports molecular diagnosis. Published approaches include
    candidate-gene Sanger sequencing, targeted panels and exome sequencing. Neither a
    normal skeletal survey nor absence of advanced bone age excludes the disorder. A VUS
    alone does not establish the diagnosis.
  diagnosis_term:
    preferred_term: ACAN sequence analysis
    term:
      id: NCIT:C153598
      label: DNA Sequencing
  presence: Heterozygous ACAN variant in all confirmed patients
  evidence:
  - reference: PMID:24762113
    reference_title: >-
      Short stature, accelerated bone maturation, and early growth cessation due
      to heterozygous aggrecan mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used whole-exome sequencing to study three families with
      autosomal-dominant short stature, advanced bone age, and premature growth
      cessation.
    explanation: >-
      Records the method that identified the gene in the short-stature
      presentation.
  - reference: PMID:29464738
    reference_title: >-
      Heterozygous aggrecan variants are associated with short stature and
      brachydactyly: Description of 16 probands and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ACAN should be considered as a candidate gene in patients with short stature
      and minor skeletal defects, particularly those with brachydactyly, and in
      patients with spondyloepiphyseal dysplasia.
    explanation: >-
      States the clinical indication for testing, which is what this diagnosis
      entry is for.
  - reference: PMID:38232712
    reference_title: "Clinical Characteristics of Pathogenic ACAN Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genetic testing for ACAN deficiency should be considered in any child with
      significant short stature, even in the absence of disproportion, specific
      dysmorphic features, or BA advancement.
    explanation: >-
      The registry study supports considering ACAN analysis beyond the stereotypical
      dysmorphic or advanced-bone-age presentation.
  notes: >-
    A variant-of-unknown-significance rate high enough to matter: 10 of 16
    variants in one series were VUS, and the probands carrying them differed from
    the pathogenic-variant probands in bone age and in coxa valga frequency. A
    reported ACAN variant is not by itself a diagnosis.
treatments:
- name: Recombinant Human Growth Hormone
  description: >-
    Growth hormone has shown improved childhood growth in retrospective cohorts and in
    an open-label, single-arm prospective study of ten children followed for three
    years. The prospective median height gain was +1.21 SDS. These results do not
    establish the size of an adult-height benefit against an untreated control group.
    Older children entering puberty showed an attenuated response; IGF-I elevations
    frequently prompted dose reduction.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During GH treatment, the height SDS increased on average by +0.4, +0.7, and
      +1.0 SDS during the first year, the first 2 years, and the first 3 years of
      treatment, respectively
    explanation: >-
      The quantified growth response in the treated subset of the 2017 cohort.
  - reference: PMID:36387899
    reference_title: >-
      Description of the molecular and phenotypic spectrum in Chinese patients
      with aggrecan deficiency: Novel ACAN heterozygous variants in eight Chinese
      children and a review of the literature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Promising therapeutic benefits were seen in the patients who received
      growth-promoting treatment, with an increase in growth velocity from 4.52 ±
      1.00 cm/year to 8.03 ± 1.16 cm/year.
    explanation: >-
      The 2022 cohort reports improved growth velocity in a small treated series that
      includes variants classified as uncertain; it is supportive observational
      evidence, not a controlled pathogenic-variant-only trial.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, to rigorously assess the efficacy and safety of GHs for the
      treatment of children with short stature due to ACAN mutations, a randomized
      controlled trial would be required.
    explanation: >-
      The 2017 authors explicitly limit the certainty of their observational treatment
      findings; this is compatible with, rather than a refutation of, the qualified
      treatment claim.
  - reference: PMID:39502477
    reference_title: "Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human GH: 3-year Response."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cumulative median ΔHtSDS over 3 years was +1.21 (range, +0.82 to +1.94).
    explanation: >-
      Quantifies the prospective childhood height response in ten participants; it is
      not measured adult-height gain.
  - reference: PMID:39502477
    reference_title: "Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human GH: 3-year Response."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten treatment-naïve prepubertal patients with genetically confirmed ACAN
      deficiency were treated with rhGH for 3 years in an open-label, single-arm
      prospective study.
    explanation: >-
      Establishes the prospective interventional design and absence of a randomized
      comparison.
  - reference: PMID:39502477
    reference_title: "Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human GH: 3-year Response."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although all patients were started on an rhGH dose of 50 mcg/kg/day
      subcutaneously, 8 subjects underwent a protocol-driven dose reduction based on
      elevated IGF-I concentrations.
    explanation: >-
      Full-text safety monitoring shows that the initial dose frequently needed
      adjustment; the starting dose should not be copied as a universal treatment
      recommendation.
  - reference: PMID:39502477
    reference_title: "Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human GH: 3-year Response."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were diagnosed with OD (2 during the trial and 1 after completion
      of the trial), a known potential phenotypic manifestation with ACAN deficiency
    explanation: >-
      Joint lesions were detected during follow-up. The study does not establish whether
      treatment caused them.
  - reference: PMID:38232712
    reference_title: "Clinical Characteristics of Pathogenic ACAN Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS
      (0.9-1.4). In pubertal children, height SDS remained relatively stable.
    explanation: >-
      The Dutch registry independently supports a larger response before puberty.
  - reference: PMID:41211650
    reference_title: Impact of Growth Hormone Treatment in Children From an Extended Family With ACAN -Related Short Stature.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The long-term impact on final adult height remains to be elucidated.
    explanation: >-
      A later extended-family follow-up retains the adult-height uncertainty despite
      improved growth during treatment.
  - reference: PMID:42498135
    reference_title: "Phenotypic Characterization and recombinant human growth hormone Therapeutic Response in ACAN Children With Short Stature: A Real-World Study."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth velocity at 3, 6, 9, 12, and 18 months was significantly higher than
      baseline (all P < .05).
    explanation: >-
      The 2026 retrospective series reports improved growth velocity during treatment in
      17 children; this is not a randomized adult-height comparison.
  target_mechanisms:
  - target: Impaired Growth Plate Chondrogenesis
    treatment_effect: MODULATES
    description: >-
      Growth hormone acts on the growth plate to increase chondrocyte
      proliferation and matrix production. It does not restore aggrecan, so the
      effect is a partial compensation at the affected node rather than a
      correction of the lesion - which is consistent with the modest observed
      response.
    evidence:
    - reference: PMID:27870580
      reference_title: >-
        Clinical Characterization of Patients With Autosomal Dominant Short Stature
        due to Aggrecan Mutations.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both of these observations suggest a modest response to GH, with a
        magnitude similar to that seen with GH treatment of idiopathic short
        stature (32, 33).
      explanation: >-
        Supports a partial, non-specific effect at the growth plate. Marked
        INDIRECT because the inference from a height gain to an action on this
        node is not measured in these patients.
  notes: >-
    Graded PROTEIN_REPLACEMENT as the modality because somatropin is recombinant
    human growth hormone given as a protein; note it replaces nothing that is
    deficient in this disease, which is the point of the MODULATES rather than
    CORRECTS link above.
- name: Pubertal Suppression with a GnRH Analogue
  description: >-
    GnRH analogues have been combined with growth hormone to delay pubertal skeletal
    maturation. The 2017 cohort had paired radiographs in only two treated individuals,
    with arrested bone-age progression during observation. This surrogate response does
    not establish improvement in final adult height.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gonadotropin-releasing hormone analogue
      term:
        id: NCIT:C1910
        label: Gonadotropin-releasing Hormone Analog
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During treatment, BA progression was halted (0 years of
      progression/chronological year) during 9 and 22 months of
      gonadotropin-releasing hormone analog treatment, respectively.
    explanation: >-
      The measured effect on the surrogate endpoint, in the two patients with
      paired radiographs.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, no adverse events or serious side effects from the treatments,
      including no new or worsened joint pain, were recorded for any of the
      patients.
    explanation: >-
      The safety observation, and specifically that the joint arm did not worsen -
      a reasonable prior concern when suppressing sex steroids in a cartilage
      disease. Marked INDIRECT because absence of recorded events in a
      retrospective cohort is weak evidence of safety.
  target_mechanisms:
  - target: Premature Epiphyseal Fusion
    treatment_effect: INHIBITS
    description: >-
      Suppression of gonadotropins and gonadal sex steroids may delay pubertal
      growth-plate maturation and fusion. This does not correct the ACAN defect, and
      advanced bone age before puberty is not necessarily estrogen dependent.
    evidence:
    - reference: PMID:24762113
      reference_title: >-
        Short stature, accelerated bone maturation, and early growth cessation due
        to heterozygous aggrecan mutations.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, the fact that affected females seem to experience sudden growth
        cessation early in puberty taken together with the finding that GnRH
        analog treatment essentially froze bone age progression in the proband of
        Family 3 suggest an important role for estrogen.
      explanation: >-
        The reasoning that links the treatment to this node through estrogen.
        Marked INDIRECT because the estrogen role is inferred from the treatment
        response and the sex difference rather than measured.
- name: Aromatase Inhibition with Letrozole
  description: >-
    One male in the 2017 cohort received growth hormone plus letrozole, with halted
    bone-age progression during treatment. This single-patient, combined-treatment
    observation does not establish efficacy or safety for routine use.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: letrozole
      term:
        id: CHEBI:6413
        label: letrozole
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, 1 male patient had received treatment with GH and an aromatase
      inhibitor (letrozole; family 1) for 11 months.
    explanation: >-
      Records the aromatase-inhibitor arm and its n, which is one.
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During letrozole treatment, BA progression was halted (Fig. 6).
    explanation: >-
      Documents the surrogate endpoint in the individual receiving combined GH and
      letrozole; no controlled adult-height effect is established.
  target_mechanisms:
  - target: Premature Epiphyseal Fusion
    treatment_effect: INHIBITS
    description: >-
      Aromatase inhibition reduces estrogen synthesis and may delay skeletal maturation;
      the disease-specific support is the observed bone-age response during combined
      treatment.
    evidence:
    - reference: PMID:27870580
      reference_title: >-
        Clinical Characterization of Patients With Autosomal Dominant Short Stature
        due to Aggrecan Mutations.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        During letrozole treatment, BA progression was halted (Fig. 6).
      explanation: >-
        Documents the surrogate endpoint in the individual receiving combined GH and
        letrozole; no controlled adult-height effect is established.
- name: Orthopaedic Management of Joint and Disc Disease
  description: >-
    The joint arm needs its own follow-up, and it is what most affected adults
    present with: early osteoarthritis, degenerative disc disease that in several
    families required surgery, and osteochondritis dissecans lesions. Nothing here
    is disease-specific - it is standard orthopaedic care - but recording it makes
    the point that a diagnosis reached in an endocrine clinic for short stature
    carries a lifelong musculoskeletal consequence.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort, the affected individuals of several families also reported
      early-onset intervertebral disc disease that often caused neurologic
      symptoms and required surgical intervention.
    explanation: >-
      Documents that surgical management was actually required, rather than
      recommending it.
  target_mechanisms:
  - target: Intervertebral disk degeneration
    treatment_effect: BYPASSES
    description: >-
      Decompressive or stabilising surgery addresses the consequence of the
      degenerated disc; it does nothing to the matrix defect. Targeted at the
      phenotype because that is where the operation acts.
    evidence:
    - reference: PMID:27870580
      reference_title: >-
        Clinical Characterization of Patients With Autosomal Dominant Short Stature
        due to Aggrecan Mutations.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In our cohort, the affected individuals of several families also reported
        early-onset intervertebral disc disease that often caused neurologic
        symptoms and required surgical intervention.
      explanation: >-
        Ties the surgical action to this specific phenotype node - the disc
        disease is what was operated on. It documents the indication, not a
        mechanistic effect, which is why the link is BYPASSES.
- name: Genetic Counselling
  description: >-
    Counselling should explain dominant transmission, variable growth and joint
    manifestations, and the difference between a pathogenic variant and a VUS. Perfect
    cosegregation within an ascertained family should not be presented as universal
    complete penetrance.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:27870580
    reference_title: >-
      Clinical Characterization of Patients With Autosomal Dominant Short Stature
      due to Aggrecan Mutations.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Identified ACAN variants showed perfect cosegregation with phenotype.
    explanation: >-
      Family segregation supports counselling about dominant transmission; the study did
      not measure counselling outcomes or population-wide penetrance.
experimental_models:
- name: Patient BM-MSC and iPSC-derived chondrocyte model of familial osteochondritis dissecans
  description: >-
    Chondrocytes differentiated from bone-marrow mesenchymal stromal cells and,
    independently, from iPSC lines of patients heterozygous for the G3 C-type
    lectin missense allele. The two routes were run in parallel and agreed, which
    is what makes the intracellular retention finding more than an artefact of one
    differentiation protocol.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  cell_source: Patient bone marrow mesenchymal stromal cells and patient fibroblast-derived iPSC lines
  publication: PMID:27388238
  modeled_mechanisms:
  - target: Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Patient-derived chondrocyte models supply the evidence for intracellular
      retention of this variant; they do not establish the same intracellular
      fate for other ACAN alleles.
    limitations: >-
      One allele, one family. Differentiated stromal and iPSC-derived chondrocytes
      are not native growth-plate or articular chondrocytes, and the pellet
      cultures have no mechanical loading, no vasculature and no growth-plate zonal
      architecture - so nothing about the growth arm of the disease can be read off
      this model. Fidelity is MODERATE rather than HIGH because the retention has
      not been confirmed in patient cartilage in situ, and because the same allele
      was earlier shown by mass spectrometry to yield aggrecan that is present in
      patient cartilage.
    readouts:
    - name: Intracellular aggrecan localisation in differentiated chondrocytes
      target: Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum
      direction: INCREASED
      interpretation: Accumulation within the endoplasmic reticulum, seen in both BM-MSC- and iPSC-derived chondrocytes.
      evidence:
      - reference: PMID:27388238
        reference_title: >-
          Chondrocytes Derived From Mesenchymal Stromal Cells and Induced
          Pluripotent Cells of Patients With Familial Osteochondritis Dissecans
          Exhibit an Endoplasmic Reticulum Stress Response and Defective Matrix
          Assembly.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        snippet: >-
          Second, it was evident that large amounts of aggrecan accumulated within
          the endoplasmic reticulum of chondrocytes differentiated from both
          BM-MSCs and iPSCs.
        explanation: >-
          The measurement this readout records, in both derivation routes.
    - name: Extracellular matrix aggrecan content
      target: Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum
      direction: DECREASED
      interpretation: The matrix counterpart of the intracellular accumulation.
      evidence:
      - reference: PMID:27388238
        reference_title: >-
          Chondrocytes Derived From Mesenchymal Stromal Cells and Induced
          Pluripotent Cells of Patients With Familial Osteochondritis Dissecans
          Exhibit an Endoplasmic Reticulum Stress Response and Defective Matrix
          Assembly.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: IN_VITRO
        snippet: >-
          In turn, there was a marked absence of aggrecan in the extracellular
          matrix.
        explanation: >-
          Records the depletion of matrix aggrecan alongside the intracellular
          accumulation.
    evidence:
    - reference: PMID:27388238
      reference_title: >-
        Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
        Cells of Patients With Familial Osteochondritis Dissecans Exhibit an Endoplasmic
        Reticulum Stress Response and Defective Matrix Assembly.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The results suggest that FOCD is a chondrocyte aggrecanosis with associated
        matrix dysregulation.
      explanation: >-
        The authors' own summary of what the model shows, which is the claim the link
        above carries.
  evidence:
  - reference: PMID:27388238
    reference_title: >-
      Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
      Cells of Patients With Familial Osteochondritis Dissecans Exhibit an
      Endoplasmic Reticulum Stress Response and Defective Matrix Assembly.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      It is associated with a heterozygous mutation in the ACAN gene, resulting in
      a Val-Met replacement in the C-type lectin domain of aggrecan.
    explanation: >-
      Establishes that the cells carry the disease allele of this spectrum, which
      is what makes the model informative for these nodes at all.
  - reference: PMID:27388238
    reference_title: >-
      Chondrocytes Derived From Mesenchymal Stromal Cells and Induced Pluripotent
      Cells of Patients With Familial Osteochondritis Dissecans Exhibit an
      Endoplasmic Reticulum Stress Response and Defective Matrix Assembly.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The results suggest that FOCD is a chondrocyte aggrecanosis with associated
      matrix dysregulation.
    explanation: >-
      The authors' own summary of what the model shows, which is the claim the
      link above carries.
differential_diagnoses:
- name: Idiopathic short stature
  description: >-
    Not a mimic so much as the label these patients carry until someone sequences
    them. What should prompt the test is short stature with a normal endocrine
    workup plus any of brachydactyly, an advanced bone age, a family history of
    early growth cessation, or a family history of early-onset osteoarthritis.
- name: Spondyloepimetaphyseal dysplasia, aggrecan type
  description: >-
    The biallelic form of the same gene, with severe short stature and a combined
    spondylo-epi-metaphyseal radiographic picture. Recessive rather than dominant,
    and curated as its own dismech entry. It is the reason this entry states its
    heterozygous scope explicitly.
- name: SHOX deficiency disorders
  description: >-
    The other common monogenic cause of mildly disproportionate short stature
    reached through an endocrine clinic, and the one ACAN is most often tested
    alongside. Distinguished by Madelung deformity and mesomelia, and by a bone
    age that is not advanced.
- name: Spondyloepiphyseal dysplasia congenita
  description: >-
    COL2A1-related spondyloepiphyseal dysplasia is a differential for the SEDK
    presentation. Congenital skeletal findings and associated ocular or hearing
    abnormalities can help distinguish it; absence of these findings alone is not
    diagnostic.
- name: Sporadic osteochondritis dissecans
  description: >-
    Far commoner than the familial form and usually attributed to repetitive
    joint loading in an athletic adolescent. Short stature in the patient or the
    family, or lesions in several joints, is what should raise the familial
    possibility.
discussions:
- discussion_id: acan_spectrum_lumping
  kind: OPEN_QUESTION
  prompt: >-
    Is one spectrum entry with two subtypes the right granularity for the
    dominant ACAN disorders, or should SED Kimberley type and SSOAOD be separate
    entries?
  rationale: >-
    SED Kimberley type, SSOAOD and familial osteochondritis dissecans form an
    overlapping ACAN allelic spectrum. The 2022 functional study discusses familial OCD
    as a potential subgroup of SSOAOD while leaving open whether its mechanism merits a
    separate entity. This entry retains the existing dominant-spectrum scope and subtype
    distinctions. The separate biallelic SEMD entry is not absorbed; enrichment of joint
    disease-associated variants in G3 does not imply that every dominant variant has the
    same molecular effect.
  attaches_to:
  - has_subtypes#SEDK
  - has_subtypes#SSOAOD
  - disease#ACAN-Related Short Stature Spectrum
- discussion_id: acan_haploinsufficiency_vs_g3
  kind: CONTROVERSY
  prompt: >-
    Do the G3 C-type lectin missense alleles act simply by reducing functional
    aggrecan dose, or by a distinct mechanism that the haploinsufficiency model
    does not capture?
  rationale: >-
    Functional haploinsufficiency is a proposed explanation for growth impairment,
    whereas selected G3 variants have experimentally separable secretion and
    ligand-binding defects. The 2017 cohort found no simple variant-class association
    with joint complaints; the 2024 Dutch cohort found an association with height. These
    observations do not establish molecular equivalence across all variants. The
    contribution of ER retention, reduced export and altered extracellular interactions
    to each clinical presentation remains unresolved.
  attaches_to:
  - pathophysiology#Aggrecan Deficiency in the Cartilage Extracellular Matrix
  - pathophysiology#Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan
  - pathophysiology#Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum
- discussion_id: acan_secretion_versus_presence
  kind: CONTROVERSY
  prompt: >-
    How do assay context and allele-specific secretion influence the amount and function
    of aggrecan in patient cartilage?
  rationale: >-
    The 2010 study detected variant protein in patient cartilage and found similar total
    proteoglycan in a patient extract and pooled osteoarthritic control extracts. The
    2016 differentiated-cell study found ER retention and extracellular depletion. The
    2022 p.V2455M explant pilot measured less variant than wild-type protein in tissue
    and medium. These are distinct measurements in different systems, not proof of
    either normal secretion or complete failure across all tissues. Splice construct and
    differentiation state may influence results; their contributions have not been
    isolated in a matched comparison.
  evidence:
  - reference: PMID:20137779
    reference_title: >-
      A missense mutation in the aggrecan C-type lectin domain disrupts
      extracellular matrix interactions and causes dominant familial
      osteochondritis dissecans.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Mass spectrometric analyses of aggrecan purified from patient cartilage
      verified that V2303M aggrecan is produced and present in the tissue.
    explanation: >-
      Mass spectrometry of purified patient-cartilage aggrecan establishes the
      presence of variant protein. It does not quantify secretion or establish
      normal extracellular abundance.
  attaches_to:
  - pathophysiology#Impaired Matrix Ligand Binding of G3-Domain Variant Aggrecan
  - pathophysiology#Aggrecan Retention in the Chondrocyte Endoplasmic Reticulum
  - pathophysiology#Reduced Secretion of G3-Domain Variant Aggrecan
- discussion_id: acan_growth_promoting_therapy_evidence
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does growth hormone, with or without bone age suppression, improve adult
    height in this condition?
  rationale: >-
    Prospective and retrospective studies support improved childhood growth, but the
    magnitude of an adult-height benefit and the added value of pubertal suppression
    remain uncertain. The 2024 three-year prospective trial was single-arm, and its
    authors caution against treating early growth response or predicted adult height as
    attained adult height. Later family follow-up likewise leaves long-term benefit
    unresolved. Some adult or near-adult outcomes exist, so the uncertainty is
    comparative effectiveness, not complete absence of adult-height observations.
  attaches_to:
  - treatments#Recombinant Human Growth Hormone
  - treatments#Pubertal Suppression with a GnRH Analogue
  - pathophysiology#Premature Epiphyseal Fusion
  - treatments#Aromatase Inhibition with Letrozole
- discussion_id: acan_heterozygous_growth_plate_evidence
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does the premature hypertrophic maturation seen in aggrecan-null animals
    actually occur in the growth plate of a human heterozygote?
  rationale: >-
    Premature hypertrophic maturation is inferred from aggrecan-null animal growth
    plates and human radiographic observations. Null animal disease and heterozygous
    human disease differ substantially in dosage and severity. Direct measurement of
    maturation timing in an appropriate heterozygous model or human growth-plate system
    would test this proposed intermediate; the cited human studies do not establish it
    directly.
  attaches_to:
  - pathophysiology#Premature Epiphyseal Fusion
  - phenotypes#Accelerated skeletal maturation
review_notes: >-
  Reviewed against cached abstracts and substantive full texts, including the 2010 and
  2022 biochemical studies, 2014 and 2017 clinical reports, and the 2024 prospective
  growth-hormone trial. Family-level observations are retained as such and are not
  converted into patient-frequency bands. G3 secretion and binding are separate nodes;
  reduced secretion does not point backwards to ER retention. The 2024 Dutch registry
  cache contains a repository abstract rather than substantive full text despite its
  content-type metadata, so only its abstract is used. The 2026 growth-treatment reports
  supplement, rather than settle, adult-height uncertainty. The offline GeneReviews
  baseline check reports no dedicated chapter. No matching deep-research artifact exists
  for this dominant spectrum; the recessive SEMD report is not treated as the same
  disease. Craniofacial findings retain no causal edge because the reviewed sources do
  not establish their mechanism.
clinical_trials:
- name: NCT03288103
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Registered phase 1/phase 2, open-label, single-arm pilot of growth hormone in
    children with ACAN deficiency, extended from one to three treatment years. The
    single-valued phase field records phase II; the registry lists both phase I and
    phase II. Phase and completed status were checked against the ClinicalTrials.gov
    record during this review.
  evidence:
  - reference: clinicaltrials:NCT03288103
    reference_title: Clinical Characterization and Trial of Growth Hormone Treatment in Patients With Aggrecan (ACAN) Deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This is an open-label, single-arm prospective pilot study to study the effects of
      a single dose regimen of daily growth hormone medication (Norditropin) on
      pre-pubertal children with Aggrecan deficiency.
    explanation: >-
      The registry summary establishes the disease, intervention and uncontrolled
      prospective design.
  - reference: PMID:39502477
    reference_title: "Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human GH: 3-year Response."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten treatment-naïve prepubertal patients with genetically confirmed ACAN
      deficiency were treated with rhGH for 3 years in an open-label, single-arm
      prospective study.
    explanation: >-
      Establishes the prospective interventional design and absence of a randomized
      comparison.

ACAN-Related Short Stature Spectrum

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