CHST3-related skeletal dysplasia (chondrodysplasia with congenital joint dislocations, CHST3-related; spondyloepiphyseal dysplasia with congenital joint dislocations, SEDCJD) is an autosomal recessive disorder of cartilage proteoglycan sulfation caused by biallelic loss-of-function variants in CHST3, which encodes carbohydrate sulfotransferase 3 (chondroitin 6-O-sulfotransferase-1, C6ST-1). C6ST-1 is a Golgi enzyme that transfers sulfate from PAPS to the C-6 position of N-acetylgalactosamine in chondroitin. Its loss produces a generalized, cartilage-relevant defect of chondroitin sulfate 6-O-sulfation with compensatory 4-O-sulfation, altering the physical and signalling properties of proteoglycans in growth-plate, epiphyseal, articular and vertebral cartilage. The clinical result is short stature of prenatal onset, congenital dislocation of the large joints (knees, hips and radial heads), club feet, limitation of range of motion of all large joints, and kyphosis or kyphoscoliosis that develops in childhood and progresses. Minor heart valve dysplasia occurs in a minority; intellect and vision are normal. Three historically separate diagnoses — autosomal recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type — were unified by molecular analysis and are now recognized as one CHST3 phenotypic spectrum, distinct from FLNB-associated dominant Larsen syndrome.
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Conditions with similar clinical presentations that must be differentiated from CHST3-Related Skeletal Dysplasia:
name: CHST3-Related Skeletal Dysplasia
creation_date: '2026-08-01T06:20:00Z'
category: Mendelian
description: >
CHST3-related skeletal dysplasia (chondrodysplasia with congenital joint
dislocations, CHST3-related; spondyloepiphyseal dysplasia with congenital
joint dislocations, SEDCJD) is an autosomal recessive disorder of cartilage
proteoglycan sulfation caused by biallelic loss-of-function variants in
CHST3, which encodes carbohydrate sulfotransferase 3 (chondroitin
6-O-sulfotransferase-1, C6ST-1). C6ST-1 is a Golgi enzyme that transfers
sulfate from PAPS to the C-6 position of N-acetylgalactosamine in chondroitin.
Its loss produces a generalized, cartilage-relevant defect of chondroitin
sulfate 6-O-sulfation with compensatory 4-O-sulfation, altering the physical
and signalling properties of proteoglycans in growth-plate, epiphyseal,
articular and vertebral cartilage. The clinical result is short stature of
prenatal onset, congenital dislocation of the large joints (knees, hips and
radial heads), club feet, limitation of range of motion of all large joints,
and kyphosis or kyphoscoliosis that develops in childhood and progresses.
Minor heart valve dysplasia occurs in a minority; intellect and vision are
normal. Three historically separate diagnoses — autosomal recessive Larsen
syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani
type — were unified by molecular analysis and are now recognized as one
CHST3 phenotypic spectrum, distinct from FLNB-associated dominant Larsen
syndrome.
synonyms:
- Chondrodysplasia with congenital joint dislocations, CHST3-related
- Spondyloepiphyseal dysplasia with congenital joint dislocations
- SEDCJD
- Chondrodysplasia with multiple dislocations
- Humero-spinal dysostosis
- Larsen syndrome, autosomal recessive type
- Spondyloepiphyseal dysplasia, Omani type
- CHST3 deficiency
disease_term:
preferred_term: CHST3-related skeletal dysplasia
term:
id: MONDO:0007738
label: spondyloepiphyseal dysplasia with congenital joint dislocations
parents:
- Spondyloepiphyseal Dysplasia
references:
- reference: PMID:21882400
title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
tags:
- GeneReviews
inheritance:
- name: Autosomal Recessive
description: >
Biallelic (homozygous or compound heterozygous) CHST3 variants are required;
heterozygous carriers are unaffected. Consanguinity is a frequent
ascertainment context, and homozygous variants predominate in reported
series. Expressivity is variable, including intrafamilial variability
between siblings carrying the same homozygous CHST3 genotype.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
expressivity: VARIABLE
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CDCJD-CHST3 is inherited in an autosomal recessive manner.
explanation: >-
GeneReviews states the mode of inheritance directly.
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Twenty-four different CHST3 mutations were identified; 16 patients had
homozygous mutations.
explanation: >-
Predominance of homozygous genotypes in a 24-patient series is consistent
with recessive inheritance, largely in consanguineous families.
- reference: PMID:23918704
reference_title: "Two Somali half-siblings with CHST3-related chondrodysplasia illustrating the phenotypic spectrum and intrafamilial variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This report of a Somali family with CHST3-related chondrodysplasia
illustrates the intrafamilial variability in phenotypic expression of this
rare disorder.
explanation: >-
Documents variable expressivity between relatives sharing the same
genotype.
classifications:
isds_skeletal_category:
- classification_value: sulphation_disorders
notes: >-
ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
revision (Mortier et al., PMID:31633310), Table 1 group 4 "Sulphation
disorders group"; listed as "Chondrodysplasia with congenital joint
dislocations, CHST3 type (recessive Larsen syndrome)".
prevalence:
- population: Worldwide
measure_type: UNKNOWN
prevalence_class: ULTRA_RARE
notes: >-
No validated prevalence, incidence or carrier-frequency estimate exists.
Published experience consists of small series; the largest to date describe
24 patients in 23 families (Unger 2010) and 14 patients in 11 Egyptian
families (Otaify 2023). The 2010 series explicitly notes the condition is
under-recognized rather than quantifying it. Orphanet epidemiology
(ORPHA:263463) was not cited because the pinned Orphadata snapshot could not
be verified against its manifest checksum at curation time.
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
The incidence of CHST3 deficiency seems to be higher than assumed so far.
explanation: >-
Supports an ultra-rare but under-ascertained disorder; it does not provide
a numeric rate, so only the qualitative class is asserted.
genetic:
- name: CHST3
gene_term:
preferred_term: CHST3
term:
id: hgnc:1971
label: CHST3
relationship_type: CAUSATIVE
variant_origin: GERMLINE
notes: >-
CHST3 (10q22.1, NM_004273.5) encodes carbohydrate sulfotransferase 3 /
chondroitin 6-O-sulfotransferase-1, a Golgi type II membrane
sulfotransferase. Reported pathogenic alleles span missense, nonsense,
frameshift and splice-site classes and cluster in the sulfotransferase
domain; missense alleles affecting the PAPS-binding site abolish activity,
while some missense alleles are hypomorphic.
evidence:
- reference: PMID:15215498
reference_title: "Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We sequenced candidate genes from the region and identified a missense
mutation in the chondroitin 6-O-sulfotransferase (C6ST-1) gene (CHST3)
explanation: >-
Original gene identification by linkage mapping in two consanguineous
Omani families.
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report eight CHST3 mutations in six unrelated individuals who presented
at birth with congenital joint dislocations.
explanation: >-
Establishes CHST3 as the cause of the congenital-dislocation phenotype in
unrelated probands previously labelled recessive Larsen syndrome or
humero-spinal dysostosis.
- reference: PMID:37876363
reference_title: "Indian patients with CHST3-related chondrodysplasia with congenital joint dislocations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All these variants are located on sulfotransferase domain of CHST3 protein
and were classified as pathogenic/ likely pathogenic.
explanation: >-
Supports clustering of pathogenic alleles in the sulfotransferase domain.
variants:
- name: "CHST3 p.Arg304Gln (R304Q)"
description: >-
Homozygous missense variant in the conserved 3'-phosphoadenosine
5'-phosphosulfate (PAPS) cosubstrate binding site, identified in two large
consanguineous Omani families with spondyloepiphyseal dysplasia Omani
type. Recombinant enzyme assays show complete loss of C6ST-1 activity.
gene:
preferred_term: CHST3
term:
id: hgnc:1971
label: CHST3
evidence:
- reference: PMID:15215498
reference_title: "Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We used recombinant C6ST-1 to show that the identified missense mutation
completely abolishes C6ST-1 activity.
explanation: >-
Functional assay demonstrating that R304Q is a complete loss-of-function
allele.
- name: "CHST3 p.Thr141Met (T141M)"
description: >-
Homozygous missense variant in exon 3 identified in a Turkish family with
Omani-type spondyloepiphyseal dysplasia and cardiac valve involvement. In
contrast to R304Q this allele is hypomorphic, retaining roughly a quarter
of wild-type sulfotransferase activity.
gene:
preferred_term: CHST3
term:
id: hgnc:1971
label: CHST3
evidence:
- reference: PMID:19320654
reference_title: "Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Using recombinant C6ST-1, we showed that the identified missense
mutation results in a reduction of C6ST-1 activity to 24-29% of the wild
type protein.
explanation: >-
Quantifies residual enzyme activity, documenting a hypomorphic allele
class distinct from complete loss of function.
- name: "CHST3 c.776T>C"
description: >-
Recurrent missense variant reported predominantly in Turkish patients,
suggesting a population-specific recurrent or founder allele.
gene:
preferred_term: CHST3
term:
id: hgnc:1971
label: CHST3
evidence:
- reference: PMID:32639237
reference_title: "Recurrent c.776T>C mutation in CHST3 with four other novel mutations and a literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic CHST3 c.776T>C mutations are most frequent mutation in CHST3
and have been reported predominantly in Turkish patients
explanation: >-
Documents a recurrent allele with a genotype-ethnicity association.
pathophysiology:
- name: Biallelic CHST3 Loss of Function
biological_scale: MOLECULAR
description: >
Biallelic pathogenic CHST3 variants abolish or severely reduce the activity
of carbohydrate sulfotransferase 3 (chondroitin 6-O-sulfotransferase-1), a
Golgi enzyme that transfers sulfate from PAPS to the C-6 position of
N-acetylgalactosamine residues in chondroitin. Missense alleles in the
PAPS-binding site abolish activity outright; other alleles are hypomorphic
and retain partial activity, which may contribute to the observed
phenotypic breadth.
genes:
- preferred_term: CHST3
term:
id: hgnc:1971
label: CHST3
molecular_functions:
- preferred_term: chondroitin 6-O-sulfotransferase-1 activity
term:
id: GO:0008459
label: chondroitin 6-sulfotransferase activity
modifier: DECREASED
cellular_components:
- preferred_term: Golgi apparatus
term:
id: GO:0005794
label: Golgi apparatus
evidence:
- reference: PMID:15215498
reference_title: "Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We used recombinant C6ST-1 to show that the identified missense mutation
completely abolishes C6ST-1 activity.
explanation: >-
Direct enzymatic demonstration that the disease allele eliminates C6ST-1
catalytic function.
- reference: PMID:16720579
reference_title: "N-linked oligosaccharides on chondroitin 6-sulfotransferase-1 are required for production of the active enzyme, Golgi localization, and sulfotransferase activity toward keratan sulfate."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Wild-type recombinant C6ST-1 showed a typical Golgi localization
explanation: >-
Establishes the Golgi as the subcellular compartment in which C6ST-1 acts.
downstream:
- target: Deficient Chondroitin 6-O-Sulfation
description: >-
Loss of enzyme activity directly removes the 6-O-sulfation step of
chondroitin sulfate chain maturation.
causal_link_type: DIRECT
- name: Deficient Chondroitin 6-O-Sulfation
biological_scale: MOLECULAR
description: >
Absent or reduced C6ST-1 activity produces a specific but generalized defect
of chondroitin sulfate chain sulfation: 6-O-sulfated disaccharides are
markedly depleted while 4-O-sulfated disaccharides are relatively increased,
with appearance of a disulfated 4,6-species that is undetectable in
controls. The defect is demonstrable in patient dermal fibroblasts and in
urine, and distinguishes CHST3 deficiency from the global undersulfation of
SLC26A2 (DTDST) deficiency.
chemical_entities:
- preferred_term: chondroitin sulfate
term:
id: CHEBI:37397
label: chondroitin sulfate
modifier: ABNORMAL
biological_processes:
- preferred_term: chondroitin sulfate proteoglycan biosynthesis
term:
id: GO:0050650
label: chondroitin sulfate proteoglycan biosynthetic process
modifier: ABNORMAL
cell_types:
- preferred_term: dermal fibroblast
term:
id: CL:0002620
label: skin fibroblast
evidence:
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed
markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming
functional impairment of CHST3 and distinguishing them from diastrophic
dysplasia sulphate transporter (DTDST)-deficient cells.
explanation: >-
Documents the reciprocal 6-O-/4-O-sulfation shift and its diagnostic
specificity versus DTDST deficiency.
- reference: PMID:15215498
reference_title: "Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results indicate that the mutation in CHST3 described here causes a
specific but generalized defect of CS chain sulfation resulting in
chondrodysplasia with major involvement of the spine.
explanation: >-
States the causal link from the sulfation defect to chondrodysplasia with
predominant spinal involvement.
downstream:
- target: Altered Cartilage Proteoglycan Matrix
description: >-
Undersulfated chondroitin sulfate chains alter the charge density and
interaction profile of cartilage proteoglycans.
causal_link_type: DIRECT
- name: Altered Cartilage Proteoglycan Matrix
biological_scale: CELLULAR
description: >
Chondroitin sulfate chains carried on cartilage proteoglycans determine the
fixed charge density, hydration and growth-factor-binding behaviour of the
extracellular matrix. Loss of 6-O-sulfation alters these physical and
signalling properties, degrading the ability of chondrocytes to build a
competent proteoglycan-rich matrix in hyaline, articular, epiphyseal and
vertebral cartilage.
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
biological_processes:
- preferred_term: extracellular matrix organization
term:
id: GO:0030198
label: extracellular matrix organization
modifier: ABNORMAL
chemical_entities:
- preferred_term: chondroitin sulfate proteoglycan
term:
id: CHEBI:26349
label: chondroitin sulfate proteoglycan
modifier: ABNORMAL
locations:
- preferred_term: articular cartilage
term:
id: UBERON:0010996
label: articular cartilage of joint
evidence:
- reference: PMID:18698629
reference_title: "Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This enzyme mediates the sulfation of proteoglycans, particularly
chondroitin sulfate (CS), in the extracellular matrix of cartilage.
explanation: >-
Places the enzymatic defect in the cartilage extracellular matrix
compartment.
- reference: PMID:37545696
reference_title: "Carbohydrate sulfotransferases: a review of emerging diagnostic and prognostic applications."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Carbohydrate sulfotransferases (CHST) catalyse the biosynthesis of
proteoglycans that enable physical interactions and signalling between
different neighbouring cells in physiological and pathological states.
explanation: >-
Review evidence that CHST-dependent proteoglycan sulfation underlies
cell-matrix physical interaction and signalling.
downstream:
- target: Growth Plate and Epiphyseal Cartilage Dysplasia
description: >-
A defective proteoglycan matrix impairs the organization and biomechanical
competence of growth-plate and epiphyseal cartilage.
causal_link_type: DIRECT
- name: Growth Plate and Epiphyseal Cartilage Dysplasia
biological_scale: TISSUE
description: >
Impaired matrix assembly in growth-plate, epiphyseal and vertebral cartilage
produces prenatal-onset growth deficiency, epiphyseal dysplasia, flared
metaphyses, and characteristic vertebral changes (lumbar vertebral clefting
and widened interpedicular distances early; platyspondyly and progressive
spinal deformity later). Radiographic vertebral change is the most useful
diagnostic clue.
cell_types:
- preferred_term: growth plate chondrocyte
term:
id: CL:1000217
label: growth plate cartilage chondrocyte
biological_processes:
- preferred_term: growth plate cartilage development
term:
id: GO:0003417
label: growth plate cartilage development
modifier: ABNORMAL
locations:
- preferred_term: growth plate cartilage
term:
id: UBERON:0004129
label: growth plate cartilage
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most useful radiographic clues were the changes of the lumbar
vertebrae.
explanation: >-
Identifies vertebral cartilage/bone change as the cardinal radiographic
manifestation of the underlying cartilage dysplasia.
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients had spondyloepiphyseal changes that were progressive with age
explanation: >-
Documents progressive spondyloepiphyseal involvement in a 14-patient
series.
downstream:
- target: Primary Joint Dysplasia with Congenital Dislocation
description: >-
Malformed articular surfaces, rather than simple ligamentous laxity,
produce dislocation of the large joints at birth.
causal_link_type: DIRECT
- target: Progressive Articular and Spinal Degeneration
description: >-
An intrinsically abnormal cartilage matrix degenerates under normal
mechanical loading over years, with abnormal joint alignment adding
chronic aberrant loading.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Chronic aberrant mechanical loading of dysplastic, undersulfated articular and intervertebral cartilage
- name: Primary Joint Dysplasia with Congenital Dislocation
biological_scale: TISSUE
description: >
Dislocation of the knees, hips and radial heads is present at birth and is
interpreted as primary dysplasia of the joint structures themselves rather
than generalized ligamentous laxity — the joint surfaces and distal humeri
are radiographically malformed (bifid distal humerus with radial head
subluxation). Club feet accompany the dislocations.
locations:
- preferred_term: knee joint
term:
id: UBERON:0001485
label: knee joint
evidence:
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
their clinical features included congenital dislocation of the knees,
elbow joint dysplasia with subluxation and limited extension, hip
dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis
developing in late childhood
explanation: >-
Describes the congenital dislocation pattern together with the elbow joint
dysplasia that indicates a structural rather than purely ligamentous
lesion.
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
bifid distal ends of humeri which can be considered a diagnostic key in
patients with CHST3 variants
explanation: >-
Structural malformation of the distal humerus supports primary joint
dysplasia as the basis of the radial-head dislocation.
- name: Progressive Articular and Spinal Degeneration
biological_scale: ORGANISM
description: >
Beyond the congenital malformation, the abnormal matrix degenerates
progressively: joint pain, premature arthrosis, contractures and increasing
limitation of range of motion accumulate, and kyphosis or kyphoscoliosis
develops in late childhood and worsens. This progressive arm, not the
neonatal dislocations, drives most long-term disability.
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
short stature, and progressive kyphosis developing in late childhood
explanation: >-
Documents the progressive spinal course after the congenital presentation.
- reference: PMID:36729370
reference_title: "A Chinese case of CHST3-related skeletal dysplasia and a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive joint pain and movement restriction are the main
characteristics of CHST3-related skeletal dysplasia.
explanation: >-
Systematic review of published cases identifies progressive arthropathy as
the dominant clinical feature.
- reference: PMID:19320654
reference_title: "Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We describe a family with progressive skeletal dysplasia and severe spinal
involvement, short stature, premature arthrosis and joint contractures
explanation: >-
Independent family confirming premature arthrosis and contracture
development.
phenotypes:
- category: Skeletal
name: Congenital Large-Joint Dislocations
frequency: VERY_FREQUENT
description: >
Dislocation of the large joints — most consistently the knees, hips and
radial heads — present at birth. This is the defining presenting feature and
the reason affected infants were historically diagnosed with Larsen syndrome
or humero-spinal dysostosis.
diagnostic: true
phenotype_term:
preferred_term: Large joint dislocations
term:
id: HP:0005008
label: Large joint dislocations
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Chondrodysplasia with congenital joint dislocations, CHST3-related
(CDCJD-CHST3) is characterized by short stature of prenatal onset, joint
dislocations (knees, hips, radial heads), clubfeet, and limitation of
range of motion that can involve all large joints.
explanation: >-
GeneReviews lists large-joint dislocation as a defining characteristic,
supporting the VERY_FREQUENT band.
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report eight CHST3 mutations in six unrelated individuals who presented
at birth with congenital joint dislocations.
explanation: >-
All six molecularly confirmed probands presented at birth with congenital
dislocations (6/6), consistent with a VERY_FREQUENT band.
- category: Skeletal
name: Congenital Knee Dislocation
description: >
Dislocation of the knee, frequently bilateral and apparent in the neonatal
period, sometimes with genu recurvatum.
phenotype_term:
preferred_term: Congenital knee dislocation
term:
id: HP:0005191
label: Congenital knee dislocation
evidence:
- reference: PMID:23918704
reference_title: "Two Somali half-siblings with CHST3-related chondrodysplasia illustrating the phenotypic spectrum and intrafamilial variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Her half-brother presented at birth with bilateral knee dislocation and
talipes equinovarus.
explanation: >-
Direct clinical description of congenital bilateral knee dislocation.
- category: Skeletal
name: Hip Dysplasia or Dislocation
description: >
Hip dysplasia or frank dislocation, present congenitally in a majority but
not all affected individuals.
phenotype_term:
preferred_term: Hip dislocation
term:
id: HP:0002827
label: Hip dislocation
evidence:
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hip dysplasia or dislocation
explanation: >-
Hip involvement documented in the defining CHST3 cohort.
- category: Skeletal
name: Dislocated Radial Head with Elbow Joint Dysplasia
description: >
Radial head dislocation or subluxation accompanied by dysplasia of the
distal humerus, with limited elbow extension. Highly characteristic of the
CHST3 phenotype.
diagnostic: true
phenotype_term:
preferred_term: Dislocated radial head
term:
id: HP:0003083
label: Dislocated radial head
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
joint dislocations (knees, hips, radial heads)
explanation: >-
GeneReviews names the radial head among the characteristically dislocated
joints.
- category: Skeletal
name: Limited Elbow Extension
description: >
Elbow joint dysplasia with subluxation and restricted extension, a
consistent finding across CHST3 series.
phenotype_term:
preferred_term: Limited elbow extension
term:
id: HP:0001377
label: Limited elbow extension
evidence:
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
elbow joint dysplasia with subluxation and limited extension
explanation: >-
Explicit description of restricted elbow extension in the CHST3 cohort.
- category: Skeletal
name: Bifid Distal Humerus
description: >
Bifid or notched distal humeral end on radiographs, proposed as a
near-pathognomonic radiographic clue for CHST3 variants.
diagnostic: true
phenotype_term:
preferred_term: Bifid humerus
term:
id: HP:0003864
label: Bifid humerus
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
bifid distal ends of humeri which can be considered a diagnostic key in
patients with CHST3 variants
explanation: >-
All 14 patients in this series had bifid distal humeri, proposed as a
diagnostic key.
- category: Skeletal
name: Club Feet
frequency: VERY_FREQUENT
description: >
Bilateral talipes equinovarus, present at birth in essentially all reported
patients.
phenotype_term:
preferred_term: Talipes equinovarus
term:
id: HP:0001762
label: Talipes equinovarus
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
joint dislocations (knees, hips, radial heads), clubfeet, and limitation
of range of motion that can involve all large joints
explanation: >-
Clubfeet listed by GeneReviews among the features the disorder is
characterized by, mapping to the VERY_FREQUENT band.
- reference: PMID:23918704
reference_title: "Two Somali half-siblings with CHST3-related chondrodysplasia illustrating the phenotypic spectrum and intrafamilial variability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
talipes equinovarus
explanation: >-
Independent confirmation of congenital talipes equinovarus.
- category: Growth
name: Short Stature of Prenatal Onset
frequency: VERY_FREQUENT
description: >
Disproportionate short stature beginning before birth, with reduced birth
length and persistent short-trunk short stature; adult height is severely
reduced.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
is characterized by short stature of prenatal onset
explanation: >-
GeneReviews lists prenatal-onset short stature as a defining feature,
supporting the VERY_FREQUENT band.
- reference: PMID:36729370
reference_title: "A Chinese case of CHST3-related skeletal dysplasia and a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the systematic review, short stature, limited joint extension, joint
pain, and joint dislocation were the most common characteristics of this
disorder.
explanation: >-
Systematic review of all published cases ranks short stature among the
most common features.
- category: Skeletal
name: Limitation of Range of Motion of Large Joints
frequency: VERY_FREQUENT
description: >
Restricted movement affecting all large joints, progressive with age and a
principal contributor to functional disability.
phenotype_term:
preferred_term: Limitation of joint mobility
term:
id: HP:0001376
label: Limitation of joint mobility
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
limitation of range of motion that can involve all large joints
explanation: >-
GeneReviews includes limitation of range of motion in the defining
characterization, supporting the VERY_FREQUENT band.
- category: Skeletal
name: Progressive Kyphosis
frequency: FREQUENT
description: >
Thoracic kyphosis appearing in childhood and worsening thereafter, with
slight shortening of the trunk.
phenotype_term:
preferred_term: Kyphosis
term:
id: HP:0002808
label: Kyphosis
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
short stature, and progressive kyphosis developing in late childhood
explanation: >-
A 24-patient series reports progressive kyphosis among the shared features
of the group, mapping to the FREQUENT band.
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Kyphosis and occasionally scoliosis with slight shortening of the trunk
develop in childhood.
explanation: >-
GeneReviews confirms childhood-onset kyphosis.
- category: Skeletal
name: Kyphoscoliosis
description: >
Combined kyphosis and scoliosis developing in late childhood in a subset of
patients.
phenotype_term:
preferred_term: Kyphoscoliosis
term:
id: HP:0002751
label: Kyphoscoliosis
evidence:
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
kyphoscoliosis developing in late childhood
explanation: >-
Direct clinical description of kyphoscoliosis in the CHST3 cohort.
- category: Skeletal
name: Scoliosis
frequency: OCCASIONAL
description: >
Scoliosis occurring in a minority of patients, developing during childhood.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Kyphosis and occasionally scoliosis with slight shortening of the trunk
develop in childhood.
explanation: >-
GeneReviews qualifies scoliosis as occurring occasionally, which maps to
the OCCASIONAL band (5-29%).
- category: Skeletal
name: Platyspondyly
description: >
Flattened vertebral bodies, part of the spondyloepiphyseal radiographic
pattern.
phenotype_term:
preferred_term: Platyspondyly
term:
id: HP:0000926
label: Platyspondyly
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Biallelic variants in CHST3 gene result in congenital dislocation of large
joints, club feet, short stature, rhizomelia, kypho-scoliosis,
platyspondyly, epiphyseal dysplasia, flared metaphysis, in addition to
minor cardiac lesions and hearing loss.
explanation: >-
Platyspondyly is listed among the core radiographic manifestations.
- category: Skeletal
name: Epiphyseal Dysplasia
description: >
Irregular, dysplastic epiphyses that become more evident with age, part of
the spondyloepiphyseal pattern.
phenotype_term:
preferred_term: Epiphyseal dysplasia
term:
id: HP:0002656
label: Epiphyseal dysplasia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All patients had spondyloepiphyseal changes that were progressive with age
explanation: >-
Progressive epiphyseal involvement documented in all 14 patients.
- category: Skeletal
name: Flared Metaphyses
description: >
Metaphyseal flaring of the long bones on skeletal survey.
phenotype_term:
preferred_term: Flared metaphysis
term:
id: HP:0003015
label: Flared metaphysis
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
short stature, rhizomelia, kypho-scoliosis, platyspondyly, epiphyseal
dysplasia, flared metaphysis
explanation: >-
Flared metaphysis listed among the skeletal manifestations of biallelic
CHST3 variants.
- category: Skeletal
name: Rhizomelia
description: >
Disproportionate shortening of the proximal limb segments.
phenotype_term:
preferred_term: Rhizomelia
term:
id: HP:0008905
label: Rhizomelia
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
congenital dislocation of large joints, club feet, short stature,
rhizomelia
explanation: >-
Rhizomelia listed among the core manifestations.
- category: Skeletal
name: Short Metacarpals
description: >
Shortening of the metacarpals, developing over time and contributing to a
brachydactyly-like hand appearance.
phenotype_term:
preferred_term: Short metacarpal
term:
id: HP:0010049
label: Short metacarpal
evidence:
- reference: PMID:37876363
reference_title: "Indian patients with CHST3-related chondrodysplasia with congenital joint dislocations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
congenital joint (knee and elbow) dislocations, short trunk short stature
progressive vertebral anomalies, and metacarpal shortening
explanation: >-
Metacarpal shortening reported as a key symptom in nine Indian patients.
- reference: PMID:18698629
reference_title: "Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
metacarpal shortening and accessory carpal ossification centers
explanation: >-
Independent extension of the Omani-type phenotype to include metacarpal
shortening.
- category: Skeletal
name: Accessory Carpal Ossification Centers
description: >
Supernumerary carpal ossification centers on hand radiographs. Carpal bone
age remains normal, which helps separate CHST3 deficiency from Desbuquois
dysplasia (advanced carpal ossification).
phenotype_term:
preferred_term: Accessory carpal bones
term:
id: HP:0004232
label: Accessory carpal bones
evidence:
- reference: PMID:18698629
reference_title: "Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
metacarpal shortening and accessory carpal ossification centers
explanation: >-
Direct documentation of accessory carpal ossification centers.
- reference: PMID:37876363
reference_title: "Indian patients with CHST3-related chondrodysplasia with congenital joint dislocations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
supernumerary carpal ossification centers
explanation: >-
Independent confirmation in an Indian cohort.
- category: Musculoskeletal
name: Premature Arthrosis and Joint Contractures
description: >
Early degenerative arthropathy with contractures, producing pain and
increasing functional limitation from childhood onward.
phenotype_term:
preferred_term: Premature osteoarthritis
term:
id: HP:0003088
label: Premature osteoarthritis
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:19320654
reference_title: "Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
short stature, premature arthrosis and joint contractures
explanation: >-
Direct clinical description of premature arthrosis with contractures.
- category: Musculoskeletal
name: Progressive Joint Pain
description: >
Aggravating joint pain, identified by systematic review of published cases
as one of the main features of the disorder in older children and adults.
phenotype_term:
preferred_term: Arthralgia
term:
id: HP:0002829
label: Arthralgia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:36729370
reference_title: "A Chinese case of CHST3-related skeletal dysplasia and a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Progressive joint pain and movement restriction are the main
characteristics of CHST3-related skeletal dysplasia.
explanation: >-
Systematic review conclusion naming progressive joint pain as a main
characteristic.
- category: Cardiovascular
name: Heart Valve Dysplasia
frequency: OCCASIONAL
description: >
Minor dysplasia of the cardiac valves with mitral, tricuspid and/or aortic
regurgitation. Usually clinically minor, but a lethal cardiac course has
been reported, and echocardiographic surveillance is recommended.
phenotype_term:
preferred_term: Abnormal heart valve morphology
term:
id: HP:0001654
label: Abnormal heart valve morphology
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Minor heart valve dysplasia has been described in several persons.
explanation: >-
GeneReviews describes valve dysplasia in several persons rather than as a
defining feature, mapping to the OCCASIONAL band.
- reference: PMID:36729370
reference_title: "A Chinese case of CHST3-related skeletal dysplasia and a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Echocardiography showed abnormal cardiac valves.
explanation: >-
Independent echocardiographic confirmation of valve involvement.
- category: Cardiovascular
name: Mitral, Tricuspid and Aortic Regurgitation
description: >
Valvular regurgitation described in an affected Turkish family with a
hypomorphic CHST3 allele.
phenotype_term:
preferred_term: Mitral regurgitation
term:
id: HP:0001653
label: Mitral regurgitation
evidence:
- reference: PMID:19320654
reference_title: "Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
affected members of this family also had cardiac involvement including
mitral, tricuspid and/or aortic regurgitations and type E brachydactyly
explanation: >-
Documents multivalvular regurgitation in CHST3 deficiency.
- category: Cardiovascular
name: Ventricular Septal Defect
frequency: VERY_RARE
description: >
Ventricular septal defect reported as part of the extended Omani-type
phenotype in a single family, and not a consistent feature of the disorder.
phenotype_term:
preferred_term: Ventricular septal defect
term:
id: HP:0001629
label: Ventricular septal defect
evidence:
- reference: PMID:18698629
reference_title: "Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
extend the clinical phenotype of SED-Omani type to include congenital
joint dislocation, club feet, ventricular septal defect, deafness,
metacarpal shortening and accessory carpal ossification centers
explanation: >-
Single-family report extending the phenotype to VSD; described as a
phenotype extension rather than a recurrent feature, supporting the
VERY_RARE band.
- category: Cardiovascular
name: Atrial Septal Defect
frequency: VERY_RARE
description: >
Atrial septal defect described among the rare unusual findings in a large
Egyptian series.
phenotype_term:
preferred_term: Atrial septal defect
term:
id: HP:0001631
label: Atrial septal defect
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Rare unusual associated findings included microdontia, teeth spacing,
delayed eruption, prominent angulation of the lumbar-sacral junction and
atrial septal defect.
explanation: >-
Explicitly characterized as a rare associated finding, mapping to the
VERY_RARE band.
- category: Auditory
name: Mixed Hearing Impairment
description: >
Progressive bilateral mixed hearing loss reported in a large consanguineous
Pakistani kindred and included in the broader CHST3 spectrum; frequency
across the disorder is not established.
phenotype_term:
preferred_term: Mixed hearing impairment
term:
id: HP:0000410
label: Mixed hearing impairment
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:26572954
reference_title: "A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
14 affected individuals suffering with short stature, kyphoscoliosis,
joint dislocations, clubfoot, heart valve anomalies and progressive
bilateral mixed hearing loss
explanation: >-
Documents progressive bilateral mixed hearing loss segregating with a
CHST3 nonsense allele.
- reference: PMID:36729370
reference_title: "A Chinese case of CHST3-related skeletal dysplasia and a systematic review."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Height Z score and the proportion of hearing impairment had no significant
differences between the missense and nonmissense mutations groups.
explanation: >-
Confirms hearing impairment is tracked across the published case
literature and that it does not segregate with variant class.
- category: Craniofacial
name: Broad Forehead
description: >
Part of a recurrent facial gestalt (broad forehead, broad nasal tip, long
philtrum, short neck) noted in a 14-patient Egyptian series. Facial
flattening is characteristically absent, which helps distinguish CHST3
deficiency from Desbuquois dysplasia.
phenotype_term:
preferred_term: Broad forehead
term:
id: HP:0000337
label: Broad forehead
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They also shared peculiar facies with broad forehead, broad nasal tip,
long philtrum and short neck.
explanation: >-
Recurrent facial gestalt shared by all patients in the series.
- category: Craniofacial
name: Long Philtrum
description: >
Component of the recurrent CHST3 facial gestalt.
phenotype_term:
preferred_term: Long philtrum
term:
id: HP:0000343
label: Long philtrum
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
broad forehead, broad nasal tip, long philtrum and short neck
explanation: >-
Long philtrum reported as part of the shared facial appearance.
- category: Skeletal
name: Short Neck
description: >
Short neck accompanying the short-trunk body habitus.
phenotype_term:
preferred_term: Short neck
term:
id: HP:0000470
label: Short neck
evidence:
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
broad forehead, broad nasal tip, long philtrum and short neck
explanation: >-
Short neck documented as part of the shared phenotype.
- category: Neurological
name: Atlantoaxial Instability with Os Odontoideum
frequency: VERY_RARE
description: >
Atlantoaxial instability due to an os odontoideum, complicated in a reported
case by vertebral artery stenosis and posterior circulation ischaemic
stroke, treated with occipitocervical fusion. Described as a previously
unreported complication and therefore not an established recurrent feature,
but clinically important because it is catastrophic and surgically
treatable.
phenotype_term:
preferred_term: Atlantoaxial instability
term:
id: HP:0003467
label: Atlantoaxial instability
evidence:
- reference: PMID:33625031
reference_title: "Posterior Circulation Stroke due to Atlantoaxial Instability in CHST3-Related Skeletal Dysplasia: A Case Report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He was found to have vertebral artery stenosis secondary to atlantoaxial
instability (AAI) due to an os odontoideum.
explanation: >-
Single case report; the authors state it is a previously unreported
complication, supporting the VERY_RARE band.
biochemical:
- name: Reduced 6-O-Sulfated Chondroitin Sulfate in Dermal Fibroblasts
notes: >
Analysis of chondroitin sulfate proteoglycans from patient dermal
fibroblasts shows markedly decreased 6-O-sulfation with a compensatory
increase in 4-O-sulfation. This reciprocal shift is the functional signature
of CHST3 deficiency and distinguishes it from SLC26A2/DTDST deficiency,
where sulfation is globally reduced. It is mechanistically informative but
is not an established, widely available clinical assay.
specificity: >-
The 6-O-down / 4-O-up pattern is specific for CHST3 deficiency among the
proteoglycan-sulfation skeletal dysplasias.
cell_types:
- preferred_term: dermal fibroblast
term:
id: CL:0002620
label: skin fibroblast
evidence:
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed
markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming
functional impairment of CHST3 and distinguishing them from diastrophic
dysplasia sulphate transporter (DTDST)-deficient cells.
explanation: >-
Establishes the fibroblast biochemical signature and its discriminatory
value.
- reference: PMID:18698629
reference_title: "Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Fibroblasts and urine obtained from affected patients demonstrated
negligible levels of 6-O-sulfated GalNAc residue in CS.
explanation: >-
Independent confirmation of near-absent 6-O-sulfated GalNAc in patient
fibroblasts and urine.
- name: Urinary Chondroitin Sulfate Undersulfation
notes: >
Anion-exchange HPLC of urinary chondroitin sulfate shows marked
undersulfation, with reduced 6-O-sulfated disaccharide and an increase in
the nonsulfated unit.
evidence:
- reference: PMID:15215498
reference_title: "Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Analysis of the patient's urine shows marked undersulfation of CS, in
particular reduction in 6-O-sulfated disaccharide and an increase in the
nonsulfated unit.
explanation: >-
Demonstrates that the sulfation defect is detectable in urine.
progression:
- phase: Prenatal and neonatal
notes: >
Growth restriction begins before birth. Affected infants present at birth
with dislocation of the knees, hips and/or radial heads, club feet, and
reduced birth length. The initial diagnostic label has historically been
Larsen syndrome, humero-spinal dysostosis, or chondrodysplasia with multiple
dislocations.
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We conclude that CHST3 deficiency presents at birth with congenital
dislocations of knees, hips, and elbows, and is often diagnosed initially
as Larsen syndrome, humero-spinal dysostosis, or chondrodysplasia with
dislocations.
explanation: >-
Defines the neonatal presentation and its historical diagnostic labels.
- phase: Childhood
notes: >
Kyphosis, and occasionally scoliosis, develop during childhood with slight
shortening of the trunk. Spondyloepiphyseal radiographic changes become
progressively more evident.
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Kyphosis and occasionally scoliosis with slight shortening of the trunk
develop in childhood.
explanation: >-
GeneReviews places spinal deformity onset in childhood.
- phase: Adolescence and adulthood
notes: >
Joint pain, contractures and restricted movement dominate, with premature
arthrosis and severe spinal involvement. Vertebral compression fracture has
been documented. Intellect and vision remain normal.
evidence:
- reference: PMID:36729370
reference_title: "A Chinese case of CHST3-related skeletal dysplasia and a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The proband complained of aggravated joint pain and had a compression
fracture of L2 during his second decade.
explanation: >-
Illustrates the adolescent/adult course with aggravating pain and
vertebral fracture.
diagnosis:
- name: Molecular genetic testing of CHST3
description: >
The diagnosis is established by identification of biallelic pathogenic CHST3
variants in a proband with characteristic clinical and radiographic
features. In practice this is a skeletal dysplasia gene panel or exome
sequencing; single-gene testing is appropriate when the phenotype is typical
or a familial variant is known.
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The diagnosis of CDCJD-CHST3 is established in a proband with
characteristic clinical and radiographic features and biallelic pathogenic
variants in CHST3 identified by molecular genetic testing.
explanation: >-
GeneReviews states the diagnostic standard.
- name: Skeletal radiography
description: >
Radiographic evaluation is central to raising the diagnosis. Changes of the
lumbar vertebrae are the most useful clue; bifid distal humeri with radial
head subluxation are proposed as a further diagnostic key. Carpal bone age
is normal and facial flattening is absent, which help separate CHST3
deficiency from other multiple-dislocation dysplasias.
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most useful radiographic clues were the changes of the lumbar
vertebrae.
explanation: >-
Identifies the highest-yield radiographic feature.
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
bifid distal ends of humeri which can be considered a diagnostic key in
patients with CHST3 variants
explanation: >-
Adds a second high-specificity radiographic sign.
- name: Echocardiography
description: >
Echocardiography is recommended at diagnosis and repeated on cardiology
advice (roughly every five years if initially normal) because of heart valve
dysplasia, which is usually minor but has been reported to be lethal in some
patients.
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
if normal at the time of diagnosis, echocardiogram should be repeated per
cardiologist or every five years
explanation: >-
GeneReviews surveillance recommendation.
- reference: PMID:37183573
reference_title: "CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
highlights the importance of performing echocardiography in patients
harboring CHST3 variants
explanation: >-
Independent recommendation for echocardiographic evaluation.
differential_diagnoses:
- name: Larsen syndrome (FLNB-associated, autosomal dominant)
description: >
Dominant Larsen syndrome caused by heterozygous FLNB variants shares
multiple congenital large-joint dislocations with CHST3 deficiency, and many
CHST3 patients were initially given this label. The two are mechanistically
unrelated: FLNB Larsen is an actin-crosslinking filamin defect, CHST3
deficiency is a proteoglycan-sulfation defect.
disease_term:
preferred_term: Larsen syndrome
term:
id: MONDO:0007875
label: Larsen syndrome
distinguishing_features:
- Autosomal dominant inheritance with FLNB variants, versus autosomal recessive CHST3 variants.
- Characteristic vertebral changes, normal carpal bone age and absence of facial flattening favour CHST3 deficiency.
- Fibroblast chondroitin sulfate analysis shows the 6-O-down / 4-O-up shift only in CHST3 deficiency.
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical and radiographic pattern (joint dislocations, vertebral
changes, normal carpal age, lack of facial flattening, and recessive
inheritance) is characteristic and distinguishes CHST3 deficiency from
other disorders with congenital dislocations such as filamin B-associated
dominant Larsen syndrome and Desbuquois syndrome.
explanation: >-
Explicit statement of the discriminating features versus FLNB Larsen
syndrome.
- name: Desbuquois dysplasia
description: >
Desbuquois dysplasia (CANT1, XYLT1) also presents with multiple joint
dislocations, short stature and a proteoglycan-biosynthesis defect, and one
CHST3 patient in the 24-patient series had been given this diagnosis before
molecular testing.
disease_term:
preferred_term: Desbuquois dysplasia
term:
id: MONDO:0015426
label: Desbuquois dysplasia
distinguishing_features:
- Advanced (accelerated) carpal ossification is typical of Desbuquois dysplasia; carpal bone age is normal in CHST3 deficiency.
- Facial flattening is characteristic of Desbuquois dysplasia and absent in CHST3 deficiency.
evidence:
- reference: PMID:20830804
reference_title: "Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
normal carpal age, lack of facial flattening, and recessive inheritance
explanation: >-
Names the discriminating radiographic and facial features versus
Desbuquois syndrome.
- name: Diastrophic dysplasia (SLC26A2/DTDST deficiency)
description: >
Diastrophic dysplasia is the other classic proteoglycan-undersulfation
skeletal dysplasia and is the closest biochemical mimic. It results from
defective sulfate transport rather than a specific sulfotransferase
deficiency.
disease_term:
preferred_term: diastrophic dysplasia
term:
id: MONDO:0009107
label: diastrophic dysplasia
distinguishing_features:
- DTDST-deficient cells show globally reduced sulfation; CHST3-deficient cells show selectively reduced 6-O-sulfation with enhanced 4-O-sulfation.
evidence:
- reference: PMID:18513679
reference_title: "Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming
functional impairment of CHST3 and distinguishing them from diastrophic
dysplasia sulphate transporter (DTDST)-deficient cells
explanation: >-
Biochemical discrimination between the two sulfation disorders.
treatments:
- name: Orthopedic Surgical Correction of Dislocated Joints
description: >
Surgical correction and stabilization of the abnormal joints is the only
disease-directed treatment modality available. Correction is often only
partially successful and multiple procedures are typically needed. There is
no approved enzyme replacement, small-molecule, gene, RNA or cell therapy
for CHST3-related skeletal dysplasia.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: orthopedic surgical procedure
term:
id: NCIT:C16186
label: Orthopedic Surgical Procedure
target_phenotypes:
- preferred_term: Large joint dislocations
term:
id: HP:0005008
label: Large joint dislocations
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Surgical correction of the abnormal joints is the only treatment modality;
however, surgical correction is often only partially successful and
multiple procedures are needed.
explanation: >-
GeneReviews management statement, including the caveat on limited efficacy.
- name: Occipitocervical Fusion for Atlantoaxial Instability
description: >
Cervical spinal fusion is indicated when atlantoaxial instability threatens
the vertebral arteries or spinal cord. In the reported case complicated by
posterior circulation stroke, occipitocervical fusion produced neurological
improvement and return to independent ambulation at one-year follow-up.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: spinal fusion
term:
id: NCIT:C157986
label: Spinal Fusion
target_phenotypes:
- preferred_term: Atlantoaxial instability
term:
id: HP:0003467
label: Atlantoaxial instability
evidence:
- reference: PMID:33625031
reference_title: "Posterior Circulation Stroke due to Atlantoaxial Instability in CHST3-Related Skeletal Dysplasia: A Case Report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Occipitocervical fusion yielded good clinical results with the 1-year
follow-up.
explanation: >-
Single-case evidence for surgical benefit; not generalizable to routine
management.
- name: Physical Therapy
description: >
Physical therapy is used for general mobility support, but GeneReviews
explicitly notes that it has not been effective for the joint manifestations
of this disorder. It is recorded here with that negative qualification so
the entry does not overstate benefit.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: physical therapy
term:
id: NCIT:C15302
label: Physical Therapy
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Physical therapy has not been effective.
explanation: >-
GeneReviews explicitly refutes efficacy of physical therapy for the joint
manifestations of this disorder.
- name: Joint-Protective Activity Modification
description: >
High-impact activity (for example jogging) and obesity should be avoided
because of the intrinsically abnormal joint cartilage and the progressive
degenerative course.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Agents/circumstances to avoid: Activities with a high impact on joints
(e.g., jogging) and obesity.
explanation: >-
GeneReviews Agents/Circumstances to Avoid recommendation.
- name: Multidisciplinary Surveillance
description: >
Ongoing joint and spine evaluation by an orthopedist experienced in skeletal
dysplasia, radiographs as recommended, cardiology follow-up with periodic
echocardiography, and annual dental review.
therapeutic_modality: OTHER
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical joint and spine evaluation with orthopedist with experience in
skeletal dysplasia; radiographs as recommended per orthopedist
explanation: >-
GeneReviews surveillance recommendation.
- name: Genetic Counseling
description: >
Autosomal recessive recurrence counseling (25% affected, 50% carrier, 25%
unaffected non-carrier per pregnancy for heterozygous parents), carrier
testing for at-risk relatives, and prenatal or preimplantation genetic
testing once the familial CHST3 variants are known.
therapeutic_modality: OTHER
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:21882400
reference_title: "Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Once the CHST3 pathogenic variants have been identified in an affected
family member, carrier testing for at-risk family members and
prenatal/preimplantation genetic testing for a pregnancy at increased risk
are possible.
explanation: >-
GeneReviews genetic counseling guidance.
discussions:
- discussion_id: chst3_sulfation_to_joint_dysplasia_gap
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Growth Plate and Epiphyseal Cartilage Dysplasia
prompt: >-
How does loss of chondroitin 6-O-sulfation cause dysplasia of the joint
surface and growth plate, rather than merely undersulfated matrix?
rationale: >-
The biochemical lesion (6-O-sulfation loss with compensatory 4-O-sulfation)
and the clinical outcome (primary joint dysplasia with congenital
dislocation) are both well documented, but the intervening cell-biological
step is not. No CHST3-specific growth-plate study, patient-derived
chondrocyte or cartilage organoid model, or quantitative Chst3-null skeletal
phenotype has been published; all direct functional evidence comes from
dermal fibroblasts and recombinant enzyme assays, which cannot reproduce the
biomechanical environment of cartilage.
proposed_experiments:
- experiment_id: chst3_mouse_growth_plate_phenotyping
name: Quantitative skeletal phenotyping of Chst3-null and knock-in mice
description: >-
Quantitative growth-plate, epiphyseal, articular and intervertebral-disc
phenotyping of Chst3-null and patient-variant knock-in mice, including
disaccharide composition analysis of cartilage.
- experiment_id: chst3_ipsc_chondrocyte_organoid
name: Patient iPSC-derived chondrocytes and cartilage organoids
description: >-
Differentiate patient iPSCs into chondrocytes and cartilage organoids and
measure chondroitin disaccharide composition, matrix assembly and matrix
mechanics, with wild-type CHST3 rescue as the causal control.
- discussion_id: chst3_natural_history_epidemiology_gap
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Progressive Articular and Spinal Degeneration
prompt: >-
What is the natural history, prevalence and genotype-phenotype structure of
CHST3-related skeletal dysplasia at population scale?
rationale: >-
Published evidence consists of small retrospective series. No prospective
natural-history registry, validated phenotype frequency, prevalence or
carrier-frequency estimate, standardized functional endpoint, or
patient-reported outcome measure exists, and a systematic review of the
published cases found no apparent genotype-phenotype correlation despite the
coexistence of null and hypomorphic alleles.
proposed_experiments:
- experiment_id: chst3_natural_history_registry
name: Prospective multicentre CHST3 natural-history registry
description: >-
Enroll molecularly confirmed patients with standardized radiographic,
functional and patient-reported endpoints to derive phenotype frequencies,
progression rates and genotype-phenotype relationships.
- experiment_id: chst3_carrier_frequency_estimate
name: Population carrier-frequency estimation for pathogenic CHST3 alleles
description: >-
Estimate cumulative pathogenic CHST3 allele frequency from large
population sequencing datasets to derive an expected birth prevalence.
evidence:
- reference: PMID:36729370
reference_title: "A Chinese case of CHST3-related skeletal dysplasia and a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
There is no apparent genotype-phenotype correlation in this disorder.
explanation: >-
Systematic review finding that motivates the genotype-phenotype arm of
this knowledge gap.
notes: >
Curation scope notes. (1) The three historical eponymic diagnoses (autosomal
recessive Larsen syndrome, humero-spinal dysostosis, spondyloepiphyseal
dysplasia Omani type) are modeled as synonyms of a single spectrum rather than
as subtypes, following Hermanns 2008 (PMID:18513679) and Unger 2010
(PMID:20830804), which showed the clinical features are similar across the
historical labels and that they form one phenotypic spectrum. (2)
Craniosynostosis has been reported in association with CHST3-related skeletal
dysplasia (PMID:24300290) but that report is indexed in PubMed without an
abstract, so no snippet-verifiable evidence item could be created and the
phenotype is intentionally omitted. (3) Orphanet (ORPHA:263463) epidemiology
was not cited because the pinned Orphadata snapshot failed its manifest
checksum at curation time; regenerating the cache would have introduced
unverified drift. (4) Progressive intervertebral disc degeneration, vertebral
fusion, lumbar vertebral clefting and widened interpedicular distances are
described in full texts and in the deep-research report but not in any
abstract that could be quoted, so they appear in prose only. (5) CHST3 also
sulfates keratan sulfate in vitro (PMID:16720579); no keratan sulfate
phenotype has been established in patients, so this is not modeled as a
disease mechanism.
CHST3-related skeletal dysplasia is an ultra-rare, autosomal-recessive disorder of cartilage extracellular-matrix biosynthesis caused by biallelic pathogenic variants in CHST3, encoding carbohydrate sulfotransferase 3/chondroitin 6-O-sulfotransferase 1. Its historically separated diagnoses—spondyloepiphyseal dysplasia with congenital joint dislocations, spondyloepiphyseal dysplasia Omani type, chondrodysplasia with multiple dislocations, recessive Larsen syndrome, and humero-spinal dysostosis—are now best understood as a phenotypic spectrum. The cardinal findings are prenatal or congenital short stature, multiple congenital joint dislocations, abnormal epiphyses and vertebrae, and progressive joint and intervertebral-disc degeneration. Intelligence is generally normal. The molecular lesion is reduced chondroitin 6-O-sulfation; patient fibroblasts showed a four- to fivefold reduction in the relevant 6-sulfated chondroitin disaccharide. No disease-modifying therapy is established; management is multidisciplinary, orthopedic, rehabilitative, and surveillance-based. Evidence remains dominated by small cohorts and case series rather than registries or trials. (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5)
| domain | high-confidence finding | quantitative detail or ontology suggestion | evidence level/source |
|---|---|---|---|
| Identity / synonyms | CHST3-related skeletal dysplasia comprises overlapping phenotypes historically labeled recessive Larsen syndrome, humero-spinal dysostosis, chondrodysplasia with multiple dislocations, and spondyloepiphyseal dysplasia with congenital joint dislocations / Omani type | MONDO/Orphanet/OMIM identifiers: require database validation; disease-level aggregated resource synthesis should be used rather than EHR-derived labels (hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5, hall2024fetalandperinatal pages 63-64) | Human clinical genetics cohort + 2023 review + 2024 skeletal dysplasia reference (hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5, hall2024fetalandperinatal pages 63-64) |
| Etiology / inheritance | Caused by biallelic pathogenic variants in CHST3; inheritance is autosomal recessive | Gene: CHST3; ontology suggestion: autosomal recessive inheritance term requires database validation; consanguinity reported in affected families (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6, hall2024fetalandperinatal pages 63-64) | Human clinical genetics evidence, strong (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6, hall2024fetalandperinatal pages 63-64) |
| Pathogenic variant classes | Reported variant classes include missense, nonsense/premature-termination, frameshift, and splice-site variants | 2008 cohort: 9 mutations across 8 alleles; examples include Y201X, F206X, R222W, L259P, c.1086delG; 2023 review lists c.590T>C p.Leu197Pro, c.603C>A p.Tyr201Ter, c.661C>T p.Arg221Cys, c.802G>T p.Glu268* (hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5) | Human molecular genetics, strong/moderate (hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5) |
| Core phenotype | Congenital multiple joint dislocations are the defining presentation | Presenting feature in 6/6 patients from the 2008 cohort; HPO suggestions: Congenital joint dislocation, Knee dislocation, Hip dislocation, Radial head dislocation, Clubfoot; exact HPO IDs require database validation (hermanns2008congenitaljointdislocations pages 2-4) | Human cohort, strong (hermanns2008congenitaljointdislocations pages 2-4) |
| Phenotype frequency: clubfoot | Clubfeet are very common | 6/6 (100%) in the 2008 cohort; HPO suggestion: Clubfoot, ID requires database validation (hermanns2008congenitaljointdislocations pages 2-4) | Human cohort, strong (hermanns2008congenitaljointdislocations pages 2-4) |
| Phenotype frequency: knee dislocation | Congenital knee dislocation is very common and can be associated with genu recurvatum | 6/6 (100%) knee dislocation; genu recurvatum reported in 50% in one evidence summary; HPO suggestions require database validation (hermanns2008congenitaljointdislocations pages 2-4) | Human cohort, strong, with some phenotype granularity from article summary (hermanns2008congenitaljointdislocations pages 2-4) |
| Phenotype frequency: hip involvement | Hip luxation/dislocation is common but not universal | 4/6 (67%) in the 2008 cohort; HPO suggestion: Hip dislocation, ID requires database validation (hermanns2008congenitaljointdislocations pages 2-4) | Human cohort, strong (hermanns2008congenitaljointdislocations pages 2-4) |
| Phenotype frequency: elbow/radial head | Radial head dislocation is highly characteristic | 6/6 (100%) radial head dislocation; associated distal humerus dysplasia reported radiographically (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) | Human cohort, strong (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) |
| Growth / stature | Prenatal-onset short stature is typical | Birth length 41.5-44 cm, below 3rd percentile; oldest reported adult height 134 cm in the 2008 cohort; HPO suggestion: Short stature, ID requires database validation (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) | Human cohort, strong (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) |
| Spine / progression | Progressive spinal disease is a major morbidity domain | Severe intervertebral disc degeneration, thoracic kyphosis/kyphoscoliosis, vertebral fusion, lumbar vertebral clefting, widened interpedicular distances reported; HPO suggestions require database validation (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) | Human cohort with longitudinal observations, strong (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) |
| Mobility / disability | Function declines over time due to progressive joint restriction and spinal disease | Loss of ambulation or need for crutches/wheelchair reported in patients aged 10.5-31 years in the 2008 cohort (hermanns2008congenitaljointdislocations pages 2-4) | Human natural-history observation, moderate/strong (hermanns2008congenitaljointdislocations pages 2-4) |
| Additional phenotype notes | Intelligence is typically normal; some facial features may be present but are not the principal diagnostic feature | Normal intellect reported; facial features described as small mouth/overfolded ears or resemblance to diastrophic dysplasia; cleft palate and myopia not observed in the cited cohort (hermanns2008congenitaljointdislocations pages 4-6) | Human cohort, moderate (hermanns2008congenitaljointdislocations pages 4-6) |
| Molecular mechanism | Disease results from CHST3 deficiency causing loss/reduction of chondroitin 6-O-sulfation | Fibroblast studies showed 4-5-fold reduction in DDi-6S, the 6-sulfated disaccharide product of chondroitin sulfate; ontology suggestion: glycosaminoglycan biosynthetic process / proteoglycan metabolic process terms require database validation (hermanns2008congenitaljointdislocations pages 2-4) | Functional human-cell evidence, strong (hermanns2008congenitaljointdislocations pages 2-4) |
| Pathophysiology interpretation | Joint dislocations likely reflect primary joint dysplasia rather than simple ligamentous laxity; extracellular matrix/proteoglycan abnormalities underlie skeletal malformation | Mechanistic interpretation supported by radiographic and biochemical findings; chondroitin sulfate sulfation defect implicated in cartilage/proteoglycan biology (hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5, hall2024fetalandperinatal pages 63-64) | Human clinical + review synthesis, moderate (hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5, hall2024fetalandperinatal pages 63-64) |
| Diagnostic clues | Diagnosis is suspected from congenital dislocations plus disproportionate short stature and characteristic radiographs, then confirmed by molecular testing of CHST3 | Radiographic clues: knee dislocation/misalignment, bifid distal humerus with radial head subluxation, vertebral clefting, widened interpedicular distances; confirmatory test: CHST3 sequencing in a skeletal dysplasia gene panel / exome context; exact testing guideline identifiers require database validation (hermanns2008congenitaljointdislocations pages 4-6, hall2024fetalandperinatal pages 63-64) | Human cohort + reference review, moderate/strong (hermanns2008congenitaljointdislocations pages 4-6, hall2024fetalandperinatal pages 63-64) |
| Differential diagnosis | Historically overlaps with recessive Larsen syndrome and humero-spinal dysostosis; broader differential includes other skeletal dysplasias with congenital dislocations | Differential list should include other glycosaminoglycan synthesis disorders and skeletal dysplasias with multiple dislocations; exact ontology/disease IDs require database validation (hermanns2008congenitaljointdislocations pages 4-6, hall2024fetalandperinatal pages 63-64) | Human clinical genetics + review synthesis, moderate (hermanns2008congenitaljointdislocations pages 4-6, hall2024fetalandperinatal pages 63-64) |
| Management | Management is supportive and orthopedic, with frequent need for surgical stabilization and long-term mobility support | “Most patients require multiple surgical stabilization procedures”; supportive devices include crutches/wheelchair in progressive cases; NCIT intervention terms require database validation (hermanns2008congenitaljointdislocations pages 4-6, hermanns2008congenitaljointdislocations pages 2-4) | Human cohort, moderate/strong (hermanns2008congenitaljointdislocations pages 4-6, hermanns2008congenitaljointdislocations pages 2-4) |
| Prognosis | Condition is chronic and progressive, with substantial musculoskeletal disability but survival data are not established in the cited evidence | Major burden: progressive arthritis, contractures, disc degeneration, kyphoscoliosis, impaired ambulation; life expectancy, mortality, and validated QoL metrics: data gap in available evidence (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) | Human cohort natural history, moderate; major prognosis data gaps remain (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6) |
| Epidemiology / population | Ultra-rare Mendelian disorder with published families from multiple populations; robust prevalence/incidence estimates are lacking | Cases reported in Pakistani, Turkish, Indian, Arab/Omani and other populations; recurrent c.776T>C variant noted in later literature; prevalence/incidence and carrier frequency: data gap in available evidence (debeljak2023carbohydratesulfotransferases pages 3-5, hall2024fetalandperinatal pages 63-64) | Review/reference-level evidence, moderate; epidemiology limited (debeljak2023carbohydratesulfotransferases pages 3-5, hall2024fetalandperinatal pages 63-64) |
| Environmental factors | No established environmental or infectious cause is supported in the cited disease-specific evidence | Gene-environment interactions and protective environmental factors: no disease-specific evidence identified in cited sources (hermanns2008congenitaljointdislocations pages 2-4, hall2024fetalandperinatal pages 63-64) | Evidence gap statement based on available sources (hermanns2008congenitaljointdislocations pages 2-4, hall2024fetalandperinatal pages 63-64) |
| 2023 development | A 2023 authoritative review summarized CHST3 deficiency within diagnostic/prognostic applications of carbohydrate sulfotransferases and reaffirmed the skeletal dysplasia / multiple dislocation phenotype spectrum | Publication date: Oct 2023; review highlights CHST3 mutations in skeletal dysplasia, chondrodysplasia, and autosomal recessive multiple joint dislocations (debeljak2023carbohydratesulfotransferases pages 3-5) | Recent review, moderate (debeljak2023carbohydratesulfotransferases pages 3-5) |
| 2024 development | A 2024 fetal/perinatal skeletal dysplasia reference continues to classify CHST3-related disorders among autosomal recessive glycosaminoglycan-synthesis skeletal dysplasias with congenital dislocations | Publication date: Mar 2024; emphasizes recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type within the CHST3 spectrum (hall2024fetalandperinatal pages 63-64) | Recent expert reference, moderate (hall2024fetalandperinatal pages 63-64) |
| Knowledge-base curation note | Best-supported assertions currently derive from small cohorts and expert reviews; identifiers and ontology IDs should be cross-checked directly in OMIM/Orphanet/HPO/MONDO before database ingestion | Mark all uncertain IDs as requiring database validation; strongest quantitative phenotype data in available evidence come from the six-patient 2008 cohort (hermanns2008congenitaljointdislocations pages 2-4) | Curation guidance from evidence quality profile (hermanns2008congenitaljointdislocations pages 2-4) |
Table: This table summarizes high-confidence, knowledge-base-ready findings on CHST3-related skeletal dysplasia from the available cited evidence. It emphasizes the strongest cohort data, core mechanism, and current gaps that require direct database validation or newer primary sources.
CHST3-related skeletal dysplasia is a Mendelian proteoglycan-sulfation disorder affecting cartilage, joints, vertebral bodies, and intervertebral discs. Congenital dislocations arise from primary dysplasia of joint structures—not merely generalized ligamentous laxity—and are followed by progressive cartilage and spinal degeneration. The 2008 molecular delineation unified patients previously diagnosed with recessive Larsen syndrome and humero-spinal dysostosis; subsequent literature has incorporated Omani-type spondyloepiphyseal dysplasia and related multiple-dislocation phenotypes into the same CHST3 spectrum. (hermanns2008congenitaljointdislocations pages 4-6, hall2024fetalandperinatal pages 63-64)
Common names/synonyms include:
This report synthesizes aggregated disease-level resources and published patients, not individual EHR records. The strongest quantitative evidence available here is a six-patient molecular cohort. (hermanns2008congenitaljointdislocations pages 2-4)
The cause is germline biallelic loss-of-function or severe hypomorphic variation in CHST3, inherited in an autosomal-recessive pattern. Reported classes include missense, nonsense, frameshift, and splice-altering variants. In the foundational cohort, nine mutations across eight alleles included five missense, three premature-termination, and one splice-site mutation. (hermanns2008congenitaljointdislocations pages 2-4)
Representative variants include p.Tyr201Ter, p.Phe206Ter, p.Arg222Trp, p.Leu259Pro, p.Leu307Pro, p.Glu372Lys, and c.1086delG. A 2023 review additionally lists c.590T>C (p.Leu197Pro), c.603C>A (p.Tyr201Ter), c.661C>T (p.Arg221Cys), and c.802G>T (p.Glu268Ter). Transcript/version and left-alignment must be checked before variant-database ingestion. (hermanns2008congenitaljointdislocations pages 4-6, debeljak2023carbohydratesulfotransferases pages 3-5)
No validated protective CHST3 allele, modifier gene, diet, exposure, or lifestyle intervention prevents disease in a person with biallelic pathogenic variants. Likewise, no disease-specific gene–environment interaction has been demonstrated. Mechanical loading may influence downstream orthopedic morbidity, but this is not evidence that environment causes or prevents the molecular disorder.
The following frequencies come from only six patients and should not be treated as population estimates. All six presented at birth with congenital dislocations and clubfeet; knee dislocation occurred in 6/6, hip luxation in 4/6, and radial-head dislocation in 6/6. Birth length was 41.5–44 cm, below the third percentile; adult height in the oldest reported individual was 134 cm. (hermanns2008congenitaljointdislocations pages 2-4)
Progressive contractures, arthritis, deformity, and disc disease substantially affect walking, self-care, education/employment access, pain, and independence. In reported patients aged 10.5–31 years, some required crutches or wheelchairs or lost independent ambulation. No disease-specific EQ-5D, SF-36, PROMIS, pain-scale, or caregiver-burden dataset was found. (hermanns2008congenitaljointdislocations pages 2-4)
CHST3 encodes chondroitin 6-O-sulfotransferase 1, a Golgi-associated sulfotransferase that modifies chondroitin chains of proteoglycans. The disease variants are germline, not somatic cancer mutations. Truncating and severe missense alleles reduce or abolish enzyme activity; p.Tyr201Ter and p.Phe206Ter truncate the sulfotransferase region, while p.Arg222Trp and p.Leu259Pro markedly impair function. (hermanns2008congenitaljointdislocations pages 4-6)
Patient-fibroblast studies demonstrated a four- to fivefold reduction in DDi-6S, the 6-sulfated chondroitin disaccharide product. This is direct human-cell functional evidence linking genotype to deficient chondroitin 6-O-sulfation. (hermanns2008congenitaljointdislocations pages 2-4)
No reliable variant-specific population frequencies were available in the retrieved texts. Individual alleles should be checked in current gnomAD and ClinVar releases; pathogenic recessive alleles are expected to be absent or very rare, but rarity alone does not establish pathogenicity. ACMG/AMP classification should integrate segregation, predicted consequence, functional evidence, population frequency, and phenotype specificity.
No validated modifier genes, disease-specific epigenetic signature, recurrent pathogenic copy-number variant, translocation, aneuploidy, or chromosomal rearrangement has been established. Consequently, routine karyotype or microarray is not the preferred confirmatory test when the phenotype strongly suggests CHST3 disease.
No toxin, radiation source, pollutant, diet, smoking behavior, alcohol exposure, occupation, or infectious agent is known to cause CHST3-related skeletal dysplasia. Environmental factors can affect general bone health, surgical recovery, pain, and mobility but should be represented as modifiers of health status—not etiologic disease assertions. Immunization and antimicrobial interventions have no disease-specific preventive role.
No CHST3-disease-specific single-cell atlas, spatial transcriptomic study, patient proteome, metabolome, lipidome, multi-omics integration, organoid study, or CRISPR screen was established by the retrieved literature. These are important research gaps.
The primary system is the musculoskeletal/connective-tissue system.
Suggested UBERON concepts include cartilage tissue, articular cartilage, epiphyseal plate, intervertebral disc, vertebral body, hip joint, knee joint, elbow joint, humerus, radius, and foot; exact accessions should be version-validated.
The disorder begins prenatally or congenitally, with short length, joint malformation, dislocations, and clubfeet apparent at birth. The course is chronic and lifelong rather than episodic. Childhood and adolescence bring increasing joint restriction, contractures, deformity, and spinal disease; older patients can develop severe disc degeneration, kyphoscoliosis, vertebral fusion, arthritis, and loss of independent mobility. (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6)
There is no recognized spontaneous remission. The most important intervention window is early childhood, when joint alignment, spine stability, mobility preservation, and avoidance of secondary deformity may be addressed. However, no prospective study defines an optimal operation age or stage-specific algorithm.
Inheritance is autosomal recessive. Penetrance appears high for individuals with two severe pathogenic alleles, but formal age-adjusted penetrance has not been calculated. Expressivity is variable, including intrafamilial variation, and the historic use of multiple diagnostic names reflects this breadth. No anticipation mechanism is expected or documented. Germline mosaicism has not been established but cannot be excluded in apparently de novo situations.
Consanguinity is a relevant population-genetic factor, and patients have been described in Omani/Arab, Pakistani, Turkish, Indian, Somali, Mediterranean, and other families. A recurrent c.776T>C allele has been reported in later literature, but robust founder-haplotype evidence was not available here. (debeljak2023carbohydratesulfotransferases pages 3-5, hall2024fetalandperinatal pages 63-64)
No credible prevalence, incidence, carrier-frequency, sex-ratio, mortality-rate, or geographic-rate estimate was found. The disorder should be classified as ultra-rare, with ascertainment biased toward consanguineous families and specialist skeletal-dysplasia centers.
Suspect CHST3-related disease in a neonate or child with multiple congenital dislocations, clubfeet, disproportionate short stature, radial-head abnormalities, and a spondyloepiphyseal radiographic pattern. Characteristic reported images include knee malalignment/dislocation, bifid distal humeri with radial-head subluxation, lumbar vertebral clefting, widened L1–L2 interpedicular distance, and later severe disc degeneration and vertebral fusion. (hermanns2008congenitaljointdislocations pages 4-6)
Baseline evaluation should include a skeletal survey interpreted by a skeletal-dysplasia radiologist; targeted spine, hip, knee, elbow, and foot imaging; neurologic examination where spinal deformity is substantial; audiology; growth measurements; pain and functional assessment; and orthopedic/rehabilitation review. MRI is useful for discs, spinal cord, neural compression, and operative planning but is not itself molecularly diagnostic.
No routine serum or urine chemistry is diagnostic. The fibroblast DDi-6S assay is mechanistically informative but is not established as a widely available clinical standard. (hermanns2008congenitaljointdislocations pages 2-4)
Important alternatives include FLNB-related dominant Larsen syndrome, B3GAT3- and other linkeropathy-associated multiple-dislocation disorders, CHST14-related musculocontractural Ehlers–Danlos syndrome, SLC26A2-related dysplasias, XYLT1-related Desbuquois dysplasia type 2, CANT1-related Desbuquois dysplasia, IMPAD1-related chondrodysplasia, and collagen-related spondyloepiphyseal dysplasias. Distinguishing features include inheritance, craniofacial pattern, hand morphology, skin/vascular signs, bone density, specific radiographic pattern, and molecular result.
No universally accepted clinical scoring criteria or population/newborn biochemical screening program exists.
The major burden is musculoskeletal morbidity: recurrent or persistent deformity, early arthritis, contractures, pain, severe disc degeneration, kyphosis/kyphoscoliosis, vertebral fusion, and impaired ambulation. Some patients require crutches or wheelchairs by later childhood or adulthood. (hermanns2008congenitaljointdislocations pages 2-4)
Intellectual prognosis is generally favorable. No reliable five- or ten-year survival rate, disease-specific mortality estimate, or life-expectancy calculation is available. Available evidence does not identify an intrinsic lethal cardiopulmonary, neurologic, or immune phenotype, but individual prognosis depends on spinal disease, operative complications, pain, and mobility. Formal prognostic biomarkers and validated patient-reported outcome measures have not been developed.
There is no approved enzyme replacement, small-molecule, gene, RNA, or cell therapy for CHST3-related skeletal dysplasia. The retrieved clinical-trial search found no relevant interventional trial; an unrelated GLP-1 study returned by broad search was excluded.
Current care is individualized and multidisciplinary:
Most patients in the foundational series required multiple stabilization operations, but the evidence does not establish response rates or a single preferred surgical pathway. (hermanns2008congenitaljointdislocations pages 4-6)
Suggested NCIT intervention concepts include orthopedic surgical procedure, osteotomy, spinal fusion, physical therapy, occupational therapy, assistive device, pain management, and genetic counseling; exact NCIT identifiers should be release-validated. No CHST3-specific pharmacogenomic recommendation exists.
The molecular disease cannot currently be prevented by diet, lifestyle modification, vaccination, or prophylactic medication.
Population-wide newborn or carrier screening is not currently supported by prevalence or utility data.
No adequately supported naturally occurring veterinary analogue attributable to orthologous CHST3 variants was identified in the retrieved evidence. CHST3 is evolutionarily conserved, and chondroitin-sulfate biology is shared across vertebrates, but conservation alone is not evidence of a natural animal disease. There is no zoonotic potential or cross-species transmission because this is a germline genetic disorder.
Relevant taxonomy concepts for experimental comparisons include Homo sapiens (NCBI Taxon 9606) and Mus musculus (10090). Species-specific CHST3 ortholog and NCBI Gene identifiers should be retrieved directly from the current NCBI orthology record before ingestion.
The retrieved evidence did not provide sufficient primary detail to curate a specific CHST3-null mouse line, its accession, or quantitative phenotype with confidence. More broadly, glycosaminoglycan-biosynthetic knockout mice have been valuable for establishing how sulfation patterns regulate cell signaling, proliferation, tissue morphogenesis, and growth-plate/cartilage development. (debeljak2023carbohydratesulfotransferases pages 3-5)
The strongest disease-specific experimental model in the available evidence is patient-derived fibroblasts, which directly reproduced the biochemical sulfation defect. (hermanns2008congenitaljointdislocations pages 2-4)
Priority future models include:
Model limitations must include species differences in skeletal loading, growth-plate closure, joint anatomy, and lifespan, and the inability of fibroblast assays to reproduce the biomechanical environment of human cartilage.
A peer-reviewed review published in October 2023 emphasized that carbohydrate sulfotransferases build proteoglycans supporting physical interactions and signaling between neighboring cells and summarized CHST3 mutations as causes of skeletal dysplasia, chondrodysplasia, and autosomal-recessive multiple dislocations. Its abstract states: “Mutations of CHST3 gene cause skeletal dysplasia, chondrodysplasia, and autosomal recessive multiple joint dislocations.” The authors cautioned that larger clinical studies and robust analytical procedures remain necessary. DOI: https://doi.org/10.11613/bm.2023.030503. (debeljak2023carbohydratesulfotransferases pages 3-5)
A March 2024 expert fetal/perinatal skeletal-dysplasia reference retained recessive Larsen syndrome, humero-spinal dysostosis, and Omani-type spondyloepiphyseal dysplasia within the autosomal-recessive CHST3/glycosaminoglycan-synthesis spectrum. DOI/book URL: https://doi.org/10.1201/9781003166948. (hall2024fetalandperinatal pages 63-64)
The most important recent disease-specific primary report identified by the search was a 2023 series titled CHST3-related skeletal dysplasia in 14 patients: identification of 8 novel variants and further expansion of the phenotypic spectrum (May 2023; DOI: https://doi.org/10.1002/ajmg.a.63246), but its full text was unavailable to the retrieval system. Accordingly, its title-level claims should not be converted into phenotype frequencies without direct verification.
The foundational primary article, published in June 2008, reports: “We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations.” DOI: https://doi.org/10.1016/j.ajhg.2008.05.006; PMID commonly indexed as 18513679. It provides the strongest retrieved human genotype, phenotype, biochemical, and longitudinal evidence. (hermanns2008congenitaljointdislocations pages 2-4, hermanns2008congenitaljointdislocations pages 4-6)
Nevertheless, the evidence base remains limited by small, retrospectively ascertained cohorts. Critical unmet needs include a prospective natural-history registry; validated phenotype frequencies; standardized radiographic and functional endpoints; prevalence and carrier-frequency estimates; patient-reported quality-of-life measures; genotype–phenotype analysis; disease-specific biomarkers; well-curated model organisms; and interventional trials. Quantitative values from six patients must therefore be labeled as cohort observations rather than general disease frequencies.
References
(hermanns2008congenitaljointdislocations pages 2-4): Pia Hermanns, Sheila Unger, Antonio Rossi, Antonio Perez-Aytes, Hector Cortina, Luisa Bonafé, Loredana Boccone, Valeria Setzu, Michel Dutoit, Luca Sangiorgi, Fabio Pecora, Kerstin Reicherter, Gen Nishimura, Jürgen Spranger, Bernhard Zabel, and Andrea Superti-Furga. Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive larsen syndrome and humero-spinal dysostosis. American journal of human genetics, 82 6:1368-74, Jun 2008. URL: https://doi.org/10.1016/j.ajhg.2008.05.006, doi:10.1016/j.ajhg.2008.05.006. This article has 131 citations and is from a highest quality peer-reviewed journal.
(hermanns2008congenitaljointdislocations pages 4-6): Pia Hermanns, Sheila Unger, Antonio Rossi, Antonio Perez-Aytes, Hector Cortina, Luisa Bonafé, Loredana Boccone, Valeria Setzu, Michel Dutoit, Luca Sangiorgi, Fabio Pecora, Kerstin Reicherter, Gen Nishimura, Jürgen Spranger, Bernhard Zabel, and Andrea Superti-Furga. Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive larsen syndrome and humero-spinal dysostosis. American journal of human genetics, 82 6:1368-74, Jun 2008. URL: https://doi.org/10.1016/j.ajhg.2008.05.006, doi:10.1016/j.ajhg.2008.05.006. This article has 131 citations and is from a highest quality peer-reviewed journal.
(debeljak2023carbohydratesulfotransferases pages 3-5): Željko Debeljak, Gramos Begolli, Ivana Marković, and Jelena Knežević. Carbohydrate sulfotransferases. Biochemia medica, 33:255-265, Oct 2023. URL: https://doi.org/10.11613/bm.2023.030503, doi:10.11613/bm.2023.030503. This article has 29 citations and is from a peer-reviewed journal.
(hall2024fetalandperinatal pages 63-64): Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Gen Nishimura, and Valerie Cormier-Daire. Fetal and perinatal skeletal dysplasias. ArXiv, Mar 2024. URL: https://doi.org/10.1201/9781003166948, doi:10.1201/9781003166948. This article has 26 citations.