Musculocontractural Ehlers-Danlos Syndrome

Mendelian MONDO:0011142 Pathograph 6 Show in embeddings browser Ehlers-Danlos Syndrome Connective Tissue Disorder

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare autosomal recessive connective-tissue disorder caused by biallelic loss-of-function variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), or in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1). Both genes act at consecutive steps of the same pathway, so both lesions converge on defective dermatan sulfate (DS) biosynthesis: the glycosaminoglycan chain of decorin, the major dermal DS-proteoglycan that organizes collagen fibril assembly, is replaced by chondroitin sulfate. The resulting failure of collagen fibril assembly produces a distinctive two-part disease — congenital multisystem malformation (multiple congenital contractures with adducted thumbs and talipes equinovarus, characteristic craniofacial features, and ocular and urogenital anomalies) followed by progressive connective-tissue fragility (skin hyperextensibility, bruisability and atrophic scarring, recurrent dislocations, large subcutaneous hematomas, pneumothorax, and diverticular perforation). The two gene-defined forms, mcEDS-CHST14 (MONDO:0020681, "musculocontractural type 1") and mcEDS-DSE (MONDO:0014236, "musculocontractural type 2"), are clinically near-indistinguishable and are curated here as subtypes of a single entry; mcEDS-DSE is rarer and appears less severe, plausibly because residual DS remains on decorin.

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1
Inheritance
5
Pathophys.
1
Histopath.
40
Phenotypes
2
Gaps
6
Pathograph
2
Genes
6
Medical Actions
2
Subtypes
2
Models
3
References
🏷

Classifications

ISDS Skeletal Nosology
sulphation disorders
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
mcEDS is autosomal recessive; both CHST14 and DSE forms require biallelic pathogenic variants, and heterozygous carriers are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"Musculocontractural EDS is inherited in an autosomal recessive manner."
GeneReviews states the mode of inheritance directly.
PMID:40373179 SUPPORT Human Clinical
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier"
The stated recurrence risks confirm autosomal recessive segregation.
◆

Subtypes

2
mcEDS-CHST14 (musculocontractural type 1) MONDO:0020681
CHST14 hgnc:24464 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CHST14 (hgnc:24464). hgnc:24464 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic loss-of-function variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1). This is the common and more severe form, accounting for the large majority of reported patients. Loss of D4ST1 activity replaces the decorin glycosaminoglycan chain with chondroitin sulfate completely, with no residual dermatan sulfate.
Show evidence (2 references)
PMID:25703627 SUPPORT Human Clinical
"Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies."
Establishes CHST14/D4ST1 as the causative gene of the archetypal mcEDS form.
PMID:31905796 SUPPORT Other
"Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature."
Quantifies mcEDS-CHST14 as the substantially more frequently reported subtype.
mcEDS-DSE (musculocontractural type 2) MONDO:0014236
DSE hgnc:21144 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in DSE (hgnc:21144). hgnc:21144 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic loss-of-function variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), which converts glucuronic acid to iduronic acid in the nascent chondroitin/dermatan sulfate chain. Ultrastructurally and clinically similar to mcEDS-CHST14 but far rarer and with a lower symptom burden, plausibly because some dermatan sulfate moieties persist on decorin through residual DS-epi1 activity or DSE2 compensation.
Show evidence (3 references)
PMID:23704329 SUPPORT Human Clinical
"DSE deficiency represents a specific defect of DS biosynthesis. We demonstrate locus heterogeneity in MCEDS"
The original report establishing DSE as the second mcEDS locus.
PMID:32130795 SUPPORT Human Clinical
"McEDS-DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS-CHST14. However, the burden of symptoms seems lower in patients with mcEDS-DSE."
Establishes clinical near-identity with mcEDS-CHST14 alongside a lower symptom burden.
PMID:25703627 SUPPORT Human Clinical
"the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype"
Independent observation of the milder mcEDS-DSE presentation.
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Discussions and Knowledge Gaps

2
Does the perinatally lethal Chst14-null mouse adequately model human mcEDS-CHST14, in which affected individuals survive and the dominant morbidity is progressive postnatal connective-tissue fragility?
HUMAN MODEL MISMATCH OPEN mceds_chst14_mouse_model_mismatch
Attached to
pathophysiology#Progressive Multisystem Connective Tissue Fragility
Homozygous Chst14-null mice die perinatally with shorter fetal length and placental vascular abnormalities, so the model speaks to the developmental arm of the disease but cannot report on the progressive fragility arm — skin fragility, recurrent dislocations, large subcutaneous hematomas, pneumothorax, and diverticular perforation — that defines long-term human morbidity. Evidence for the fragility mechanism therefore rests on human ultrastructural and biochemical studies rather than on the mouse.
Proposed experiments
Conditional or hypomorphic Chst14 allele surviving to adulthood
mceds_conditional_chst14_postnatal_fragility
Generate and characterize conditional or hypomorphic Chst14 alleles that bypass perinatal lethality, then assess postnatal skin, joint, vascular, and hollow-organ fragility against the human phenotype.
Dse-null mouse phenotyping
mceds_dse_null_mouse_survival
Test whether a Dse-null mouse, expected to retain residual dermatan sulfate as in human mcEDS-DSE, survives to adulthood and develops the milder progressive fragility phenotype seen in patients.
Show evidence (1 reference)
PMID:31905796 SUPPORT Model Organism
"Homozygous (Chst14-/-) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities."
The perinatal-lethal murine phenotype is the source of the translational mismatch with the surviving human phenotype.
Is the residual decorin dermatan sulfate seen in DS-epi1 deficiency actually the cause of the milder mcEDS-DSE phenotype, and is DSE2 the compensating activity?
KNOWLEDGE GAP OPEN mceds_dse_residual_ds_severity_gap
Attached to
pathophysiology#Decorin Glycosaminoglycan Chain Replacement
The persistence of some dermatan sulfate moieties in DS-epi1-deficient fibroblasts, in contrast to complete chondroitin sulfate replacement in D4ST1 deficiency, is the leading explanation for the lower symptom burden in mcEDS-DSE. The source literature states this only as a hedged proposal, and with only a handful of reported mcEDS-DSE patients the genotype-phenotype comparison is underpowered. Whether DSE2 provides the compensating epimerase activity is untested.
Proposed experiments
Decorin dermatan sulfate content versus clinical severity
mceds_decorin_ds_severity_correlation
Quantify decorin dermatan sulfate content across a matched series of mcEDS-CHST14 and mcEDS-DSE fibroblast lines and correlate with a standardized clinical severity score.
DSE2 knockdown in DS-epi1-deficient fibroblasts
mceds_dse2_compensation_test
Knock down or knock out DSE2 in DS-epi1-deficient patient fibroblasts and test whether residual dermatan sulfate is lost, establishing or excluding DSE2 compensation.
Show evidence (1 reference)
PMID:31905796 SUPPORT Other
"Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity."
The hedged phrasing in the source review is itself the evidence that this remains an open question rather than a settled mechanism.
⚙

Pathophysiology

5
Dermatan Sulfate Biosynthesis Failure
Biallelic loss-of-function variants in CHST14 (dermatan 4-O-sulfotransferase-1, D4ST1) or DSE (dermatan sulfate epimerase-1, DS-epi1) abolish consecutive steps required to build iduronic acid-containing dermatan sulfate domains within hybrid chondroitin sulfate/dermatan sulfate glycosaminoglycan chains. DS-epi1 epimerizes glucuronic acid to iduronic acid and D4ST1 4-O-sulfates the adjacent N-acetylgalactosamine; loss of either leaves a negligible amount of dermatan sulfate and a reciprocal excess of chondroitin sulfate. This is the single lesion shared by both gene-defined subtypes.
skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
dermatan sulfate proteoglycan biosynthesis GO:0050651 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dermatan sulfate proteoglycan biosynthesis, annotated with dermatan sulfate proteoglycan biosynthetic process (GO:0050651). GO:0050651 is a biological process from the Gene Ontology. ↓ DECREASED chondroitin sulfate proteoglycan biosynthesis GO:0050650 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased chondroitin sulfate proteoglycan biosynthesis, annotated with chondroitin sulfate proteoglycan biosynthetic process (GO:0050650). GO:0050650 is a biological process from the Gene Ontology. ↑ INCREASED
dermatan sulfate epimerase activity GO:0047757 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dermatan sulfate epimerase activity, annotated with chondroitin-glucuronate 5-epimerase activity (GO:0047757). GO:0047757 is a molecular function from the Gene Ontology. ↓ DECREASED dermatan 4-O-sulfotransferase activity GO:0001537 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dermatan 4-O-sulfotransferase activity, annotated with dermatan 4-sulfotransferase activity (GO:0001537). GO:0001537 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Xenopus DS-epi1 (dse) morphant embryos Xenopus laevis recapitulates Reproduces the mcEDS-DSE biochemical lesion directly: loss of DS-epi1 removes iduronic acid residues from hybrid CS/DS glycosaminoglycan chains.
Downstream
Decorin Glycosaminoglycan Chain Replacement Absent dermatan sulfate synthesis leaves the glycosaminoglycan chain of decorin, the principal dermal DS-proteoglycan, glycanated with chondroitin sulfate instead.
Show evidence (4 references)
PMID:31905796 SUPPORT Other
"Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate."
States the shared enzymatic and biochemical lesion of both mcEDS subtypes.
PMID:25703627 SUPPORT Other
"DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs)."
Places both enzymes on the same DS biosynthetic pathway.
PMID:23704329 SUPPORT In Vitro
"Heterologous expression of mutant full-length and soluble recombinant DSE proteins showed a loss of activity towards partially desulfated DS. Patient-derived fibroblasts also showed a significant reduction in epimerase activity."
Direct enzymatic demonstration that DSE variants abolish epimerase activity in patient cells.
+ 1 more reference
Decorin Glycosaminoglycan Chain Replacement
Decorin is the major dermatan sulfate proteoglycan of skin and normally tethers adjacent collagen fibrils through electrostatic interactions mediated by its dermatan sulfate side chain. In mcEDS this side chain is replaced by chondroitin sulfate. The replacement is complete in D4ST1 (CHST14) deficiency, whereas in DS-epi1 (DSE) deficiency some dermatan sulfate moieties persist — the leading explanation for the milder mcEDS-DSE phenotype.
skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
proteoglycan biosynthesis GO:0030166 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal proteoglycan biosynthesis, annotated with proteoglycan biosynthetic process (GO:0030166). GO:0030166 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Disorganized Collagen Fibril Assembly Loss of the dermatan sulfate side chain removes the electrostatic bridging that decorin normally provides between neighboring collagen fibrils, so fibril assembly fails.
Show evidence (3 references)
PMID:25703627 SUPPORT In Vitro
"However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present."
Establishes the quantitative difference in decorin glycanation between the two subtypes, the proposed basis of the severity gradient.
PMID:31905796 SUPPORT Other
"Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly."
Identifies altered decorin glycosaminoglycan composition as the proximate cause of tissue fragility.
PMID:31905796 SUPPORT Other
"Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity."
Explicitly hedged proposal linking residual decorin dermatan sulfate to the milder mcEDS-DSE phenotype; recorded as PARTIAL because it is a proposed rather than demonstrated explanation.
Disorganized Collagen Fibril Assembly
In affected skin, collagen fibrils are dispersed through the papillary to reticular dermis rather than being regularly and tightly assembled, and the glycosaminoglycan chains run linearly from the surface of one fibril to adjacent fibrils instead of curving to stay in close contact with the fibril they decorate. This ultrastructural signature is the tissue-level readout of the decorin defect and the immediate substrate of connective-tissue fragility.
skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ⚠ ABNORMAL extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Progressive Multisystem Connective Tissue Fragility Failure of ordered collagen fibril assembly leaves skin, joints, vessels, and hollow organs mechanically weak, producing the progressive fragility-related complications that dominate the disease after infancy.
Congenital Malformation of Connective-Tissue-Dependent Structures Because dermatan sulfate proteoglycans are required during fetal development, the same biosynthetic block also produces the congenital malformation arm of the disease, present at birth rather than acquired.
Show evidence (2 references)
PMID:31905796 SUPPORT Other
"Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled."
Describes the diagnostic ultrastructural collagen abnormality in mcEDS skin.
PMID:31905796 SUPPORT Other
"Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils."
Documents the altered glycosaminoglycan-collagen geometry that follows replacement of decorin dermatan sulfate by chondroitin sulfate.
Congenital Malformation of Connective-Tissue-Dependent Structures
The developmental arm of mcEDS, evident at birth: multiple congenital contractures (characteristically adduction-flexion contractures of the thumbs and talipes equinovarus), a recognizable craniofacial gestalt, and visceral and ophthalmological malformations. These features are congenital and non-progressive in origin, distinguishing them from the fragility arm.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Xenopus DS-epi1 (dse) morphant embryos Xenopus laevis partially recapitulates Supplies a developmental mechanism for the congenital craniofacial features: neural crest cells are induced normally but fail to undergo EMT and migrate, so crest-derived craniofacial skeleton is reduced.
Show evidence (2 references)
PMID:26646600 SUPPORT Human Clinical
"multiple congenital contractures including adduction-flexion contractures and talipes equinovarus as well as other visceral or ophthalmological malformations"
Describes the congenital malformation component of the mcEDS phenotype.
PMID:40373179 SUPPORT Human Clinical
"characteristic craniofacial features (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high..."
GeneReviews enumerates the characteristic craniofacial gestalt.
Progressive Multisystem Connective Tissue Fragility
The progressive arm of mcEDS, emerging and worsening after infancy: skin hyperextensibility, bruisability and fragility with atrophic scars, recurrent dislocations, progressive talipes and spinal deformities, large subcutaneous hematomas, pneumothorax or pneumohemothorax, and diverticular perforation. These complications dominate long-term morbidity and drive the surveillance schedule.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:26646600 SUPPORT Human Clinical
"progressive multisystem fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation)"
Enumerates the progressive fragility-related complications of mcEDS.
PMID:31905796 SUPPORT Other
"Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations."
Confirms the two-arm disease structure of mcEDS.
✶

Histopathology

1
Disorganized Dermal Collagen Fibril Architecture
The hallmark electron-microscopic finding in mcEDS skin: collagen fibrils are dispersed through the papillary to reticular dermis instead of being regularly and tightly assembled, and the glycosaminoglycan chains run linearly between fibrils rather than curving to stay in contact with the fibril they decorate.
Show evidence (2 references)
PMID:31905796 SUPPORT Other
"Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled."
Describes the diagnostic ultrastructural collagen abnormality in mcEDS skin.
PMID:31905796 SUPPORT Other
"Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils."
Documents the altered glycosaminoglycan-collagen geometry seen on electron microscopy.
⬡

Pathograph

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

Phenotypes

40
Blood 1
Bruising Susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
GeneReviews lists bruisability as a core cutaneous feature.
Cardiovascular 2
Cardiac Valve Abnormalities Abnormal heart valve morphology HP:0001654 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart valve morphology (HP:0001654). HP:0001654 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:40373179 SUPPORT Human Clinical
"treatment of cardiac valve abnormalities and congenital heart defects per cardiologist and cardiac surgeon"
GeneReviews names cardiac valve abnormalities and congenital heart defects as treated mcEDS manifestations.
PMID:40373179 SUPPORT Human Clinical
"cardiac evaluation, and otologic evaluation annually beginning in infancy"
Annual cardiac surveillance from infancy confirms cardiovascular involvement as an expected feature.
PMID:32130795 SUPPORT Human Clinical
"congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems"
Independently confirms cardiovascular involvement in the mcEDS-DSE subtype.
Congenital Heart Defects Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"treatment of cardiac valve abnormalities and congenital heart defects per cardiologist and cardiac surgeon"
GeneReviews names congenital heart defects as a treated mcEDS manifestation, distinct from valve abnormalities.
Digestive 1
Chronic Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019), qualified as temporality chronic. HP:0002019 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"standard treatment for osteoporosis and constipation"
GeneReviews management guidance identifies constipation as a treated mcEDS manifestation.
Ear 2
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"treatment of diverticula per gastroenterologist; hearing aids as needed"
GeneReviews lists hearing aids among mcEDS management, implying clinically significant hearing impairment. This is inferred from a management line rather than a direct prevalence statement, so the claim is marked PARTIAL.
PMID:40373179 SUPPORT Human Clinical
"cardiac evaluation, and otologic evaluation annually beginning in infancy"
Annual otologic surveillance from infancy corroborates expected hearing involvement, again indirectly.
Low-Set Ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"low-set posteriorly rotated ears"
GeneReviews lists low-set ears in the craniofacial gestalt.
Eye 4
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"characteristic craniofacial features (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high..."
GeneReviews enumerates the craniofacial gestalt including hypertelorism.
PMID:32130795 SUPPORT Human Clinical
"craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia)"
Confirms hypertelorism in the mcEDS-DSE subtype as well.
Blue Sclerae HP:0000592 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blue sclerae (HP:0000592). HP:0000592 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32130795 SUPPORT Human Clinical
"craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia)"
Documents blue sclerae in molecularly confirmed mcEDS-DSE patients.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"ocular abnormalities (strabismus, refractive errors, and glaucoma)"
GeneReviews lists strabismus among the ocular abnormalities of mcEDS.
Glaucoma HP:0000501 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glaucoma (HP:0000501). HP:0000501 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"ocular abnormalities (strabismus, refractive errors, and glaucoma)"
GeneReviews lists glaucoma among the ocular abnormalities of mcEDS.
Genitourinary 2
Nephrolithiasis and Cystolithiasis HP:0000787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrolithiasis (HP:0000787). HP:0000787 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"treatment of nephrolithiasis and urolithiasis per nephrologist and/or urologist"
GeneReviews identifies nephrolithiasis as a recognized mcEDS manifestation requiring management.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31905796 SUPPORT Other
"nephrolithiasis/cystolithiasis, 11) hydronephrosis, 12) cryptorchidism in males"
Cryptorchidism is listed as minor diagnostic criterion 12 for mcEDS.
Head and Neck 6
Downslanted and Short Palpebral Fissures Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"short and downslanted palpebral fissures, hypertelorism, blue sclera"
GeneReviews lists short and downslanted palpebral fissures in the craniofacial gestalt.
Short Nose with Hypoplastic Columella HP:0003196 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short nose (HP:0003196). HP:0003196 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"short nose with hypoplastic columella"
GeneReviews lists a short nose with hypoplastic columella in the craniofacial gestalt.
Long Philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
GeneReviews lists a long philtrum in the craniofacial gestalt.
Narrow Mouth HP:0000160 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow mouth (HP:0000160). HP:0000160 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
GeneReviews lists a small mouth in the craniofacial gestalt.
High Palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
GeneReviews lists a high palate in the craniofacial gestalt.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
GeneReviews lists micrognathia in the craniofacial gestalt.
Integument 3
Skin Hyperextensibility VERY_FREQUENT Hyperextensible skin HP:0000974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperextensible skin (HP:0000974). HP:0000974 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
GeneReviews lists skin hyperextensibility as a core mcEDS feature.
PMID:31905796 SUPPORT Other
"characteristic cutaneous features including hyperextensibility, bruisability and fragility with atrophic scars"
Snippet supports the disease-phenotype association. The VERY_FREQUENT band is a clinical estimate, not a reported statistic: the author wording "characteristic cutaneous features" maps to VERY_FREQUENT under the dismech qualitative mapping (docs/frequency-evidence-guidelines.md, Pattern C). No quantitative cohort frequency has been published.
Atrophic Scarring Atrophic scars HP:0001075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrophic scars (HP:0001075). HP:0001075 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
GeneReviews lists skin fragility with atrophic scars among the mcEDS skin features.
Poor Wound Healing HP:0001058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor wound healing (HP:0001058). HP:0001058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
GeneReviews lists delayed wound healing among the mcEDS skin features.
Limbs 1
Talipes Equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26646600 SUPPORT Human Clinical
"multiple congenital contractures including adduction-flexion contractures and talipes equinovarus"
Documents talipes equinovarus as a congenital mcEDS feature.
Musculoskeletal 5
Small Joint Hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"hypermobility of the small joints, recurrent dislocations, spinal deformities"
GeneReviews lists small-joint hypermobility among the core mcEDS features.
Recurrent Joint Dislocations HP:0001373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint dislocation (HP:0001373), qualified as temporality recurrent. HP:0001373 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"hypermobility of the small joints, recurrent dislocations, spinal deformities"
GeneReviews lists recurrent dislocations as a core mcEDS feature.
Progressive Spinal Deformity Kyphoscoliosis HP:0002751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphoscoliosis (HP:0002751), qualified as course progressive. HP:0002751 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:26646600 SUPPORT Human Clinical
"progressive talipes or spinal deformities"
Documents progressive spinal deformity as an mcEDS complication.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"physical therapy for hypotonia and motor delay"
GeneReviews management recommendations identify hypotonia as a recognized mcEDS manifestation requiring treatment.
PMID:40373179 SUPPORT Human Clinical
"Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal."
GeneReviews records neurologic involvement as part of the mcEDS multisystem phenotype.
Osteoporosis HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"standard treatment for osteoporosis and constipation"
GeneReviews lists osteoporosis among manifestations requiring treatment in mcEDS.
Nervous System 1
Motor Delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"physical therapy for hypotonia and motor delay"
GeneReviews management recommendations identify motor delay as a recognized mcEDS manifestation requiring treatment.
PMID:40373179 SUPPORT Human Clinical
"assessment of gross motor skills every three months beginning in infancy and every six months throughout childhood"
The dedicated gross-motor surveillance schedule confirms motor delay as an expected manifestation.
Respiratory 1
Pneumothorax HP:0002107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pneumothorax (HP:0002107). HP:0002107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26646600 SUPPORT Human Clinical
"pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation"
Lists pneumothorax among the progressive fragility complications of mcEDS.
Other 11
Multiple Congenital Contractures VERY_FREQUENT Multiple joint contractures HP:0002828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple joint contractures (HP:0002828). HP:0002828 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26646600 SUPPORT Human Clinical
"multiple congenital contractures including adduction-flexion contractures and talipes equinovarus"
Documents adduction-flexion contractures as a congenital feature of mcEDS.
PMID:31905796 SUPPORT Other
"Major diagnostic criteria of the disorder are as follows: 1) congenital multiple contractures"
Snippet supports the disease-phenotype association as a defining feature. The VERY_FREQUENT band is a clinical estimate, not a reported statistic: GeneReviews states mcEDS is "characterized by multiple congenital contractures", which maps to VERY_FREQUENT under the dismech qualitative mapping (docs/frequency-evidence-guidelines.md, Pattern C). No quantitative cohort frequency has been published.
Adducted Thumb HP:0001181 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adducted thumb (HP:0001181). HP:0001181 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26646600 SUPPORT Human Clinical
"multiple congenital contractures including adduction-flexion contractures and talipes equinovarus"
Documents adduction-flexion contractures of the thumbs as a congenital mcEDS feature.
Large Subcutaneous Hematoma Subcutaneous hemorrhage HP:0001933 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Subcutaneous hemorrhage (HP:0001933). HP:0001933 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"large subcutaneous hematoma, and ocular abnormalities (strabismus, refractive errors, and glaucoma)"
GeneReviews lists large subcutaneous hematoma as a characteristic mcEDS feature.
Short Palpebral Fissure HP:0012745 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short palpebral fissure (HP:0012745). HP:0012745 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"short and downslanted palpebral fissures, hypertelorism, blue sclera"
GeneReviews lists short palpebral fissures in the craniofacial gestalt.
Wide Anterior Fontanel HP:0000260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide anterior fontanel (HP:0000260). HP:0000260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"large anterior fontanel with delayed closure"
GeneReviews lists a large anterior fontanel in the craniofacial gestalt.
Delayed Closure of the Anterior Fontanelle HP:0001476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed closure of the anterior fontanelle (HP:0001476). HP:0001476 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"large anterior fontanel with delayed closure"
GeneReviews explicitly records delayed closure of the anterior fontanel.
Posteriorly Rotated Ears HP:0000358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"low-set posteriorly rotated ears"
GeneReviews lists posteriorly rotated ears in the craniofacial gestalt.
Thin Upper Lip Vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
GeneReviews lists a thin upper lip vermilion in the craniofacial gestalt.
Refractive Errors Abnormality of refraction HP:0000539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of refraction (HP:0000539). HP:0000539 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"ocular abnormalities (strabismus, refractive errors, and glaucoma)"
GeneReviews lists refractive errors among the ocular abnormalities of mcEDS.
PMID:32130795 SUPPORT Human Clinical
"skin features (fine or acrogeria-like palmar creases), and ocular refractive errors"
Confirms refractive errors in the mcEDS-DSE subtype.
Colonic Diverticula and Diverticular Perforation HP:0002253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Colonic diverticula (HP:0002253). HP:0002253 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26646600 SUPPORT Human Clinical
"pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation"
Documents diverticular perforation as an mcEDS complication.
Hydronephrosis HP:0000126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydronephrosis (HP:0000126). HP:0000126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31905796 SUPPORT Other
"nephrolithiasis/cystolithiasis, 11) hydronephrosis, 12) cryptorchidism in males"
Hydronephrosis is listed as minor diagnostic criterion 11 for mcEDS.
🧬

Genetic Associations

2
CHST14
Gene: CHST14 hgnc:24464 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CHST14 (hgnc:24464). hgnc:24464 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:25703627 SUPPORT Human Clinical
"Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies."
Establishes the CHST14-mcEDS gene-disease relationship and its recessive mode.
PMID:26646600 SUPPORT Human Clinical
"This is the first reported human disorder that specifically affects biosynthesis of DS."
Frames CHST14 deficiency as the founding dermatan-sulfate biosynthesis disorder.
DSE
Gene: DSE hgnc:21144 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DSE (hgnc:21144). hgnc:21144 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:23704329 SUPPORT Human Clinical
"We now identified a homozygous DSE missense mutation (c.803C>T, p.S268L) by the positional candidate approach in a male child with MCEDS, who was born to consanguineous parents."
The index report establishing DSE as an mcEDS locus.
PMID:32130795 SUPPORT Human Clinical
"Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3."
Documents additional loss-of-function DSE variants in molecularly confirmed patients.
💊

Medical Actions

6
Orthopedic Bracing and Surgical Correction
Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Braces for joint and spine deformities with surgical correction as needed. Orthopedic surveillance is intensive: foot deformities every three months in infancy, every six months in childhood, and annually thereafter; spine deformities and digit contractures every six to twelve months from infancy.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"Braces for joint and spine deformities with surgical correction as needed per orthopedist"
GeneReviews management recommendation for the musculoskeletal manifestations.
PMID:40373179 SUPPORT Human Clinical
"Orthopedic evaluation of foot deformities every three months in infancy, every six months in childhood, and annually in adolescence and adulthood"
Specifies the orthopedic surveillance schedule accompanying this management.
Physical Therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Physical therapy for hypotonia and motor delay, with gross motor skills assessed every three months from infancy and every six months through childhood.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"physical therapy for hypotonia and motor delay"
GeneReviews management recommendation for neuromuscular manifestations.
Desmopressin for Large Subcutaneous Hematoma
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: desmopressin CHEBI:4450 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses desmopressin (CHEBI:4450). CHEBI:4450 is a therapeutic agent from Chemical Entities of Biological Interest.
Large subcutaneous hematomas are managed with compression, icing, and surgical drainage, with desmopressin administered if necessary.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"compression, icing, surgical drainage, and administration of desmopressin if necessary for large subcutaneous hematomas"
GeneReviews management recommendation naming desmopressin for this specific complication.
Activity Restriction and Injury Avoidance
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Contact or competitive sports should be avoided. In individuals with hyperalgesia to pressure, upper-arm sphygmomanometry and tight tourniquets during blood collection should also be avoided. This is the mcEDS agents-and-circumstances-to-avoid guidance.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"Agents/circumstances to avoid: Contact or competitive sports; upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure."
GeneReviews explicitly enumerates the circumstances to avoid in mcEDS.
Perinatal Management and Planned Cesarean Delivery
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Pregnancy and delivery should be managed in a perinatal center. Planned cesarean section is considered reasonable given the risks of premature rupture of membranes, birth canal laceration, and excessive bleeding with vaginal delivery.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"planned cesarean section would be a reasonable approach due to risk of premature rupture of membranes, birth canal laceration, and excessive bleeding with vaginal delivery"
GeneReviews pregnancy-management recommendation for mcEDS.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal recessive counseling with 25% sibling recurrence risk; carrier testing for at-risk relatives and prenatal or preimplantation genetic testing are possible once the familial variants are known.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"Once the mcEDS-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
GeneReviews genetic-counseling guidance for mcEDS families.
🔬

Biochemical Markers

2
Urinary Dermatan Sulfate (ABSENT)
Show evidence (1 reference)
PMID:32130795 SUPPORT Human Clinical
"No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS."
Direct in vivo biochemical evidence of dermatan sulfate depletion in an mcEDS-DSE patient.
Fibroblast Dermatan Sulfate Epimerase Activity (DECREASED)
Show evidence (1 reference)
PMID:23704329 SUPPORT In Vitro
"Patient-derived fibroblasts also showed a significant reduction in epimerase activity."
Establishes reduced epimerase activity as a measurable cellular biochemical phenotype.
🔬

Diagnosis

3
Molecular Genetic Testing of CHST14 and DSE
The definitive diagnostic test. mcEDS is established in a proband with suggestive clinical findings plus biallelic pathogenic variants in CHST14 or DSE. In practice this is delivered by a next-generation sequencing panel covering the EDS and hereditary connective-tissue disorder genes, with exome sequencing reserved for suggestive patients who have no CHST14 or DSE variant.
Show evidence (2 references)
PMID:40373179 SUPPORT Human Clinical
"The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic variants in CHST14 or DSE identified by molecular genetic testing."
GeneReviews states the molecular diagnostic criterion for mcEDS.
PMID:31905796 SUPPORT Other
"genetic testing is provided as part of routine medical care covered by national health insurance, using a custom next generation sequencing-based panel that includes all EDS-related genes and genes for hereditary connective tissue disorders"
Describes the panel-based testing route used in practice for suspected mcEDS.
Clinical Diagnostic Criteria
Three major criteria support the clinical diagnosis before molecular confirmation: congenital multiple contractures (characteristically adduction-flexion contractures and/or talipes equinovarus), characteristic craniofacial features evident at birth or in early infancy, and characteristic cutaneous features (hyperextensibility, bruisability, and fragility with atrophic scars, plus increased palmar wrinkles).
Show evidence (1 reference)
PMID:31905796 SUPPORT Other
"Major diagnostic criteria of the disorder are as follows: 1) congenital multiple contractures"
Sets out the major clinical diagnostic criteria for mcEDS.
Skin Fibroblast Glycosaminoglycan and Decorin Analysis
Biochemical analysis of extracellular matrix components in patient skin fibroblasts — collagens and dermatan sulfate proteoglycans including decorin and biglycan — demonstrates the characteristic replacement of the decorin dermatan sulfate chain by chondroitin sulfate, supporting the diagnosis and distinguishing the two subtypes by residual dermatan sulfate content.
Show evidence (2 references)
PMID:31905796 SUPPORT Other
"Biochemical abnormalities of the extracellular matrix are investigated (e.g., various types of collagen and DS-PGs, including decorin and biglycan), using patient skin fibroblasts."
Describes the fibroblast biochemical workup used in mcEDS diagnosis and research.
PMID:25703627 SUPPORT In Vitro
"The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients."
Establishes the decorin glycanation abnormality detectable in patient fibroblasts.
📈

Progression

2
Congenital presentation
Age: Birth to early infancy
The malformation arm is present at birth: multiple congenital contractures with adducted thumbs and talipes equinovarus, plus a craniofacial gestalt that is evident at birth or in early infancy.
Show evidence (1 reference)
PMID:26646600 SUPPORT Human Clinical
"multiple congenital contractures including adduction-flexion contractures and talipes equinovarus as well as other visceral or ophthalmological malformations"
Establishes the congenital malformation features present from birth.
Progressive connective-tissue fragility
Age: Childhood through adulthood
After infancy the disease is dominated by progressive fragility: skin hyperextensibility, bruisability and atrophic scarring, recurrent dislocations, progressive talipes and spinal deformities, large subcutaneous hematomas, pneumothorax, and diverticular perforation. The escalating orthopedic surveillance schedule tracks this progression.
Show evidence (2 references)
PMID:26646600 SUPPORT Human Clinical
"Considering that patients with CHST14/D4ST1 deficiency develop progressive multisystem fragility-related manifestations"
States explicitly that the fragility manifestations are progressive over time.
PMID:31905796 SUPPORT Other
"Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations."
Confirms the two-phase congenital-then-progressive course.
📊

Prevalence

1
Worldwide reported cases
Cases In Literature Ultra Rare
As of the 2019 pathophysiology review, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE had been reported. Population prevalence has not been estimated.
Show evidence (1 reference)
PMID:31905796 SUPPORT Other
"Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature."
Cumulative published case counts for both mcEDS subtypes.
🐁

Animal Models

2
Chst14-/- Mus musculus Knockout
Homozygous Chst14-null mice show perinatal lethality, shorter fetal length, and vessel-related placental abnormalities. The model demonstrates that dermatan sulfate is required for fetal development, but its perinatal lethality means it does not recapitulate the progressive postnatal connective-tissue fragility that dominates the human disease.
Species
Mus musculus
Genotype
Chst14-/-
Genes
CHST14 hgnc:24464 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CHST14 (hgnc:24464). hgnc:24464 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:31905796 SUPPORT Model Organism
"Homozygous (Chst14-/-) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities."
Supports a developmental requirement for dermatan sulfate, but the perinatal-lethal murine phenotype differs from the surviving, progressively fragile human phenotype, so support for the human disease model is partial.
Xenopus DS-epi1 (dse) morphant embryos Targeted knockdown model of dermatan sulfate epimerase deficiency
The only model of this disease that addresses the embryonic origin of its congenital features. Knocking down DS-epi1 in frog embryos removes iduronic acid from chondroitin sulfate/dermatan sulfate chains and leaves neural crest induction intact while blocking epithelial-mesenchymal transition and migration; transplantation shows the requirement is tissue-autonomous, and explants place the defect in adhesion and spreading on fibronectin. The downstream loss of neural-crest-derived craniofacial skeleton offers a developmental account of the congenital malformations, complementing the Chst14-null mouse, which dies perinatally, and the human fibroblast work, which is postnatal.
Species
Xenopus laevis
Genotype
Morpholino knockdown of DS-epi1/dse, with cranial neural crest transplantation and explant culture
Genes
DSE hgnc:21144 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns DSE (hgnc:21144). hgnc:21144 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:27101845
Pathograph links
Dermatan Sulfate Biosynthesis Failure recapitulates fidelity: high Reproduces the mcEDS-DSE biochemical lesion directly: loss of DS-epi1 removes iduronic acid residues from hybrid CS/DS glycosaminoglycan chains.
Limitations: Morpholino knockdown rather than the biallelic null genotype of patients, and it models the DSE half of the disease only — mcEDS-CHST14, the more common form, acts one step later at 4-O-sulfation and is not addressed.
Readouts
Isolated iduronic acid residues in CS/DS proteoglycans
Direction: DECREASED
Interpretation: The epimerase product itself, measured in the embryo, which is what makes this a model of the enzymatic lesion rather than of its consequences.
Show evidence (1 reference)
PMID:27101845 SUPPORT Model Organism
"We demonstrate that DS-epi1 is important for the generation of isolated iduronic acid residues in chondroitin sulfate (CS)/DS proteoglycans in early Xenopus embryos."
Reports the biochemical readout of epimerase loss in the model.
Show evidence (1 reference)
PMID:27101845 SUPPORT Model Organism
"this syndrome comprises multiple congenital malformations that are caused by dysfunction of dermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE)"
Identifies the knocked-down enzyme as one of the disease genes for this entry.
Congenital Malformation of Connective-Tissue-Dependent Structures partially recapitulates fidelity: moderate Supplies a developmental mechanism for the congenital craniofacial features: neural crest cells are induced normally but fail to undergo EMT and migrate, so crest-derived craniofacial skeleton is reduced.
Limitations: The craniofacial readouts are frog structures — dorsal fin and larval cartilage — that have no direct human counterpart, and melanocyte loss is not an mcEDS feature. The authors themselves put the link to human malformation as a proposal. Nothing here addresses the postnatal progressive fragility that dominates the disease.
Readouts
Neural crest EMT transcription factor activation and extent of migration
Direction: DECREASED
Interpretation: Localizes the defect to EMT and migration rather than to crest induction, which the same experiment shows is unaffected.
Show evidence (1 reference)
PMID:27101845 SUPPORT Model Organism
"The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial-mesenchymal transition (EMT) and reduces the extent of NC cell migration, which leads to a decrease in NC-derived..."
Reports both the preserved induction and the reduced EMT, migration and crest-derived structures.
Cranial neural crest adhesion and spreading on fibronectin
Direction: DECREASED
Interpretation: Reduces the migration defect to a cell-matrix interaction, the level at which a missing glycosaminoglycan modification would be expected to act.
Show evidence (1 reference)
PMID:27101845 SUPPORT In Vitro
"Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin."
The explant and single-cell culture arm is cell-based, so it is graded in vitro rather than model organism.
Show evidence (2 references)
PMID:27101845 SUPPORT Model Organism
"Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo"
Transplantation rules out a non-autonomous environmental effect, which is what makes the model informative about the crest cells themselves.
+ 1 more reference
{ }

Source YAML

click to show 
name: Musculocontractural Ehlers-Danlos Syndrome
category: Mendelian
creation_date: "2026-07-31T00:00:00Z"
description: >
  Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare autosomal
  recessive connective-tissue disorder caused by biallelic loss-of-function
  variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), or in
  DSE, encoding dermatan sulfate epimerase-1 (DS-epi1). Both genes act at
  consecutive steps of the same pathway, so both lesions converge on defective
  dermatan sulfate (DS) biosynthesis: the glycosaminoglycan chain of decorin,
  the major dermal DS-proteoglycan that organizes collagen fibril assembly, is
  replaced by chondroitin sulfate. The resulting failure of collagen fibril
  assembly produces a distinctive two-part disease — congenital multisystem
  malformation (multiple congenital contractures with adducted thumbs and
  talipes equinovarus, characteristic craniofacial features, and ocular and
  urogenital anomalies) followed by progressive connective-tissue fragility
  (skin hyperextensibility, bruisability and atrophic scarring, recurrent
  dislocations, large subcutaneous hematomas, pneumothorax, and diverticular
  perforation). The two gene-defined forms, mcEDS-CHST14 (MONDO:0020681,
  "musculocontractural type 1") and mcEDS-DSE (MONDO:0014236,
  "musculocontractural type 2"), are clinically near-indistinguishable and are
  curated here as subtypes of a single entry; mcEDS-DSE is rarer and appears
  less severe, plausibly because residual DS remains on decorin.
disease_term:
  preferred_term: musculocontractural Ehlers-Danlos syndrome
  term:
    id: MONDO:0011142
    label: Ehlers-Danlos syndrome, musculocontractural type
synonyms:
- mcEDS
- musculocontractural EDS
- Ehlers-Danlos syndrome, Kosho type
- adducted thumb-clubfoot syndrome
- D4ST1-deficient Ehlers-Danlos syndrome
parents:
- Ehlers-Danlos Syndrome
- Connective Tissue Disorder
references:
- reference: PMID:40373179
  title: "Musculocontractural Ehlers-Danlos Syndrome."
  tags:
  - GeneReviews
  findings:
  - statement: >
      mcEDS is established by suggestive clinical findings plus biallelic
      pathogenic variants in CHST14 or DSE.
    evidence:
    - reference: PMID:40373179
      reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic variants in CHST14 or DSE identified by molecular genetic testing."
      explanation: GeneReviews states the molecular diagnostic criterion for mcEDS.
  - statement: >
      Beyond the core musculoskeletal, craniofacial, cutaneous, and ocular
      features, genitourinary, cardiovascular, neurologic, and gastrointestinal
      systems can also be involved.
    evidence:
    - reference: PMID:40373179
      reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal."
      explanation: GeneReviews records the multisystem extent of mcEDS.
- reference: PMID:31905796
  title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
  findings:
  - statement: >
      Loss of CHST14 or DSE activity leaves a negligible amount of dermatan
      sulfate and an excess of chondroitin sulfate.
    evidence:
    - reference: PMID:31905796
      reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate."
      explanation: States the shared biochemical lesion of both mcEDS subtypes.
- reference: PMID:28306229
  title: "The 2017 international classification of the Ehlers-Danlos syndromes."
  findings:
  - statement: >
      mcEDS is one of the 13 EDS subtypes recognized by the 2017 International
      EDS Classification.
    evidence:
    - reference: PMID:28306229
      reference_title: "The 2017 international classification of the Ehlers-Danlos syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes."
      explanation: Anchors mcEDS in the current EDS nosology.
has_subtypes:
- name: mcEDS-CHST14
  display_name: mcEDS-CHST14 (musculocontractural type 1)
  subtype_term:
    preferred_term: Ehlers-Danlos syndrome, musculocontractural type 1
    term:
      id: MONDO:0020681
      label: Ehlers-Danlos syndrome, musculocontractural type 1
  genes:
  - preferred_term: CHST14
    term:
      id: hgnc:24464
      label: CHST14
  description: >
    Caused by biallelic loss-of-function variants in CHST14, encoding dermatan
    4-O-sulfotransferase-1 (D4ST1). This is the common and more severe form,
    accounting for the large majority of reported patients. Loss of D4ST1
    activity replaces the decorin glycosaminoglycan chain with chondroitin
    sulfate completely, with no residual dermatan sulfate.
  evidence:
  - reference: PMID:25703627
    reference_title: "Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies."
    explanation: Establishes CHST14/D4ST1 as the causative gene of the archetypal mcEDS form.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature."
    explanation: Quantifies mcEDS-CHST14 as the substantially more frequently reported subtype.
- name: mcEDS-DSE
  display_name: mcEDS-DSE (musculocontractural type 2)
  subtype_term:
    preferred_term: Ehlers-Danlos syndrome, musculocontractural type 2
    term:
      id: MONDO:0014236
      label: Ehlers-Danlos syndrome, musculocontractural type 2
  genes:
  - preferred_term: DSE
    term:
      id: hgnc:21144
      label: DSE
  description: >
    Caused by biallelic loss-of-function variants in DSE, encoding dermatan
    sulfate epimerase-1 (DS-epi1), which converts glucuronic acid to iduronic
    acid in the nascent chondroitin/dermatan sulfate chain. Ultrastructurally
    and clinically similar to mcEDS-CHST14 but far rarer and with a lower
    symptom burden, plausibly because some dermatan sulfate moieties persist on
    decorin through residual DS-epi1 activity or DSE2 compensation.
  evidence:
  - reference: PMID:23704329
    reference_title: "Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DSE deficiency represents a specific defect of DS biosynthesis. We demonstrate locus heterogeneity in MCEDS"
    explanation: The original report establishing DSE as the second mcEDS locus.
  - reference: PMID:32130795
    reference_title: "Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "McEDS-DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS-CHST14. However, the burden of symptoms seems lower in patients with mcEDS-DSE."
    explanation: Establishes clinical near-identity with mcEDS-CHST14 alongside a lower symptom burden.
  - reference: PMID:25703627
    reference_title: "Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype"
    explanation: Independent observation of the milder mcEDS-DSE presentation.
inheritance:
- name: Autosomal recessive inheritance
  description: >
    mcEDS is autosomal recessive; both CHST14 and DSE forms require biallelic
    pathogenic variants, and heterozygous carriers are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Musculocontractural EDS is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the mode of inheritance directly.
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier"
    explanation: The stated recurrence risks confirm autosomal recessive segregation.
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 "Ehlers-Danlos syndrome, musculocontractural
      type".
prevalence:
- population: Worldwide reported cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    As of the 2019 pathophysiology review, 41 patients from 28 families with
    mcEDS-CHST14 and five patients from four families with mcEDS-DSE had been
    reported. Population prevalence has not been estimated.
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature."
    explanation: Cumulative published case counts for both mcEDS subtypes.
pathophysiology:
- name: Dermatan Sulfate Biosynthesis Failure
  biological_scale: MOLECULAR
  description: >
    Biallelic loss-of-function variants in CHST14 (dermatan
    4-O-sulfotransferase-1, D4ST1) or DSE (dermatan sulfate epimerase-1,
    DS-epi1) abolish consecutive steps required to build iduronic
    acid-containing dermatan sulfate domains within hybrid chondroitin
    sulfate/dermatan sulfate glycosaminoglycan chains. DS-epi1 epimerizes
    glucuronic acid to iduronic acid and D4ST1 4-O-sulfates the adjacent
    N-acetylgalactosamine; loss of either leaves a negligible amount of dermatan
    sulfate and a reciprocal excess of chondroitin sulfate. This is the single
    lesion shared by both gene-defined subtypes.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: dermatan sulfate proteoglycan biosynthesis
    modifier: DECREASED
    term:
      id: GO:0050651
      label: dermatan sulfate proteoglycan biosynthetic process
  - preferred_term: chondroitin sulfate proteoglycan biosynthesis
    modifier: INCREASED
    term:
      id: GO:0050650
      label: chondroitin sulfate proteoglycan biosynthetic process
  molecular_functions:
  - preferred_term: dermatan sulfate epimerase activity
    modifier: DECREASED
    term:
      id: GO:0047757
      label: chondroitin-glucuronate 5-epimerase activity
  - preferred_term: dermatan 4-O-sulfotransferase activity
    modifier: DECREASED
    term:
      id: GO:0001537
      label: dermatan 4-sulfotransferase activity
  chemical_entities:
  - preferred_term: dermatan sulfate
    modifier: DECREASED
    term:
      id: CHEBI:18376
      label: dermatan sulfate
  - preferred_term: chondroitin sulfate
    modifier: INCREASED
    term:
      id: CHEBI:37397
      label: chondroitin sulfate
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate."
    explanation: States the shared enzymatic and biochemical lesion of both mcEDS subtypes.
  - reference: PMID:25703627
    reference_title: "Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs)."
    explanation: Places both enzymes on the same DS biosynthetic pathway.
  - reference: PMID:23704329
    reference_title: "Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Heterologous expression of mutant full-length and soluble recombinant DSE proteins showed a loss of activity towards partially desulfated DS. Patient-derived fibroblasts also showed a significant reduction in epimerase activity."
    explanation: Direct enzymatic demonstration that DSE variants abolish epimerase activity in patient cells.
  - reference: PMID:23704329
    reference_title: "Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Iduronic acid-containing domains in DS have a key role in mediating the functions of DS proteoglycans."
    explanation: Establishes iduronic acid-containing DS domains as the functionally critical product lost in mcEDS.
  downstream:
  - target: Decorin Glycosaminoglycan Chain Replacement
    description: >
      Absent dermatan sulfate synthesis leaves the glycosaminoglycan chain of
      decorin, the principal dermal DS-proteoglycan, glycanated with chondroitin
      sulfate instead.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25703627
      reference_title: "Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients."
      explanation: Directly links loss of either enzyme to impaired decorin glycanation in patient fibroblasts.
- name: Decorin Glycosaminoglycan Chain Replacement
  biological_scale: MOLECULAR
  description: >
    Decorin is the major dermatan sulfate proteoglycan of skin and normally
    tethers adjacent collagen fibrils through electrostatic interactions
    mediated by its dermatan sulfate side chain. In mcEDS this side chain is
    replaced by chondroitin sulfate. The replacement is complete in D4ST1
    (CHST14) deficiency, whereas in DS-epi1 (DSE) deficiency some dermatan
    sulfate moieties persist — the leading explanation for the milder mcEDS-DSE
    phenotype.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: proteoglycan biosynthesis
    modifier: ABNORMAL
    term:
      id: GO:0030166
      label: proteoglycan biosynthetic process
  chemical_entities:
  - preferred_term: dermatan sulfate
    modifier: DECREASED
    term:
      id: CHEBI:18376
      label: dermatan sulfate
  evidence:
  - reference: PMID:25703627
    reference_title: "Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present."
    explanation: >
      Establishes the quantitative difference in decorin glycanation between the
      two subtypes, the proposed basis of the severity gradient.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly."
    explanation: Identifies altered decorin glycosaminoglycan composition as the proximate cause of tissue fragility.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity."
    explanation: >
      Explicitly hedged proposal linking residual decorin dermatan sulfate to the
      milder mcEDS-DSE phenotype; recorded as PARTIAL because it is a proposed
      rather than demonstrated explanation.
  downstream:
  - target: Disorganized Collagen Fibril Assembly
    description: >
      Loss of the dermatan sulfate side chain removes the electrostatic bridging
      that decorin normally provides between neighboring collagen fibrils, so
      fibril assembly fails.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26646600
      reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "multisystem fragility is presumably caused by impaired assembly of collagen fibrils resulting from loss of dermatan sulfate (DS) in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen fibrils"
      explanation: States the decorin-to-collagen-fibril mechanistic link explicitly.
- name: Disorganized Collagen Fibril Assembly
  biological_scale: TISSUE
  description: >
    In affected skin, collagen fibrils are dispersed through the papillary to
    reticular dermis rather than being regularly and tightly assembled, and the
    glycosaminoglycan chains run linearly from the surface of one fibril to
    adjacent fibrils instead of curving to stay in close contact with the fibril
    they decorate. This ultrastructural signature is the tissue-level readout of
    the decorin defect and the immediate substrate of connective-tissue
    fragility.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: ABNORMAL
    term:
      id: GO:0030199
      label: collagen fibril organization
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled."
    explanation: Describes the diagnostic ultrastructural collagen abnormality in mcEDS skin.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils."
    explanation: >
      Documents the altered glycosaminoglycan-collagen geometry that follows
      replacement of decorin dermatan sulfate by chondroitin sulfate.
  downstream:
  - target: Progressive Multisystem Connective Tissue Fragility
    description: >
      Failure of ordered collagen fibril assembly leaves skin, joints, vessels,
      and hollow organs mechanically weak, producing the progressive
      fragility-related complications that dominate the disease after infancy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26646600
      reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "multisystem fragility is presumably caused by impaired assembly of collagen fibrils resulting from loss of dermatan sulfate (DS) in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen fibrils"
      explanation: Attributes the multisystem fragility phenotype to impaired collagen fibril assembly.
  - target: Congenital Malformation of Connective-Tissue-Dependent Structures
    description: >
      Because dermatan sulfate proteoglycans are required during fetal
      development, the same biosynthetic block also produces the congenital
      malformation arm of the disease, present at birth rather than acquired.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26646600
      reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CHST14/D4ST1 and, more fundamentally, DS, play a critical role in fetal development and maintenance of connective tissues in multiple organs"
      explanation: >
        Separates the developmental role of dermatan sulfate from its
        tissue-maintenance role, the basis for the two-arm disease structure.
- name: Congenital Malformation of Connective-Tissue-Dependent Structures
  biological_scale: ORGANISM
  description: >
    The developmental arm of mcEDS, evident at birth: multiple congenital
    contractures (characteristically adduction-flexion contractures of the
    thumbs and talipes equinovarus), a recognizable craniofacial gestalt, and
    visceral and ophthalmological malformations. These features are congenital
    and non-progressive in origin, distinguishing them from the fragility arm.
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple congenital contractures including adduction-flexion contractures and talipes equinovarus as well as other visceral or ophthalmological malformations"
    explanation: Describes the congenital malformation component of the mcEDS phenotype.
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic craniofacial features (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia)"
    explanation: GeneReviews enumerates the characteristic craniofacial gestalt.
- name: Progressive Multisystem Connective Tissue Fragility
  biological_scale: ORGANISM
  description: >
    The progressive arm of mcEDS, emerging and worsening after infancy: skin
    hyperextensibility, bruisability and fragility with atrophic scars,
    recurrent dislocations, progressive talipes and spinal deformities, large
    subcutaneous hematomas, pneumothorax or pneumohemothorax, and diverticular
    perforation. These complications dominate long-term morbidity and drive the
    surveillance schedule.
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive multisystem fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation)"
    explanation: Enumerates the progressive fragility-related complications of mcEDS.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations."
    explanation: Confirms the two-arm disease structure of mcEDS.
phenotypes:
- category: Musculoskeletal
  name: Multiple Congenital Contractures
  description: >
    Multiple contractures present at birth — the major diagnostic criterion and
    the source of the "musculocontractural" designation. The individual
    component deformities (adducted thumbs, talipes equinovarus) are curated as
    separate phenotype entries below.
  phenotype_term:
    preferred_term: Multiple joint contractures
    term:
      id: HP:0002828
      label: Multiple joint contractures
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple congenital contractures including adduction-flexion contractures and talipes equinovarus"
    explanation: Documents adduction-flexion contractures as a congenital feature of mcEDS.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Major diagnostic criteria of the disorder are as follows: 1) congenital multiple contractures"
    explanation: >
      Snippet supports the disease-phenotype association as a defining feature.
      The VERY_FREQUENT band is a clinical estimate, not a reported statistic:
      GeneReviews states mcEDS is "characterized by multiple congenital
      contractures", which maps to VERY_FREQUENT under the dismech qualitative
      mapping (docs/frequency-evidence-guidelines.md, Pattern C). No
      quantitative cohort frequency has been published.
- category: Musculoskeletal
  name: Adducted Thumb
  description: >
    Adduction-flexion contracture of the thumbs, the most characteristic
    individual component of the congenital contracture complex and the source of
    the historical name "adducted thumb-clubfoot syndrome".
  phenotype_term:
    preferred_term: Adducted thumb
    term:
      id: HP:0001181
      label: Adducted thumb
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple congenital contractures including adduction-flexion contractures and talipes equinovarus"
    explanation: Documents adduction-flexion contractures of the thumbs as a congenital mcEDS feature.
- category: Musculoskeletal
  name: Talipes Equinovarus
  description: >
    Clubfoot present at birth, part of the congenital contracture complex, with
    progressive talipes deformities (valgus, planus, or cavum) developing later.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple congenital contractures including adduction-flexion contractures and talipes equinovarus"
    explanation: Documents talipes equinovarus as a congenital mcEDS feature.
- category: Musculoskeletal
  name: Small Joint Hypermobility
  description: >
    Hypermobility of the small joints, coexisting with the congenital
    contractures of larger joints — a combination characteristic of mcEDS.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypermobility of the small joints, recurrent dislocations, spinal deformities"
    explanation: GeneReviews lists small-joint hypermobility among the core mcEDS features.
- category: Musculoskeletal
  name: Recurrent Joint Dislocations
  description: >
    Recurrent or chronic dislocations, a minor diagnostic criterion, reflecting
    progressive ligamentous fragility.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
    temporality: RECURRENT
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypermobility of the small joints, recurrent dislocations, spinal deformities"
    explanation: GeneReviews lists recurrent dislocations as a core mcEDS feature.
- category: Musculoskeletal
  name: Progressive Spinal Deformity
  description: >
    Scoliosis or kyphoscoliosis, typically progressive, requiring bracing and
    sometimes surgical correction.
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive talipes or spinal deformities"
    explanation: Documents progressive spinal deformity as an mcEDS complication.
- category: Neurologic
  name: Hypotonia
  description: >
    Muscular hypotonia, managed with physical therapy. Neurologic involvement is
    one of the additional organ systems GeneReviews records as affected in mcEDS.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical therapy for hypotonia and motor delay"
    explanation: >
      GeneReviews management recommendations identify hypotonia as a recognized
      mcEDS manifestation requiring treatment.
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal."
    explanation: GeneReviews records neurologic involvement as part of the mcEDS multisystem phenotype.
- category: Neurologic
  name: Motor Delay
  description: >
    Delayed gross motor milestones, with gross motor skills assessed every three
    months from infancy and every six months through childhood.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical therapy for hypotonia and motor delay"
    explanation: >
      GeneReviews management recommendations identify motor delay as a
      recognized mcEDS manifestation requiring treatment.
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "assessment of gross motor skills every three months beginning in infancy and every six months throughout childhood"
    explanation: The dedicated gross-motor surveillance schedule confirms motor delay as an expected manifestation.
- category: Cardiovascular
  name: Cardiac Valve Abnormalities
  description: >
    Cardiac valve abnormalities requiring cardiology and cardiac-surgical
    management, with cardiac evaluation recommended annually from infancy.
    Cardiovascular involvement is one of the additional organ systems
    GeneReviews records as affected in mcEDS. Congenital structural heart
    defects are curated as a separate phenotype entry.
  phenotype_term:
    preferred_term: Abnormal heart valve morphology
    term:
      id: HP:0001654
      label: Abnormal heart valve morphology
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of cardiac valve abnormalities and congenital heart defects per cardiologist and cardiac surgeon"
    explanation: GeneReviews names cardiac valve abnormalities and congenital heart defects as treated mcEDS manifestations.
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac evaluation, and otologic evaluation annually beginning in infancy"
    explanation: Annual cardiac surveillance from infancy confirms cardiovascular involvement as an expected feature.
  - reference: PMID:32130795
    reference_title: "Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems"
    explanation: Independently confirms cardiovascular involvement in the mcEDS-DSE subtype.
- category: Cardiovascular
  name: Congenital Heart Defects
  description: >
    Congenital structural cardiac malformations requiring cardiology and
    cardiac-surgical management, a distinct lesion class from the acquired or
    progressive valve abnormalities curated above.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of cardiac valve abnormalities and congenital heart defects per cardiologist and cardiac surgeon"
    explanation: GeneReviews names congenital heart defects as a treated mcEDS manifestation, distinct from valve abnormalities.
- category: Otologic
  name: Hearing Impairment
  description: >
    Hearing loss requiring hearing aids, with otologic evaluation recommended
    annually from infancy. Note that the supporting evidence is indirect: it is
    inferred from management and surveillance recommendations rather than from a
    direct statement of hearing loss prevalence, so the association is recorded
    as PARTIAL.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of diverticula per gastroenterologist; hearing aids as needed"
    explanation: >
      GeneReviews lists hearing aids among mcEDS management, implying clinically
      significant hearing impairment. This is inferred from a management line
      rather than a direct prevalence statement, so the claim is marked PARTIAL.
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac evaluation, and otologic evaluation annually beginning in infancy"
    explanation: Annual otologic surveillance from infancy corroborates expected hearing involvement, again indirectly.
- category: Skeletal
  name: Osteoporosis
  description: >
    Reduced bone density warranting annual bone-density surveillance from
    adulthood and standard osteoporosis treatment.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for osteoporosis and constipation"
    explanation: GeneReviews lists osteoporosis among manifestations requiring treatment in mcEDS.
- category: Dermatologic
  name: Skin Hyperextensibility
  description: >
    Hyperextensible skin, one of the characteristic cutaneous features forming a
    major diagnostic criterion.
  phenotype_term:
    preferred_term: Hyperextensible skin
    term:
      id: HP:0000974
      label: Hyperextensible skin
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
    explanation: GeneReviews lists skin hyperextensibility as a core mcEDS feature.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characteristic cutaneous features including hyperextensibility, bruisability and fragility with atrophic scars"
    explanation: >
      Snippet supports the disease-phenotype association. The VERY_FREQUENT band
      is a clinical estimate, not a reported statistic: the author wording
      "characteristic cutaneous features" maps to VERY_FREQUENT under the
      dismech qualitative mapping (docs/frequency-evidence-guidelines.md,
      Pattern C). No quantitative cohort frequency has been published.
- category: Dermatologic
  name: Bruising Susceptibility
  description: Easy bruisability, part of the characteristic cutaneous major criterion.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
    explanation: GeneReviews lists bruisability as a core cutaneous feature.
- category: Dermatologic
  name: Atrophic Scarring
  description: >
    Skin fragility with atrophic scars; skin lacerations require surgical
    suturing.
  phenotype_term:
    preferred_term: Atrophic scars
    term:
      id: HP:0001075
      label: Atrophic scars
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
    explanation: GeneReviews lists skin fragility with atrophic scars among the mcEDS skin features.
- category: Dermatologic
  name: Poor Wound Healing
  description: >
    Delayed wound healing, a distinct skin manifestation from atrophic scarring
    and part of the characteristic cutaneous criterion.
  phenotype_term:
    preferred_term: Poor wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars)"
    explanation: GeneReviews lists delayed wound healing among the mcEDS skin features.
- category: Hematologic
  name: Large Subcutaneous Hematoma
  description: >
    Large subcutaneous hematomas, a distinctive and potentially serious mcEDS
    complication requiring compression, icing, drainage, or desmopressin.
  phenotype_term:
    preferred_term: Subcutaneous hemorrhage
    term:
      id: HP:0001933
      label: Subcutaneous hemorrhage
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large subcutaneous hematoma, and ocular abnormalities (strabismus, refractive errors, and glaucoma)"
    explanation: GeneReviews lists large subcutaneous hematoma as a characteristic mcEDS feature.
- category: Craniofacial
  name: Hypertelorism
  description: >
    Increased interorbital distance, one component of the characteristic mcEDS
    craniofacial gestalt that is evident at birth or in early infancy and forms
    a major diagnostic criterion. The remaining components of that gestalt are
    curated as separate phenotype entries below.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic craniofacial features (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia)"
    explanation: GeneReviews enumerates the craniofacial gestalt including hypertelorism.
  - reference: PMID:32130795
    reference_title: "Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia)"
    explanation: Confirms hypertelorism in the mcEDS-DSE subtype as well.
- category: Craniofacial
  name: Blue Sclerae
  description: Blue sclerae, part of the characteristic craniofacial gestalt.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:32130795
    reference_title: "Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia)"
    explanation: Documents blue sclerae in molecularly confirmed mcEDS-DSE patients.
- category: Craniofacial
  name: Downslanted and Short Palpebral Fissures
  description: >
    Short and downslanted palpebral fissures, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short and downslanted palpebral fissures, hypertelorism, blue sclera"
    explanation: GeneReviews lists short and downslanted palpebral fissures in the craniofacial gestalt.
- category: Craniofacial
  name: Short Palpebral Fissure
  description: Shortened horizontal palpebral fissure length, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Short palpebral fissure
    term:
      id: HP:0012745
      label: Short palpebral fissure
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short and downslanted palpebral fissures, hypertelorism, blue sclera"
    explanation: GeneReviews lists short palpebral fissures in the craniofacial gestalt.
- category: Craniofacial
  name: Wide Anterior Fontanel
  description: >
    Large anterior fontanel, an early-infancy component of the craniofacial
    gestalt. The delayed closure of that fontanel is curated as a separate
    phenotype entry.
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large anterior fontanel with delayed closure"
    explanation: GeneReviews lists a large anterior fontanel in the craniofacial gestalt.
- category: Craniofacial
  name: Delayed Closure of the Anterior Fontanelle
  description: >
    Late closure of the anterior fontanel, a distinct temporal feature from its
    enlarged size.
  phenotype_term:
    preferred_term: Delayed closure of the anterior fontanelle
    term:
      id: HP:0001476
      label: Delayed closure of the anterior fontanelle
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "large anterior fontanel with delayed closure"
    explanation: GeneReviews explicitly records delayed closure of the anterior fontanel.
- category: Craniofacial
  name: Low-Set Ears
  description: Low-set ear placement, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low-set posteriorly rotated ears"
    explanation: GeneReviews lists low-set ears in the craniofacial gestalt.
- category: Craniofacial
  name: Posteriorly Rotated Ears
  description: Posterior rotation of the ears, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low-set posteriorly rotated ears"
    explanation: GeneReviews lists posteriorly rotated ears in the craniofacial gestalt.
- category: Craniofacial
  name: Short Nose with Hypoplastic Columella
  description: >
    Shortened nose with an underdeveloped columella, part of the craniofacial
    gestalt. The HP binding captures the short nose; columellar hypoplasia is
    described in the entry text.
  phenotype_term:
    preferred_term: Short nose
    term:
      id: HP:0003196
      label: Short nose
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short nose with hypoplastic columella"
    explanation: GeneReviews lists a short nose with hypoplastic columella in the craniofacial gestalt.
- category: Craniofacial
  name: Long Philtrum
  description: Elongated philtrum, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
    explanation: GeneReviews lists a long philtrum in the craniofacial gestalt.
- category: Craniofacial
  name: Thin Upper Lip Vermilion
  description: Thin vermilion border of the upper lip, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
    explanation: GeneReviews lists a thin upper lip vermilion in the craniofacial gestalt.
- category: Craniofacial
  name: Narrow Mouth
  description: Small mouth, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Narrow mouth
    term:
      id: HP:0000160
      label: Narrow mouth
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
    explanation: GeneReviews lists a small mouth in the craniofacial gestalt.
- category: Craniofacial
  name: High Palate
  description: >
    High-arched palate, part of the craniofacial gestalt; cleft palate also
    occurs and may require surgical closure and speech therapy.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
    explanation: GeneReviews lists a high palate in the craniofacial gestalt.
- category: Craniofacial
  name: Micrognathia
  description: Small or retruded mandible, part of the craniofacial gestalt.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia"
    explanation: GeneReviews lists micrognathia in the craniofacial gestalt.
- category: Ophthalmologic
  name: Refractive Errors
  description: >
    Myopia or astigmatism requiring corrective lenses; ophthalmologic evaluation
    is recommended annually from infancy.
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular abnormalities (strabismus, refractive errors, and glaucoma)"
    explanation: GeneReviews lists refractive errors among the ocular abnormalities of mcEDS.
  - reference: PMID:32130795
    reference_title: "Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "skin features (fine or acrogeria-like palmar creases), and ocular refractive errors"
    explanation: Confirms refractive errors in the mcEDS-DSE subtype.
- category: Ophthalmologic
  name: Strabismus
  description: Strabismus, sometimes requiring surgical correction.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular abnormalities (strabismus, refractive errors, and glaucoma)"
    explanation: GeneReviews lists strabismus among the ocular abnormalities of mcEDS.
- category: Ophthalmologic
  name: Glaucoma
  description: >
    Glaucoma or elevated intraocular pressure, a minor diagnostic criterion
    requiring specialist management.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular abnormalities (strabismus, refractive errors, and glaucoma)"
    explanation: GeneReviews lists glaucoma among the ocular abnormalities of mcEDS.
- category: Respiratory
  name: Pneumothorax
  description: >
    Pneumothorax or pneumohemothorax from pleural connective-tissue fragility, a
    minor diagnostic criterion and a potentially life-threatening complication.
  phenotype_term:
    preferred_term: Pneumothorax
    term:
      id: HP:0002107
      label: Pneumothorax
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation"
    explanation: Lists pneumothorax among the progressive fragility complications of mcEDS.
- category: Gastrointestinal
  name: Colonic Diverticula and Diverticular Perforation
  description: >
    Colonic diverticula that may perforate — a serious fragility complication of
    the hollow viscera, alongside chronic constipation.
  phenotype_term:
    preferred_term: Colonic diverticula
    term:
      id: HP:0002253
      label: Colonic diverticula
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation"
    explanation: Documents diverticular perforation as an mcEDS complication.
- category: Gastrointestinal
  name: Chronic Constipation
  description: Chronic constipation, a minor diagnostic criterion.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
    temporality: CHRONIC
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for osteoporosis and constipation"
    explanation: GeneReviews management guidance identifies constipation as a treated mcEDS manifestation.
- category: Genitourinary
  name: Nephrolithiasis and Cystolithiasis
  description: >
    Urinary tract stones requiring nephrology or urology management; urologic
    evaluation including ultrasound is recommended annually from infancy.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of nephrolithiasis and urolithiasis per nephrologist and/or urologist"
    explanation: GeneReviews identifies nephrolithiasis as a recognized mcEDS manifestation requiring management.
- category: Genitourinary
  name: Hydronephrosis
  description: Hydronephrosis, part of the urogenital malformation spectrum.
  phenotype_term:
    preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "nephrolithiasis/cystolithiasis, 11) hydronephrosis, 12) cryptorchidism in males"
    explanation: Hydronephrosis is listed as minor diagnostic criterion 11 for mcEDS.
- category: Genitourinary
  name: Cryptorchidism
  description: Cryptorchidism in males, requiring surgical fixation.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "nephrolithiasis/cystolithiasis, 11) hydronephrosis, 12) cryptorchidism in males"
    explanation: Cryptorchidism is listed as minor diagnostic criterion 12 for mcEDS.
diagnosis:
- name: Molecular Genetic Testing of CHST14 and DSE
  description: >
    The definitive diagnostic test. mcEDS is established in a proband with
    suggestive clinical findings plus biallelic pathogenic variants in CHST14 or
    DSE. In practice this is delivered by a next-generation sequencing panel
    covering the EDS and hereditary connective-tissue disorder genes, with
    exome sequencing reserved for suggestive patients who have no CHST14 or DSE
    variant.
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic variants in CHST14 or DSE identified by molecular genetic testing."
    explanation: GeneReviews states the molecular diagnostic criterion for mcEDS.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "genetic testing is provided as part of routine medical care covered by national health insurance, using a custom next generation sequencing-based panel that includes all EDS-related genes and genes for hereditary connective tissue disorders"
    explanation: Describes the panel-based testing route used in practice for suspected mcEDS.
- name: Clinical Diagnostic Criteria
  description: >
    Three major criteria support the clinical diagnosis before molecular
    confirmation: congenital multiple contractures (characteristically
    adduction-flexion contractures and/or talipes equinovarus), characteristic
    craniofacial features evident at birth or in early infancy, and
    characteristic cutaneous features (hyperextensibility, bruisability, and
    fragility with atrophic scars, plus increased palmar wrinkles).
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Major diagnostic criteria of the disorder are as follows: 1) congenital multiple contractures"
    explanation: Sets out the major clinical diagnostic criteria for mcEDS.
- name: Skin Fibroblast Glycosaminoglycan and Decorin Analysis
  description: >
    Biochemical analysis of extracellular matrix components in patient skin
    fibroblasts — collagens and dermatan sulfate proteoglycans including decorin
    and biglycan — demonstrates the characteristic replacement of the decorin
    dermatan sulfate chain by chondroitin sulfate, supporting the diagnosis and
    distinguishing the two subtypes by residual dermatan sulfate content.
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Biochemical abnormalities of the extracellular matrix are investigated (e.g., various types of collagen and DS-PGs, including decorin and biglycan), using patient skin fibroblasts."
    explanation: Describes the fibroblast biochemical workup used in mcEDS diagnosis and research.
  - reference: PMID:25703627
    reference_title: "Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients."
    explanation: Establishes the decorin glycanation abnormality detectable in patient fibroblasts.
progression:
- phase: Congenital presentation
  age_range: Birth to early infancy
  notes: >
    The malformation arm is present at birth: multiple congenital contractures
    with adducted thumbs and talipes equinovarus, plus a craniofacial gestalt
    that is evident at birth or in early infancy.
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple congenital contractures including adduction-flexion contractures and talipes equinovarus as well as other visceral or ophthalmological malformations"
    explanation: Establishes the congenital malformation features present from birth.
- phase: Progressive connective-tissue fragility
  age_range: Childhood through adulthood
  notes: >
    After infancy the disease is dominated by progressive fragility: skin
    hyperextensibility, bruisability and atrophic scarring, recurrent
    dislocations, progressive talipes and spinal deformities, large subcutaneous
    hematomas, pneumothorax, and diverticular perforation. The escalating
    orthopedic surveillance schedule tracks this progression.
  evidence:
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considering that patients with CHST14/D4ST1 deficiency develop progressive multisystem fragility-related manifestations"
    explanation: States explicitly that the fragility manifestations are progressive over time.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations."
    explanation: Confirms the two-phase congenital-then-progressive course.
histopathology:
- name: Disorganized Dermal Collagen Fibril Architecture
  description: >
    The hallmark electron-microscopic finding in mcEDS skin: collagen fibrils
    are dispersed through the papillary to reticular dermis instead of being
    regularly and tightly assembled, and the glycosaminoglycan chains run
    linearly between fibrils rather than curving to stay in contact with the
    fibril they decorate.
  diagnostic: true
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled."
    explanation: Describes the diagnostic ultrastructural collagen abnormality in mcEDS skin.
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils."
    explanation: Documents the altered glycosaminoglycan-collagen geometry seen on electron microscopy.
biochemical:
- name: Urinary Dermatan Sulfate
  notes: >
    Dermatan sulfate is undetectable in urine in mcEDS-DSE, providing direct
    biochemical confirmation of dermatan sulfate depletion in vivo and a
    potential non-invasive biomarker.
  presence: ABSENT
  evidence:
  - reference: PMID:32130795
    reference_title: "Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS."
    explanation: Direct in vivo biochemical evidence of dermatan sulfate depletion in an mcEDS-DSE patient.
- name: Fibroblast Dermatan Sulfate Epimerase Activity
  notes: >
    Epimerase activity is significantly reduced in cultured fibroblasts from
    patients with DSE variants, confirming the enzymatic defect in patient cells.
  presence: DECREASED
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  evidence:
  - reference: PMID:23704329
    reference_title: "Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient-derived fibroblasts also showed a significant reduction in epimerase activity."
    explanation: Establishes reduced epimerase activity as a measurable cellular biochemical phenotype.
genetic:
- name: CHST14
  notes: >
    Encodes carbohydrate sulfotransferase 14 / dermatan 4-O-sulfotransferase-1
    (D4ST1), which 4-O-sulfates N-acetylgalactosamine residues in the
    chondroitin/dermatan sulfate chain. Biallelic loss-of-function variants
    cause mcEDS-CHST14, the common and more severe subtype. This form was
    originally described under three separate names — adducted thumb-clubfoot
    syndrome, EDS Kosho type, and a subset of kyphoscoliotic EDS without lysyl
    hydroxylase deficiency — before being unified.
  gene_term:
    preferred_term: CHST14
    term:
      id: hgnc:24464
      label: CHST14
  relationship_type: CAUSATIVE
  subtype: mcEDS-CHST14
  evidence:
  - reference: PMID:25703627
    reference_title: "Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies."
    explanation: Establishes the CHST14-mcEDS gene-disease relationship and its recessive mode.
  - reference: PMID:26646600
    reference_title: "CHST14/D4ST1 deficiency: New form of Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first reported human disorder that specifically affects biosynthesis of DS."
    explanation: Frames CHST14 deficiency as the founding dermatan-sulfate biosynthesis disorder.
- name: DSE
  notes: >
    Encodes dermatan sulfate epimerase-1 (DS-epi1), which converts glucuronic
    acid to iduronic acid in the nascent chondroitin/dermatan sulfate chain —
    the step immediately upstream of D4ST1 sulfation. Biallelic loss-of-function
    variants cause mcEDS-DSE, establishing locus heterogeneity for mcEDS.
    Reported variants include the original homozygous missense c.803C>T
    (p.S268L) and the later nonsense and frameshift variants c.960T>A
    (p.Tyr320*) and c.996dupT (p.Val333Cysfs*4).
  gene_term:
    preferred_term: DSE
    term:
      id: hgnc:21144
      label: DSE
  relationship_type: CAUSATIVE
  subtype: mcEDS-DSE
  evidence:
  - reference: PMID:23704329
    reference_title: "Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now identified a homozygous DSE missense mutation (c.803C>T, p.S268L) by the positional candidate approach in a male child with MCEDS, who was born to consanguineous parents."
    explanation: The index report establishing DSE as an mcEDS locus.
  - reference: PMID:32130795
    reference_title: "Delineation of musculocontractural Ehlers-Danlos Syndrome caused by dermatan sulfate epimerase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3."
    explanation: Documents additional loss-of-function DSE variants in molecularly confirmed patients.
treatments:
- name: Orthopedic Bracing and Surgical Correction
  description: >
    Braces for joint and spine deformities with surgical correction as needed.
    Orthopedic surveillance is intensive: foot deformities every three months in
    infancy, every six months in childhood, and annually thereafter; spine
    deformities and digit contractures every six to twelve months from infancy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Braces for joint and spine deformities with surgical correction as needed per orthopedist"
    explanation: GeneReviews management recommendation for the musculoskeletal manifestations.
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthopedic evaluation of foot deformities every three months in infancy, every six months in childhood, and annually in adolescence and adulthood"
    explanation: Specifies the orthopedic surveillance schedule accompanying this management.
- name: Physical Therapy
  description: >
    Physical therapy for hypotonia and motor delay, with gross motor skills
    assessed every three months from infancy and every six months through
    childhood.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical therapy for hypotonia and motor delay"
    explanation: GeneReviews management recommendation for neuromuscular manifestations.
- name: Desmopressin for Large Subcutaneous Hematoma
  description: >
    Large subcutaneous hematomas are managed with compression, icing, and
    surgical drainage, with desmopressin administered if necessary.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: desmopressin
      term:
        id: CHEBI:4450
        label: desmopressin
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compression, icing, surgical drainage, and administration of desmopressin if necessary for large subcutaneous hematomas"
    explanation: GeneReviews management recommendation naming desmopressin for this specific complication.
- name: Activity Restriction and Injury Avoidance
  description: >
    Contact or competitive sports should be avoided. In individuals with
    hyperalgesia to pressure, upper-arm sphygmomanometry and tight tourniquets
    during blood collection should also be avoided. This is the mcEDS
    agents-and-circumstances-to-avoid guidance.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Contact or competitive sports; upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure."
    explanation: GeneReviews explicitly enumerates the circumstances to avoid in mcEDS.
- name: Perinatal Management and Planned Cesarean Delivery
  description: >
    Pregnancy and delivery should be managed in a perinatal center. Planned
    cesarean section is considered reasonable given the risks of premature
    rupture of membranes, birth canal laceration, and excessive bleeding with
    vaginal delivery.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "planned cesarean section would be a reasonable approach due to risk of premature rupture of membranes, birth canal laceration, and excessive bleeding with vaginal delivery"
    explanation: GeneReviews pregnancy-management recommendation for mcEDS.
- name: Genetic Counseling
  description: >
    Autosomal recessive counseling with 25% sibling recurrence risk; carrier
    testing for at-risk relatives and prenatal or preimplantation genetic
    testing are possible once the familial variants are known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40373179
    reference_title: "Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the mcEDS-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
    explanation: GeneReviews genetic-counseling guidance for mcEDS families.
animal_models:
- species: Mus musculus
  genotype: Chst14-/-
  category: Knockout
  description: >
    Homozygous Chst14-null mice show perinatal lethality, shorter fetal length,
    and vessel-related placental abnormalities. The model demonstrates that
    dermatan sulfate is required for fetal development, but its perinatal
    lethality means it does not recapitulate the progressive postnatal
    connective-tissue fragility that dominates the human disease.
  genes:
  - preferred_term: CHST14
    term:
      id: hgnc:24464
      label: CHST14
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous (Chst14-/-) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities."
    explanation: >
      Supports a developmental requirement for dermatan sulfate, but the
      perinatal-lethal murine phenotype differs from the surviving, progressively
      fragile human phenotype, so support for the human disease model is partial.
- name: Xenopus DS-epi1 (dse) morphant embryos
  species: Xenopus laevis
  genotype: Morpholino knockdown of DS-epi1/dse, with cranial neural crest transplantation and explant culture
  category: Targeted knockdown model of dermatan sulfate epimerase deficiency
  publication: PMID:27101845
  description: >-
    The only model of this disease that addresses the embryonic origin of its
    congenital features. Knocking down DS-epi1 in frog embryos removes iduronic
    acid from chondroitin sulfate/dermatan sulfate chains and leaves neural crest
    induction intact while blocking epithelial-mesenchymal transition and
    migration; transplantation shows the requirement is tissue-autonomous, and
    explants place the defect in adhesion and spreading on fibronectin. The
    downstream loss of neural-crest-derived craniofacial skeleton offers a
    developmental account of the congenital malformations, complementing the
    Chst14-null mouse, which dies perinatally, and the human fibroblast work,
    which is postnatal.
  genes:
  - preferred_term: DSE
    term:
      id: hgnc:21144
      label: DSE
  modeled_mechanisms:
  - target: Dermatan Sulfate Biosynthesis Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the mcEDS-DSE biochemical lesion directly: loss of DS-epi1
      removes iduronic acid residues from hybrid CS/DS glycosaminoglycan chains.
    limitations: >-
      Morpholino knockdown rather than the biallelic null genotype of patients,
      and it models the DSE half of the disease only — mcEDS-CHST14, the more
      common form, acts one step later at 4-O-sulfation and is not addressed.
    readouts:
    - name: Isolated iduronic acid residues in CS/DS proteoglycans
      target: Dermatan Sulfate Biosynthesis Failure
      direction: DECREASED
      interpretation: >-
        The epimerase product itself, measured in the embryo, which is what makes
        this a model of the enzymatic lesion rather than of its consequences.
      evidence:
      - reference: PMID:27101845
        reference_title: "Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We demonstrate that DS-epi1 is important for the generation of isolated iduronic acid residues in chondroitin sulfate (CS)/DS proteoglycans in early Xenopus embryos."
        explanation: Reports the biochemical readout of epimerase loss in the model.
    evidence:
    - reference: PMID:27101845
      reference_title: "Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "this syndrome comprises multiple congenital malformations that are caused by dysfunction of dermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE)"
      explanation: Identifies the knocked-down enzyme as one of the disease genes for this entry.
  - target: Congenital Malformation of Connective-Tissue-Dependent Structures
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Supplies a developmental mechanism for the congenital craniofacial features:
      neural crest cells are induced normally but fail to undergo EMT and migrate,
      so crest-derived craniofacial skeleton is reduced.
    limitations: >-
      The craniofacial readouts are frog structures — dorsal fin and larval
      cartilage — that have no direct human counterpart, and melanocyte loss is
      not an mcEDS feature. The authors themselves put the link to human
      malformation as a proposal. Nothing here addresses the postnatal
      progressive fragility that dominates the disease.
    readouts:
    - name: Neural crest EMT transcription factor activation and extent of migration
      target: Congenital Malformation of Connective-Tissue-Dependent Structures
      direction: DECREASED
      interpretation: >-
        Localizes the defect to EMT and migration rather than to crest induction,
        which the same experiment shows is unaffected.
      evidence:
      - reference: PMID:27101845
        reference_title: "Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The knockdown of DS-epi1 does not affect the formation of early NC progenitors; however, it impairs the correct activation of transcription factors involved in the epithelial-mesenchymal transition (EMT) and reduces the extent of NC cell migration, which leads to a decrease in NC-derived craniofacial skeleton, melanocytes and dorsal fin structures."
        explanation: Reports both the preserved induction and the reduced EMT, migration and crest-derived structures.
    - name: Cranial neural crest adhesion and spreading on fibronectin
      target: Congenital Malformation of Connective-Tissue-Dependent Structures
      direction: DECREASED
      interpretation: >-
        Reduces the migration defect to a cell-matrix interaction, the level at
        which a missing glycosaminoglycan modification would be expected to act.
      evidence:
      - reference: PMID:27101845
        reference_title: "Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Cranial NC explant and single-cell cultures indicate a requirement of DS-epi1 in cell adhesion, spreading and extension of polarized cell processes on fibronectin."
        explanation: The explant and single-cell culture arm is cell-based, so it is graded in vitro rather than model organism.
    evidence:
    - reference: PMID:27101845
      reference_title: "Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Transplantation experiments demonstrate a tissue-autonomous role for DS-epi1 in cranial NC cell migration in vivo"
      explanation: >-
        Transplantation rules out a non-autonomous environmental effect, which is
        what makes the model informative about the crest cells themselves.
    - reference: PMID:27101845
      reference_title: "Musculocontractural Ehlers-Danlos syndrome and neurocristopathies: dermatan sulfate is required for Xenopus neural crest cells to migrate and adhere to fibronectin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that NC defects in the EMT and cell migration might account for the craniofacial anomalies and other congenital malformations in MCEDS"
      explanation: >-
        The authors' link to human malformation is offered as a possibility, which
        is why this link is partial rather than full recapitulation.
discussions:
- discussion_id: mceds_chst14_mouse_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the perinatally lethal Chst14-null mouse adequately model human
    mcEDS-CHST14, in which affected individuals survive and the dominant
    morbidity is progressive postnatal connective-tissue fragility?
  attaches_to:
  - pathophysiology#Progressive Multisystem Connective Tissue Fragility
  rationale: >-
    Homozygous Chst14-null mice die perinatally with shorter fetal length and
    placental vascular abnormalities, so the model speaks to the developmental
    arm of the disease but cannot report on the progressive fragility arm —
    skin fragility, recurrent dislocations, large subcutaneous hematomas,
    pneumothorax, and diverticular perforation — that defines long-term human
    morbidity. Evidence for the fragility mechanism therefore rests on human
    ultrastructural and biochemical studies rather than on the mouse.
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous (Chst14-/-) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities."
    explanation: >-
      The perinatal-lethal murine phenotype is the source of the translational
      mismatch with the surviving human phenotype.
  proposed_experiments:
  - experiment_id: mceds_conditional_chst14_postnatal_fragility
    name: Conditional or hypomorphic Chst14 allele surviving to adulthood
    description: >-
      Generate and characterize conditional or hypomorphic Chst14 alleles that
      bypass perinatal lethality, then assess postnatal skin, joint, vascular,
      and hollow-organ fragility against the human phenotype.
  - experiment_id: mceds_dse_null_mouse_survival
    name: Dse-null mouse phenotyping
    description: >-
      Test whether a Dse-null mouse, expected to retain residual dermatan
      sulfate as in human mcEDS-DSE, survives to adulthood and develops the
      milder progressive fragility phenotype seen in patients.
- discussion_id: mceds_dse_residual_ds_severity_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the residual decorin dermatan sulfate seen in DS-epi1 deficiency actually
    the cause of the milder mcEDS-DSE phenotype, and is DSE2 the compensating
    activity?
  attaches_to:
  - pathophysiology#Decorin Glycosaminoglycan Chain Replacement
  rationale: >-
    The persistence of some dermatan sulfate moieties in DS-epi1-deficient
    fibroblasts, in contrast to complete chondroitin sulfate replacement in
    D4ST1 deficiency, is the leading explanation for the lower symptom burden in
    mcEDS-DSE. The source literature states this only as a hedged proposal, and
    with only a handful of reported mcEDS-DSE patients the genotype-phenotype
    comparison is underpowered. Whether DSE2 provides the compensating epimerase
    activity is untested.
  evidence:
  - reference: PMID:31905796
    reference_title: "Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity."
    explanation: >-
      The hedged phrasing in the source review is itself the evidence that this
      remains an open question rather than a settled mechanism.
  proposed_experiments:
  - experiment_id: mceds_decorin_ds_severity_correlation
    name: Decorin dermatan sulfate content versus clinical severity
    description: >-
      Quantify decorin dermatan sulfate content across a matched series of
      mcEDS-CHST14 and mcEDS-DSE fibroblast lines and correlate with a
      standardized clinical severity score.
  - experiment_id: mceds_dse2_compensation_test
    name: DSE2 knockdown in DS-epi1-deficient fibroblasts
    description: >-
      Knock down or knock out DSE2 in DS-epi1-deficient patient fibroblasts and
      test whether residual dermatan sulfate is lost, establishing or excluding
      DSE2 compensation.
notes: >
  Curated as a single entry covering both gene-defined forms. MONDO models
  mcEDS-CHST14 (MONDO:0020681) and mcEDS-DSE (MONDO:0014236) as a
  disease_series_by_gene split beneath MONDO:0011142; MONDO:0020681 carries no
  definition of its own, and the two forms are clinically near-indistinguishable,
  differing chiefly in frequency and symptom burden. They are therefore modeled
  here as has_subtypes of one disease rather than as separate entries, following
  the precedent of Spondylodysplastic Ehlers-Danlos Syndrome, which likewise
  unifies three gene-defined forms of a glycosaminoglycan-biosynthesis EDS.

  Mechanistic neighbor: spondylodysplastic EDS (B4GALT7/B3GALT6) also arises
  from a proteoglycan glycosaminoglycan-biosynthesis defect, but at the common
  tetrasaccharide linker that initiates every GAG chain rather than at the
  dermatan-sulfate-specific epimerization and 4-O-sulfation steps modeled here.
  The pair is a candidate for a future shared GAG-biosynthesis mechanism module;
  no such module exists yet, so no conforms_to edge is declared.

  Sourcing note: no deep-research provider artifact backs this entry. It was
  built directly from primary literature located via the PubMed E-utilities API,
  with the GeneReviews chapter (PMID:40373179) mined as the phenotype baseline
  across its Clinical Characteristics, Diagnosis, Management, Genetic
  Counseling, and agents-to-avoid sections. Every PMID is cached through the
  reference validator and every snippet is machine-verified as an exact quote.
  All four organ systems GeneReviews names as additionally involved —
  genitourinary, cardiovascular, neurologic, and gastrointestinal — now carry
  curated phenotypes.

  Note on nosology: although MONDO places this disorder under congenital
  disorder of glycosylation and IEMbase codes CHST14 deficiency as a CDG, the
  dismech congenital_disorder_of_glycosylation module is scoped specifically to
  N-glycosylation (lipid-linked oligosaccharide assembly and Golgi N-glycan
  processing converging on protein hypoglycosylation). mcEDS is a
  glycosaminoglycan/proteoglycan defect and does not conform to that module.
📚

References & Deep Research

References

3
PMID:40373179
Musculocontractural Ehlers-Danlos Syndrome.
2 findings
mcEDS is established by suggestive clinical findings plus biallelic pathogenic variants in CHST14 or DSE.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic variants in CHST14 or DSE identified by molecular genetic testing."
GeneReviews states the molecular diagnostic criterion for mcEDS.
Beyond the core musculoskeletal, craniofacial, cutaneous, and ocular features, genitourinary, cardiovascular, neurologic, and gastrointestinal systems can also be involved.
Show evidence (1 reference)
PMID:40373179 SUPPORT Human Clinical
"Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal."
GeneReviews records the multisystem extent of mcEDS.
PMID:31905796
Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome.
1 finding
Loss of CHST14 or DSE activity leaves a negligible amount of dermatan sulfate and an excess of chondroitin sulfate.
Show evidence (1 reference)
PMID:31905796 SUPPORT Other
"Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate."
States the shared biochemical lesion of both mcEDS subtypes.
PMID:28306229
The 2017 international classification of the Ehlers-Danlos syndromes.
1 finding
mcEDS is one of the 13 EDS subtypes recognized by the 2017 International EDS Classification.
Show evidence (1 reference)
PMID:28306229 SUPPORT Other
"The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes."
Anchors mcEDS in the current EDS nosology.