Dermatosparaxis Ehlers-Danlos Syndrome

Mendelian MONDO:0009161 Pathograph 9 Show in embeddings browser Ehlers-Danlos Syndrome

Type I procollagen is secreted with propeptides at both ends, and both must be removed before the molecule can pack into a normal fibril. ADAMTS2 is the enzyme that removes the N-terminal one. Dermatosparaxis Ehlers-Danlos syndrome is what happens when biallelic ADAMTS2 variants abolish that activity: the N-propeptide is never excised, and the cell secretes pN-collagen into the dermis instead of collagen. The consequence is structural rather than quantitative. There is no shortage of collagen. The retained N-propeptides sit on the outside of the growing fibril, and because they are bulky and charged they prevent the fibril from closing into a cylinder. What assembles instead is a flattened, branching ribbon that is irregular in cross-section - the "hieroglyphic" appearance that is the diagnostic electron-microscopic finding, and the reason a skin biopsy is informative here in a way it is not for most EDS subtypes. Fibrils shaped like that cannot interdigitate, so the dermis loses the fibril-fibril interaction that carries tensile load. This is what separates dermatosparaxis from the rest of the EDS family. The classical subtypes alter a collagen chain or a collagen-modifying enzyme and produce a spectrum of laxity and fragility; here a single processing step fails completely, and the skin becomes fragile enough to tear and redundant enough to hang in folds from birth. It is also the one EDS subtype with a long-standing veterinary counterpart - dermatosparaxis was described in cattle and other domestic species decades before the human disease was recognised, and the bovine disease was what identified the enzyme.

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1
Inheritance
5
Pathophys.
15
Phenotypes
1
Gaps
9
Pathograph
1
Genes
3
Medical Actions
2
Models
9
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Two loss-of-function ADAMTS2 alleles are required, either in homozygous form or as compound heterozygotes. Heterozygous carriers are unaffected - roughly half-normal N-proteinase activity is sufficient to process procollagen, which is why this disease has no dominant counterpart in the way that several other EDS subtypes do.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26765342 SUPPORT Human Clinical
"The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2"
States the recessive inheritance and the enzymatic basis together.
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Discussions and Knowledge Gaps

1
Why do some patients with biallelic loss-of-function ADAMTS2 alleles have a strikingly milder phenotype than others?
KNOWLEDGE GAP deds_mild_phenotype_molecular_basis_unexplained
Attached to
pathophysiology#Generalised Connective Tissue Fragility genetic#ADAMTS2
The 2016 series reported that three of five new patients were much milder than any previously published case, and it did so while identifying alleles that are, on their face, of the same class as the severe ones - homozygous frameshift and splice variants. If the mechanism is simple loss of enzyme, and the alleles are all null, the severity range has no obvious explanation within the gene. Several possibilities are open and none has been tested. Residual ADAMTS2 activity from leaky splicing or from an alternative transcript would predict a genotype-severity relationship that has not been looked for. Compensation by ADAMTS3 or ADAMTS14, whose contribution to skin has been assumed rather than measured, would predict variation driven outside the ADAMTS2 locus. Ascertainment is the third and most deflating candidate: the severe phenotype was defined from the first ten patients, so a milder tail may always have existed and simply never reached a specialist. Distinguishing these matters clinically, because the 2016 authors proposed revised diagnostic criteria on the strength of the milder cases, and how those criteria should be applied depends on whether mild disease is a distinct biological state or the bottom of one distribution.
Proposed experiments
Quantify residual N-proteinase activity against reported allele severity
deds_residual_adamts2_activity_vs_severity
Measure procollagen I N-propeptide processing in dermal fibroblasts from patients across the reported severity range, and relate residual activity to phenotype score. A correlation would support leaky alleles; its absence would move the explanation outside the locus.
Would support
pathophysiology#Biallelic ADAMTS2 Loss of Function
Supporting outcome
  • Measurable residual N-propeptide cleavage in fibroblasts from mildly affected patients and none in severely affected patients.
Refuting outcome
  • Uniformly absent N-propeptide cleavage across the severity range, which would place the modifier outside ADAMTS2.
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Pathophysiology

5
Biallelic ADAMTS2 Loss of Function
Both ADAMTS2 alleles carry variants that abolish procollagen I N-proteinase activity. The reported alleles are overwhelmingly truncating - nonsense, frameshift and splice variants distributed across the gene rather than clustered in one domain - which is consistent with the mechanism being simple loss of the enzyme rather than any position-specific effect on how it behaves. Five of the first six patients identified were homozygous for the same nonsense allele, Q225X.
dermal fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dermal fibroblast, annotated with skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
Genetic context ADAMTS2 hgnc:218 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ADAMTS2 (hgnc:218). hgnc:218 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: LOSS_OF_FUNCTION
procollagen I N-proteinase activity GO:0004222 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves procollagen I N-proteinase activity, annotated with metalloendopeptidase activity (GO:0004222), qualified as loss of function. GO:0004222 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Failure of Procollagen N-Propeptide Excision
Show evidence (2 references)
PMID:10417273 SUPPORT Human Clinical
"These data provide direct evidence that EDS type VIIC and dermatosparaxis result from mutations in the pNPI gene."
The study that established the gene-disease relationship, in humans and in the bovine disease simultaneously.
PMID:10417273 SUPPORT Human Clinical
"Five of the individuals with EDS type VIIC were homozygous for a C-->T transition that results in a premature termination codon, Q225X."
Documents the truncating character of the founding alleles.
Failure of Procollagen N-Propeptide Excision
ADAMTS2 normally cleaves the aminoterminal propeptide from types I, II and III procollagen. Without it the N-propeptide is retained and the secreted molecule remains pN-collagen. This is a processing defect, not a synthesis defect: the amount of collagen protein reaching the matrix is not reduced, only its maturation state. ADAMTS3 and ADAMTS14 are homologous N-proteinases but do not compensate in skin, which is why the phenotype is dermatological even though the substrate is ubiquitous.
protein processing GO:0016485 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves protein processing (GO:0016485), qualified as loss of function. GO:0016485 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION collagen biosynthetic process GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Adamts2/Adamts14 double-deficient mouse Mouse recapitulates Reproduces the processing defect and the fibril alterations, and adds the paralogue test that human genetics cannot supply.
Downstream
Hieroglyphic Collagen Fibril Assembly
Show evidence (4 references)
PMID:26765342 SUPPORT Human Clinical
"an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen"
Names the substrate specificity of the missing enzymatic step.
PMID:25863161 SUPPORT Other
"the amino-propeptide is usually processed by procollagen N-proteinases: ADAMTS2, 3 and 14"
Establishes that ADAMTS2 belongs to a three-member family, which is what makes the absence of compensation in skin a substantive observation rather than an assumption. Graded OTHER rather than IN_VITRO: the publication is a review and this sentence is its background statement, not an experiment it reports.
PMID:29649548 SUPPORT Model Organism
"They are healthy, fertile and display normal aminoprocollagen processing."
Adamts14-deficient mice process aminoprocollagen normally, which is the direct evidence that the paralogue does not carry this function on its own.
+ 1 more reference
Hieroglyphic Collagen Fibril Assembly
Retained N-propeptides end up on the surface of the assembling fibril, in the overlap zone of the D-period. Being there, they prevent the fibril from achieving a circular cross-section, and the fibril grows as a flattened, branching ribbon - "hieroglyphic" in transverse section, and in the most severely affected skin appearing as sheets rather than discrete fibrils. The dermatosparactic calf, in which this was quantified, carried 57% pN-collagen in its dermal fibrils. Notably the propeptides on such fibrils can no longer be removed even by exogenous N-proteinase, so the lesion is self-locking once assembly has occurred.
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
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Dermatosparactic calf Cattle recapitulates The calf reproduces the human fibril pathology and is the system in which it was quantified - dermal fibrils containing 57% pN-collagen, irregularly bundled and hieroglyphic in cross-section.
Downstream
Loss of Dermal Tensile Strength
Show evidence (3 references)
PMID:9571043 SUPPORT Model Organism
"the collagen fibrils in the skin of a dermatosparactic calf contained 57% type I pNcollagen and 43% type I collagen and the fibrils were irregularly arranged in bundles and hieroglyphic in cross-section"
The quantitative measurement of pN-collagen content alongside the fibril morphology it produces.
PMID:9571043 SUPPORT Model Organism
"Image analysis of the fibril cross-sections suggested that the deviation from circularity of dermatosparactic fibrils was caused by N-propeptides of pNcollagen being located at the fibril surface."
Attributes the abnormal fibril geometry specifically to the surface location of the retained propeptides.
PMID:1403389 SUPPORT Human Clinical
"Electron microscopic examination of the skin shows collagen sheets rather than fibrils, and characteristic distortions resembling hieroglyphs."
Confirms the same fibril pathology in human skin, and is the source of the descriptive term used throughout the literature.
Loss of Dermal Tensile Strength
The tensile strength of dermis depends on near-cylindrical fibrils packing closely enough to interact along their length. Ribbon-shaped fibrils cannot do that, so load is no longer distributed between fibrils and the tissue tears at low force. This is the step at which a molecular processing defect becomes a mechanical one, and it explains why the skin is simultaneously fragile and redundant - the same loss of fibril-fibril engagement that lets it tear also lets it stretch and hang.
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
skin of body UBERON:0002097 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skin of body (UBERON:0002097). UBERON:0002097 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Generalised Connective Tissue Fragility
Show evidence (2 references)
PMID:9571043 SUPPORT Model Organism
"the normal mechanical properties of skin are strongly dependent on the close association of near-cylindrical fibrils, thereby enabling maximal fibril-fibril interactions"
States the mechanical principle that the abnormal fibril shape violates.
PMID:9571043 SUPPORT Model Organism
"Partial loss of enzyme activity results in accumulation of pNcollagen (collagen with N-propeptides) and abnormal collagen fibrils in the fragile skin."
Links the accumulated pN-collagen directly to the fragility of the skin.
Generalised Connective Tissue Fragility
Type I collagen is not confined to skin, so the processing defect is expressed wherever fibrillar collagen carries load. Clinically this appears as umbilical and inguinal herniation, joint laxity, craniofacial features reflecting a soft cranial vault with wide sutures and large fontanelles, and - in the more severely affected - visceral and vascular fragility including bladder and diaphragmatic rupture. The severity of this systemic component is what the 2016 expansion of the phenotype turned on: three of five newly reported patients were substantially milder than every previously published case, so the multisystem burden is variable rather than obligate.
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:26765342 SUPPORT Human Clinical
"extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility"
Establishes that the fragility extends beyond skin to viscera and vessels in some patients.
PMID:26765342 SUPPORT Human Clinical
"Three of these displayed a phenotype that was strikingly milder than that of previously reported patients."
The observation behind treating the systemic burden as variable rather than uniform.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dermatosparaxis 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.
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Phenotypes

15
Blood 2
Excessive Bruising FREQUENT 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 (3 references)
PMID:26765342 SUPPORT Human Clinical
"Easy bruising was frequent (n = 11) and often very severe, with the formation of large subcutaneous hematomas."
The counted frequency, 11 of 15, plus the severity that distinguishes it from ordinary easy bruising.
PMID:26765342 SUPPORT Human Clinical
"a soft, doughy skin texture, easy bruising, premature rupture of fetal membranes, and large hernias (umbilical, inguinal) as minor criteria"
Names easy bruising among the diagnostic criteria derived from the reported cohort.
PMID:26765342 SUPPORT Human Clinical
"extreme skin fragility and laxity, excessive bruising"
Lists excessive bruising among the recognisable phenotype.
Bleeding Complications FREQUENT Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26765342 SUPPORT Human Clinical
"and the propensity for bruising and bleeding (type III collagen)."
Attributes the bruising and bleeding propensity to type III collagen involvement, which is the mechanistic basis for treating bleeding as distinct from dermal bruising.
PMID:26765342 SUPPORT Human Clinical
"Bleeding problems were reported for seven patients and ranged from severe epistaxis and gum bleeding to internal and (congenital) cerebral hemorrhages."
Gives the 7 of 15 count in prose and the severity range behind this phenotype's description, up to intracranial haemorrhage.
Eye 1
Blue Sclerae VERY_FREQUENT 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 (2 references)
PMID:26765342 SUPPORT Human Clinical
"orofacial gestalt at birth with swelling of the periorbital soft tissues, blue sclerae, down-slanting palpebral fissures"
Names blue sclerae as part of the recognisable orofacial gestalt. The 13 of 15 count is from Table 1.
PMID:1403389 SUPPORT Human Clinical
"large fontanels and wide sagittal and metopic sutures, blue sclerae, micrognathia, and umbilical hernia"
Documents blue sclerae as part of the neonatal presentation.
Head and Neck 2
Large Fontanelles and Wide Sutures FREQUENT HP:0000239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large fontanelles (HP:0000239). HP:0000239 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:1403389 SUPPORT Human Clinical
"large fontanels and wide sagittal and metopic sutures, blue sclerae, micrognathia, and umbilical hernia"
Reports the cranial findings directly.
PMID:1403389 SUPPORT Human Clinical
"normal mineralization of the skeleton except for the cranial vault"
Establishes that the defect of ossification is restricted to the cranial vault.
Micrognathia VERY_FREQUENT 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:1403389 SUPPORT Human Clinical
"blue sclerae, micrognathia, and umbilical hernia"
Names micrognathia in the original human clinical description.
Integument 3
Extreme Skin Fragility VERY_FREQUENT Fragile skin HP:0001030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fragile skin (HP:0001030). HP:0001030 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10417273 SUPPORT Human Clinical
"characterized by extreme skin fragility, characteristic facies, joint laxity, droopy skin, umbilical hernia, and blue sclera"
Lists skin fragility first among the defining features of the syndrome.
PMID:10417273 SUPPORT Human Clinical
"characterized by extreme skin fragility, characteristic facies, joint laxity, droopy skin, umbilical hernia, and blue sclera"
Lists skin fragility first among the defining features of the syndrome.
Redundant Skin Folds FREQUENT HP:0001582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Redundant skin (HP:0001582). HP:0001582 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:1403389 SUPPORT Human Clinical
"the disorder is characterized by redundant skin folds and edema, healing with minimal scar formation"
Describes the redundant skin and the associated neonatal oedema.
PMID:1403389 SUPPORT Human Clinical
"the disorder is characterized by redundant skin folds and edema, healing with minimal scar formation"
Describes the redundant skin and the associated neonatal oedema.
Atrophic Scarring FREQUENT 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:26765342 SUPPORT Human Clinical
"included soft and doughy skin texture (n = 12), increased palmar wrinkling (n = 6), and atrophic scarring (n = 5)"
The counted frequency, 5 of 15, stated in prose.
Limbs 1
Short Limbs and Digits FREQUENT Limb undergrowth HP:0009826 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short limbs, annotated with Limb undergrowth (HP:0009826). HP:0009826 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26765342 SUPPORT Human Clinical
"Eleven patients presented with nonrhizomelic shortening of the limbs and short, plump hands and feet with stubby fingers and toes."
The counted frequency, 11 of 15, and the specific limb morphology.
Musculoskeletal 1
Joint Hypermobility FREQUENT 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 (2 references)
PMID:26765342 SUPPORT Human Clinical
"Joint hypermobility was a consistent finding (n = 11) but was often mild at birth."
The counted frequency, 11 of 15, stated in prose along with the observation that it is often mild at birth.
PMID:1403389 SUPPORT Human Clinical
"after the neonatal period there are joint laxity, growth failure, short limbs"
Places joint laxity in its post-neonatal time course.
Growth 1
Postnatal Growth Failure VERY_FREQUENT Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322), qualified as course progressive. HP:0004322 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:26765342 SUPPORT Human Clinical
"postnatal growth restriction was reported in all patients, except for those who died soon after birth (n = 13)"
States the 13 of 15 count in prose, and qualifies it - the three patients not counted are those who died in the neonatal period, before postnatal growth could be assessed.
PMID:1403389 SUPPORT Human Clinical
"after the neonatal period there are joint laxity, growth failure, short limbs"
Reports growth failure and short limbs as post-neonatal developments.
Other 4
Umbilical Hernia VERY_FREQUENT HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26765342 SUPPORT Human Clinical
"clinical findings was an umbilical hernia at birth (n = 14)"
The counted frequency, 14 of 15, stated in prose.
PMID:26765342 SUPPORT Human Clinical
"a soft, doughy skin texture, easy bruising, premature rupture of fetal membranes, and large hernias (umbilical, inguinal) as minor criteria"
Names large umbilical and inguinal hernias among the diagnostic criteria derived from the reported cohort.
PMID:10417273 SUPPORT Human Clinical
"joint laxity, droopy skin, umbilical hernia, and blue sclera"
Names umbilical hernia among the defining features.
Soft Doughy Skin Texture VERY_FREQUENT Soft skin HP:0000977 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Soft skin (HP:0000977). HP:0000977 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26765342 SUPPORT Human Clinical
"included soft and doughy skin texture (n = 12), increased palmar wrinkling (n = 6), and atrophic scarring (n = 5)"
The counted frequency, 12 of 15, stated in prose.
PMID:26765342 SUPPORT Human Clinical
"a soft, doughy skin texture, easy bruising, premature rupture of fetal membranes, and large hernias (umbilical, inguinal) as minor criteria"
Names a soft, doughy skin texture among the diagnostic criteria derived from the reported cohort.
Fractures OCCASIONAL Increased susceptibility to fractures HP:0002659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased susceptibility to fractures (HP:0002659). HP:0002659 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26765342 SUPPORT Human Clinical
"including (congenital) skull fractures in three"
The Discussion reports congenital skull fractures in three patients while Table 1 counts two. The paper disagrees with itself; this entry records the prose figure and the discrepancy rather than silently picking one.
PMID:39641471 SUPPORT Human Clinical
"Complications include extreme skin fragility resulting in iatrogenic injury, redundant skin folds often requiring surgical resection, severe complications following a gastric volvulus secondary to a diaphragmatic hernia, and multiple fractures."
Adult follow-up confirming fractures as a recurring adult complication rather than a paediatric one.
Diaphragmatic Hernia VERY_RARE Congenital diaphragmatic hernia HP:0000776 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital diaphragmatic hernia (HP:0000776). HP:0000776 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39641471 SUPPORT Human Clinical
"severe complications following a gastric volvulus secondary to a diaphragmatic hernia"
The visceral complication reported in the adult case series.
🧬

Genetic Associations

1
ADAMTS2
Gene: ADAMTS2 hgnc:218 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ADAMTS2 (hgnc:218). hgnc:218 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:26765342 SUPPORT Human Clinical
"We identified three novel homozygous loss-of-function mutations"
Reports the loss-of-function character of the newly identified alleles.
💊

Medical Actions

3
Skin Protection and Wound Care
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. Ontology label: Supportive Care NCIT:C15747
No therapy addresses the enzymatic defect, and that is a documented position rather than an absence of searching: the EDS care-pathway review states there is no specific treatment for non-vascular EDS and that management is symptomatic, multidisciplinary and personalised. In practice that means avoiding trauma, careful consideration of skin closure techniques and manual handling, thorough investigation of acute pain, and caution with adhesive dressings, which can themselves tear the skin.
Mechanism Target:
MODULATES Loss of Dermal Tensile Strength — Reduces the mechanical load the weakened dermis has to bear. It does not alter fibril structure.
Show evidence (2 references)
PMID:40887396 SUPPORT Other
"There is no specific treatment for non-vascular EDS to date, so the care management is symptomatic, multidisciplinary and personalized."
The guideline-level statement that management is symptomatic, which is the claim this entry makes.
PMID:39641471 SUPPORT Human Clinical
"Discussion of management considerations includes thorough investigations of acute pain, careful consideration of skin closure techniques and manual handling, as well as monitoring for reduced bone mineral density after low-impact fracture and/or post-menopause."
The concrete protective measures named for adults, which this entry describes.
Surgical Resection of Redundant Skin Folds
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. Ontology label: Surgical Procedure NCIT:C15329
Redundant skin folds often grow enough in adulthood to require surgical resection. Recorded as its own treatment because it is an intervention performed on the tissue consequence, in a disease whose skin tears easily and heals atrophically - so the operation carries the disease's own risk. Hernia repair falls in the same category.
Mechanism Target:
MODULATES Generalised Connective Tissue Fragility — Removes accumulated redundant tissue. It does not alter fibril structure, and the operative site heals with the same defective collagen.
Show evidence (1 reference)
PMID:39641471 SUPPORT Human Clinical
"redundant skin folds often requiring surgical resection"
Documents surgical resection as a recurring adult intervention.
Genetic Counselling
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. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive recurrence counselling for the parents, with a 25% recurrence risk in each pregnancy, and carrier testing once the familial ADAMTS2 alleles are known.
Show evidence (1 reference)
PMID:26765342 SUPPORT Human Clinical
"The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder"
The recessive inheritance that determines the recurrence risk being counselled.
🔬

Diagnosis

2
Skin Biopsy with Transmission Electron Microscopy
Ultrastructural examination of dermal collagen shows the hieroglyphic fibril profiles, or in severe cases collagen sheets in place of discrete fibrils. This is unusually informative for an EDS subtype: most others have non-specific or normal ultrastructure, whereas here the fibril morphology is close to pathognomonic and follows directly from the biochemical lesion.
skin biopsy NCIT:C51692 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:1403389 SUPPORT Human Clinical
"Electron microscopic examination of the skin shows collagen sheets rather than fibrils, and characteristic distortions resembling hieroglyphs."
Describes the ultrastructural finding the test looks for.
ADAMTS2 Molecular Testing
Sequencing of ADAMTS2 to identify biallelic variants, which confirms the diagnosis and enables carrier testing in the family.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26765342 SUPPORT Human Clinical
"mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families"
Demonstrates molecular confirmation by ADAMTS2 sequencing in a clinical series.
📈

Progression

1
Adulthood
Age: 22-42 years
The molecular defect is static - the enzyme is absent from birth and the fibrils are laid down abnormally throughout - but the consequences accumulate. Adults reported at 22 to 42 years carry iatrogenic injury from earlier medical handling, redundant skin folds that have grown enough to warrant surgical resection, fractures, and in one case a gastric volvulus from a diaphragmatic hernia. Reduced bone mineral density becomes a monitoring concern after a low-impact fracture or the menopause. Until 2025 the oldest reported patient was 19, so the adult natural history is new information rather than established knowledge.
Show evidence (2 references)
PMID:39641471 SUPPORT Human Clinical
"Given the lack of information regarding adults with dEDS, our aim was to describe adults with dEDS to inform management recommendations in adulthood."
Establishes that adult natural history was unknown before this series, which is why this record exists at all.
PMID:39641471 SUPPORT Human Clinical
"Discussion of management considerations includes thorough investigations of acute pain, careful consideration of skin closure techniques and manual handling, as well as monitoring for reduced bone mineral density after low-impact fracture and/or post-menopause."
The adult management concerns, including the bone-density monitoring this record describes.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
No population estimate exists. Fifteen individuals have been reported in the literature as of the 2025 adult series - the 2016 series that added five to a prior ten is where that total comes from. Recorded as a literature count; the prevalence_class band is inferred from that count and is not a measured rate.
Show evidence (2 references)
PMID:39641471 SUPPORT Human Clinical
"Fifteen individuals with dEDS have been reported in the literature, with the oldest being 19 years at follow-up."
The current literature count, which supersedes the 2016 figure of ten.
PMID:26765342 SUPPORT Human Clinical
"Only 10 EDS dermatosparaxis patients have been reported"
The earlier count, retained to show where the current total comes from - this series added five.
🐁

Animal Models

2
Dermatosparactic calf
Bovine dermatosparaxis is the disease in which the enzymatic defect was first characterised, decades before the human condition was recognised. It is a naturally occurring homologue rather than an engineered model, and the causative allele was identified in the same study that solved the human disease.
Species
Cattle
Genotype
ADAMTS2 17-bp deletion, homozygous
Publication
PMID:10417273
Pathograph links
Hieroglyphic Collagen Fibril Assembly recapitulates fidelity: high The calf reproduces the human fibril pathology and is the system in which it was quantified - dermal fibrils containing 57% pN-collagen, irregularly bundled and hieroglyphic in cross-section.
Limitations: The bovine allele is a 17-bp deletion causing a reading-frame shift, so it models complete loss of function specifically. It says nothing about the milder human phenotypes reported in 2016, whose molecular basis is not a different class of allele but is not fully explained either.
Readouts
pN-collagen content of dermal fibrils
Direction: INCREASED
Interpretation: Direct measurement of the unprocessed substrate accumulating in the matrix.
Show evidence (1 reference)
PMID:9571043 SUPPORT Model Organism
"the collagen fibrils in the skin of a dermatosparactic calf contained 57% type I pNcollagen and 43% type I collagen"
The quantitative pN-collagen measurement in the bovine dermis.
Show evidence (1 reference)
PMID:10417273 SUPPORT Model Organism
"In the dermatosparactic calf, the mutation is a 17-bp deletion that changes the reading frame of the message."
Establishes that the bovine disease has the same genetic basis, which is what makes it informative for the human mechanism.
Adamts2/Adamts14 double-deficient mouse
Built to ask whether the closest paralogue of ADAMTS2 compensates for it. The answer is that it does not: Adamts14-deficient mice are healthy with normal aminoprocollagen processing, and removing both enzymes produces no worse procollagen processing and no worse fibril pathology than removing ADAMTS2 alone. That negative result is what licenses this entry to describe ADAMTS2 as the non-redundant dermal N-proteinase rather than merely the principal one.
Species
Mouse
Genotype
Adamts2 and Adamts14 double-deficient
Publication
PMID:29649548
Pathograph links
Failure of Procollagen N-Propeptide Excision recapitulates fidelity: high Reproduces the processing defect and the fibril alterations, and adds the paralogue test that human genetics cannot supply.
Limitations: The double-knockout develops a spontaneous atopic-dermatitis-like phenotype from about two months of age, driven by abnormal Th1 T-lymphocyte activation. That is not a reported feature of human dermatosparaxis EDS, so any skin finding in aged animals of this genotype has to be read against an immune phenotype the human disease does not have.
Readouts
Aminoprocollagen processing
Direction: UNCHANGED
Interpretation: Unchanged relative to Adamts2-single-deficient animals - a real negative result, and the point of the experiment.
Show evidence (1 reference)
PMID:29649548 SUPPORT Model Organism
"showed the same phenotype as that of Adamts2-deficient mice, with no further reduction of procollagen processing and no significant aggravation of the structural alterations of collagen fibrils"
The measurement establishing that removing ADAMTS14 as well adds nothing.
Show evidence (1 reference)
PMID:29649548 SUPPORT Model Organism
"They were further crossed with Adamts2-deficient mice to evaluate potential functional redundancies between these two highly related enzymes."
States the purpose of the model, which is what makes it informative for this node.
{ }

Source YAML

click to show 
name: Dermatosparaxis Ehlers-Danlos Syndrome
creation_date: '2026-08-28T21:45:00Z'
category: Mendelian
description: 'Type I procollagen is secreted with propeptides at both ends, and both must be removed before
  the molecule can pack into a normal fibril. ADAMTS2 is the enzyme that removes the N-terminal one. Dermatosparaxis
  Ehlers-Danlos syndrome is what happens when biallelic ADAMTS2 variants abolish that activity: the N-propeptide
  is never excised, and the cell secretes pN-collagen into the dermis instead of collagen.

  The consequence is structural rather than quantitative. There is no shortage of collagen. The retained N-propeptides
  sit on the outside of the growing fibril, and because they are bulky and charged they prevent the fibril
  from closing into a cylinder. What assembles instead is a flattened, branching ribbon that is irregular in
  cross-section - the "hieroglyphic" appearance that is the diagnostic electron-microscopic finding, and the
  reason a skin biopsy is informative here in a way it is not for most EDS subtypes. Fibrils shaped like that
  cannot interdigitate, so the dermis loses the fibril-fibril interaction that carries tensile load.

  This is what separates dermatosparaxis from the rest of the EDS family. The classical subtypes alter a collagen
  chain or a collagen-modifying enzyme and produce a spectrum of laxity and fragility; here a single processing
  step fails completely, and the skin becomes fragile enough to tear and redundant enough to hang in folds
  from birth. It is also the one EDS subtype with a long-standing veterinary counterpart - dermatosparaxis
  was described in cattle and other domestic species decades before the human disease was recognised, and the
  bovine disease was what identified the enzyme.'
disease_term:
  preferred_term: Ehlers-Danlos syndrome, dermatosparaxis type
  term:
    id: MONDO:0009161
    label: Ehlers-Danlos syndrome, dermatosparaxis type
synonyms:
- EDS dermatosparaxis type
- Ehlers-Danlos syndrome type VIIC
- dermatosparaxis
- dEDS
- procollagen I N-proteinase deficiency
parents:
- Ehlers-Danlos Syndrome
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: Two loss-of-function ADAMTS2 alleles are required, either in homozygous form or as compound
    heterozygotes. Heterozygous carriers are unaffected - roughly half-normal N-proteinase activity is sufficient
    to process procollagen, which is why this disease has no dominant counterpart in the way that several other
    EDS subtypes do.
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective
      tissue disorder caused by deficient activity of ADAMTS-2
    explanation: States the recessive inheritance and the enzymatic basis together.
pathophysiology:
- name: Biallelic ADAMTS2 Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: Both ADAMTS2 alleles carry variants that abolish procollagen I N-proteinase activity. The reported
    alleles are overwhelmingly truncating - nonsense, frameshift and splice variants distributed across the
    gene rather than clustered in one domain - which is consistent with the mechanism being simple loss of
    the enzyme rather than any position-specific effect on how it behaves. Five of the first six patients identified
    were homozygous for the same nonsense allele, Q225X.
  genetic_context:
    gene:
      preferred_term: ADAMTS2
      term:
        id: hgnc:218
        label: ADAMTS2
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: procollagen I N-proteinase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  downstream:
  - target: Failure of Procollagen N-Propeptide Excision
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10417273
    reference_title: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations
      in the procollagen I N-proteinase gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These data provide direct evidence that EDS type VIIC and dermatosparaxis result from mutations
      in the pNPI gene.
    explanation: The study that established the gene-disease relationship, in humans and in the bovine disease
      simultaneously.
  - reference: PMID:10417273
    reference_title: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations
      in the procollagen I N-proteinase gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five of the individuals with EDS type VIIC were homozygous for a C-->T transition that results
      in a premature termination codon, Q225X.
    explanation: Documents the truncating character of the founding alleles.
- name: Failure of Procollagen N-Propeptide Excision
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: 'ADAMTS2 normally cleaves the aminoterminal propeptide from types I, II and III procollagen.
    Without it the N-propeptide is retained and the secreted molecule remains pN-collagen. This is a processing
    defect, not a synthesis defect: the amount of collagen protein reaching the matrix is not reduced, only
    its maturation state. ADAMTS3 and ADAMTS14 are homologous N-proteinases but do not compensate in skin,
    which is why the phenotype is dermatological even though the substrate is ubiquitous.'
  biological_processes:
  - preferred_term: protein processing
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0016485
      label: protein processing
  - preferred_term: collagen biosynthetic process
    modifier: ABNORMAL
    term:
      id: GO:0032964
      label: collagen biosynthetic process
  downstream:
  - target: Hieroglyphic Collagen Fibril Assembly
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: an enzyme that cleaves the aminoterminal propeptide domain of types I, II, and III procollagen
    explanation: Names the substrate specificity of the missing enzymatic step.
  - reference: PMID:25863161
    reference_title: The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'the amino-propeptide is usually processed by procollagen N-proteinases: ADAMTS2, 3 and 14'
    explanation: 'Establishes that ADAMTS2 belongs to a three-member family, which is what makes the absence
      of compensation in skin a substantive observation rather than an assumption. Graded OTHER rather than
      IN_VITRO: the publication is a review and this sentence is its background statement, not an experiment
      it reports.'
  - reference: PMID:29649548
    reference_title: Spontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2 and
      14.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: They are healthy, fertile and display normal aminoprocollagen processing.
    explanation: Adamts14-deficient mice process aminoprocollagen normally, which is the direct evidence that
      the paralogue does not carry this function on its own.
  - reference: PMID:26446156
    reference_title: ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental
      angiogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Procollagens I, II and III processing was unaffected in these embryos.
    explanation: The ADAMTS3 half of the non-compensation claim. Adamts3-null embryos die of failed lymphangiogenesis
      with procollagen processing intact, so ADAMTS3's essential role is elsewhere and it does not cover for
      ADAMTS2 in this pathway.
- name: Hieroglyphic Collagen Fibril Assembly
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: Retained N-propeptides end up on the surface of the assembling fibril, in the overlap zone of
    the D-period. Being there, they prevent the fibril from achieving a circular cross-section, and the fibril
    grows as a flattened, branching ribbon - "hieroglyphic" in transverse section, and in the most severely
    affected skin appearing as sheets rather than discrete fibrils. The dermatosparactic calf, in which this
    was quantified, carried 57% pN-collagen in its dermal fibrils. Notably the propeptides on such fibrils
    can no longer be removed even by exogenous N-proteinase, so the lesion is self-locking once assembly has
    occurred.
  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
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  downstream:
  - target: Loss of Dermal Tensile Strength
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:9571043
    reference_title: Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not
      cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the collagen fibrils in the skin of a dermatosparactic calf contained 57% type I pNcollagen and
      43% type I collagen and the fibrils were irregularly arranged in bundles and hieroglyphic in cross-section
    explanation: The quantitative measurement of pN-collagen content alongside the fibril morphology it produces.
  - reference: PMID:9571043
    reference_title: Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not
      cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Image analysis of the fibril cross-sections suggested that the deviation from circularity of dermatosparactic
      fibrils was caused by N-propeptides of pNcollagen being located at the fibril surface.
    explanation: Attributes the abnormal fibril geometry specifically to the surface location of the retained
      propeptides.
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electron microscopic examination of the skin shows collagen sheets rather than fibrils, and characteristic
      distortions resembling hieroglyphs.
    explanation: Confirms the same fibril pathology in human skin, and is the source of the descriptive term
      used throughout the literature.
- name: Loss of Dermal Tensile Strength
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: The tensile strength of dermis depends on near-cylindrical fibrils packing closely enough to
    interact along their length. Ribbon-shaped fibrils cannot do that, so load is no longer distributed between
    fibrils and the tissue tears at low force. This is the step at which a molecular processing defect becomes
    a mechanical one, and it explains why the skin is simultaneously fragile and redundant - the same loss
    of fibril-fibril engagement that lets it tear also lets it stretch and hang.
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  downstream:
  - target: Generalised Connective Tissue Fragility
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:9571043
    reference_title: Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not
      cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the normal mechanical properties of skin are strongly dependent on the close association of near-cylindrical
      fibrils, thereby enabling maximal fibril-fibril interactions
    explanation: States the mechanical principle that the abnormal fibril shape violates.
  - reference: PMID:9571043
    reference_title: Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not
      cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Partial loss of enzyme activity results in accumulation of pNcollagen (collagen with N-propeptides)
      and abnormal collagen fibrils in the fragile skin.
    explanation: Links the accumulated pN-collagen directly to the fragility of the skin.
- name: Generalised Connective Tissue Fragility
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: 'Type I collagen is not confined to skin, so the processing defect is expressed wherever fibrillar
    collagen carries load. Clinically this appears as umbilical and inguinal herniation, joint laxity, craniofacial
    features reflecting a soft cranial vault with wide sutures and large fontanelles, and - in the more severely
    affected - visceral and vascular fragility including bladder and diaphragmatic rupture. The severity of
    this systemic component is what the 2016 expansion of the phenotype turned on: three of five newly reported
    patients were substantially milder than every previously published case, so the multisystem burden is variable
    rather than obligate.'
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to
      visceral and vascular fragility
    explanation: Establishes that the fragility extends beyond skin to viscera and vessels in some patients.
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three of these displayed a phenotype that was strikingly milder than that of previously reported
      patients.
    explanation: The observation behind treating the systemic burden as variable rather than uniform.
phenotypes:
- category: Dermatologic
  name: Extreme Skin Fragility
  frequency: VERY_FREQUENT
  description: Skin tears with minor trauma from the neonatal period. This is the cardinal feature and the
    one that gives the disease its name - dermatosparaxis is Greek for "torn skin". Counted in 14 of the 15
    patients reported to 2016.
  phenotype_term:
    preferred_term: Fragile skin
    term:
      id: HP:0001030
      label: Fragile skin
  evidence:
  - reference: PMID:10417273
    reference_title: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations
      in the procollagen I N-proteinase gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characterized by extreme skin fragility, characteristic facies, joint laxity, droopy skin, umbilical
      hernia, and blue sclera
    explanation: Lists skin fragility first among the defining features of the syndrome.
  - reference: PMID:10417273
    reference_title: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations
      in the procollagen I N-proteinase gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characterized by extreme skin fragility, characteristic facies, joint laxity, droopy skin, umbilical
      hernia, and blue sclera
    explanation: Lists skin fragility first among the defining features of the syndrome.
- category: Dermatologic
  name: Redundant Skin Folds
  frequency: FREQUENT
  description: Loose, doughy, sagging skin with excess folds, most obvious on the face, neck and limbs, and
    typically accompanied by oedema in the newborn. Counted in 11 of 15 - frequent rather than near-universal,
    which is why the band here is FREQUENT and not VERY_FREQUENT. The count is taken from Table 1 of PMID:26765342.
    The paper's Discussion does not restate this particular figure in prose, so the number lives here rather
    than in a snippet; the table rows themselves fail check_snippet_length.
  phenotype_term:
    preferred_term: Redundant skin
    term:
      id: HP:0001582
      label: Redundant skin
  evidence:
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the disorder is characterized by redundant skin folds and edema, healing with minimal scar formation
    explanation: Describes the redundant skin and the associated neonatal oedema.
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the disorder is characterized by redundant skin folds and edema, healing with minimal scar formation
    explanation: Describes the redundant skin and the associated neonatal oedema.
- category: Dermatologic
  name: Excessive Bruising
  frequency: FREQUENT
  description: Easy bruising out of proportion to trauma, reflecting fragility of the perivascular connective
    tissue rather than a defect of haemostasis. Counted in 11 of 15.
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Easy bruising was frequent (n = 11) and often very severe, with the formation of large subcutaneous
      hematomas.
    explanation: The counted frequency, 11 of 15, plus the severity that distinguishes it from ordinary easy
      bruising.
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a soft, doughy skin texture, easy bruising, premature rupture of fetal membranes, and large hernias
      (umbilical, inguinal) as minor criteria
    explanation: Names easy bruising among the diagnostic criteria derived from the reported cohort.
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: extreme skin fragility and laxity, excessive bruising
    explanation: Lists excessive bruising among the recognisable phenotype.
- category: Musculoskeletal
  name: Umbilical Hernia
  frequency: VERY_FREQUENT
  description: Herniation through the umbilical ring, reflecting weakness of the abdominal wall fascia. Counted
    in 14 of 15.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: clinical findings was an umbilical hernia at birth (n = 14)
    explanation: The counted frequency, 14 of 15, stated in prose.
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a soft, doughy skin texture, easy bruising, premature rupture of fetal membranes, and large hernias
      (umbilical, inguinal) as minor criteria
    explanation: Names large umbilical and inguinal hernias among the diagnostic criteria derived from the
      reported cohort.
  - reference: PMID:10417273
    reference_title: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations
      in the procollagen I N-proteinase gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: joint laxity, droopy skin, umbilical hernia, and blue sclera
    explanation: Names umbilical hernia among the defining features.
- category: Ophthalmologic
  name: Blue Sclerae
  frequency: VERY_FREQUENT
  description: Bluish scleral hue from a thin sclera allowing the underlying uveal pigment to show through
    - the same mechanism as in osteogenesis imperfecta, arrived at through a different collagen defect. Counted
    in 13 of 15 patients in the cohort table, under Orofacial appearance. The count is taken from Table 1 of
    PMID:26765342. The paper's Discussion does not restate this particular figure in prose, so the number lives
    here rather than in a snippet; the table rows themselves fail check_snippet_length.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: orofacial gestalt at birth with swelling of the periorbital soft tissues, blue sclerae, down-slanting
      palpebral fissures
    explanation: Names blue sclerae as part of the recognisable orofacial gestalt. The 13 of 15 count is from
      Table 1.
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: large fontanels and wide sagittal and metopic sutures, blue sclerae, micrognathia, and umbilical
      hernia
    explanation: Documents blue sclerae as part of the neonatal presentation.
- category: Craniofacial
  name: Large Fontanelles and Wide Sutures
  frequency: FREQUENT
  description: A soft, poorly ossified cranial vault with large fontanelles and wide sagittal and metopic sutures.
    Notably the rest of the skeleton mineralises normally, which distinguishes this from a generalised bone
    disorder. Counted in 11 of 15 patients in the cohort table, under Orofacial appearance. The count is taken
    from Table 1 of PMID:26765342. The paper's Discussion does not restate this particular figure in prose,
    so the number lives here rather than in a snippet; the table rows themselves fail check_snippet_length.
  phenotype_term:
    preferred_term: Large fontanelles
    term:
      id: HP:0000239
      label: Large fontanelles
  evidence:
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: large fontanels and wide sagittal and metopic sutures, blue sclerae, micrognathia, and umbilical
      hernia
    explanation: Reports the cranial findings directly.
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: normal mineralization of the skeleton except for the cranial vault
    explanation: Establishes that the defect of ossification is restricted to the cranial vault.
- category: Craniofacial
  name: Micrognathia
  frequency: VERY_FREQUENT
  description: Small mandible, part of the characteristic facial gestalt that also includes a puffy, oedematous
    face with epicanthal folds. Counted in 12 of 15 patients in the cohort table, under Orofacial appearance.
    The count is taken from Table 1 of PMID:26765342. The paper's Discussion does not restate this particular
    figure in prose, so the number lives here rather than in a snippet; the table rows themselves fail check_snippet_length.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: blue sclerae, micrognathia, and umbilical hernia
    explanation: Names micrognathia in the original human clinical description.
- category: Musculoskeletal
  name: Joint Hypermobility
  frequency: FREQUENT
  description: Generalised joint laxity, appearing after the neonatal period rather than at birth. Counted
    in 11 of 15.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Joint hypermobility was a consistent finding (n = 11) but was often mild at birth.
    explanation: The counted frequency, 11 of 15, stated in prose along with the observation that it is often
      mild at birth.
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: after the neonatal period there are joint laxity, growth failure, short limbs
    explanation: Places joint laxity in its post-neonatal time course.
- category: Growth
  name: Postnatal Growth Failure
  frequency: VERY_FREQUENT
  description: Short stature with short limbs, developing after the newborn period. Counted in 13 of 15,
    a figure the paper states both in Table 1 and in prose in the Discussion.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postnatal growth restriction was reported in all patients, except for those who died soon after
      birth (n = 13)"
    explanation: States the 13 of 15 count in prose, and qualifies it - the three patients not counted are
      those who died in the neonatal period, before postnatal growth could be assessed.
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: after the neonatal period there are joint laxity, growth failure, short limbs
    explanation: Reports growth failure and short limbs as post-neonatal developments.
- category: Dermatologic
  name: Soft Doughy Skin Texture
  frequency: VERY_FREQUENT
  description: A characteristically soft, doughy skin texture on palpation, counted in 12 of 15 patients.
  phenotype_term:
    preferred_term: Soft skin
    term:
      id: HP:0000977
      label: Soft skin
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: included soft and doughy skin texture (n = 12), increased palmar wrinkling (n = 6), and atrophic
      scarring (n = 5)
    explanation: The counted frequency, 12 of 15, stated in prose.
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a soft, doughy skin texture, easy bruising, premature rupture of fetal membranes, and large hernias
      (umbilical, inguinal) as minor criteria
    explanation: Names a soft, doughy skin texture among the diagnostic criteria derived from the reported
      cohort.
- category: Hematologic
  name: Bleeding Complications
  frequency: FREQUENT
  description: Bleeding beyond simple bruising, counted in 7 of 15 patients. Categorised as haematologic here
    in contrast to easy bruising, which this entry treats as dermatologic because its mechanism is perivascular
    connective tissue rather than haemostasis. The paper states the count and the severity range in prose.
  phenotype_term:
    preferred_term: Abnormal bleeding
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: and the propensity for bruising and bleeding (type III collagen).
    explanation: Attributes the bruising and bleeding propensity to type III collagen involvement, which is
      the mechanistic basis for treating bleeding as distinct from dermal bruising.
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bleeding problems were reported for seven patients and ranged from severe epistaxis and gum bleeding
      to internal and (congenital) cerebral hemorrhages.
    explanation: Gives the 7 of 15 count in prose and the severity range behind this phenotype's description,
      up to intracranial haemorrhage.
- category: Musculoskeletal
  name: Fractures
  frequency: OCCASIONAL
  description: Fractures in 4 of 15 patients, including congenital skull fractures in 2. This qualifies the
    entry's other skeletal statement, taken from the 1992 case report, that mineralisation is normal except
    for the cranial vault - normal mineralisation and a real fracture burden are both true here. Adult follow-up
    adds reduced bone mineral density as a management concern. The
    congenital skull fracture subset is reported as two in Table 1 and three in the Discussion of the same
    paper - the discrepancy is the source's, and is recorded rather than resolved.
  phenotype_term:
    preferred_term: Increased susceptibility to fractures
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: including (congenital) skull fractures in three
    explanation: The Discussion reports congenital skull fractures in three patients while Table 1 counts two.
      The paper disagrees with itself; this entry records the prose figure and the discrepancy rather than
      silently picking one.
  - reference: PMID:39641471
    reference_title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Complications include extreme skin fragility resulting in iatrogenic injury, redundant skin folds
      often requiring surgical resection, severe complications following a gastric volvulus secondary to a
      diaphragmatic hernia, and multiple fractures.
    explanation: Adult follow-up confirming fractures as a recurring adult complication rather than a paediatric
      one.
- category: Gastrointestinal
  name: Diaphragmatic Hernia
  frequency: VERY_RARE
  description: Herniation through the diaphragm, reported in the adult series as the origin of a gastric volvulus
    with severe complications. Recorded because it is the most serious visceral event documented in adults
    with this disease, not because it is common.
  phenotype_term:
    preferred_term: Congenital diaphragmatic hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
  evidence:
  - reference: PMID:39641471
    reference_title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe complications following a gastric volvulus secondary to a diaphragmatic hernia
    explanation: The visceral complication reported in the adult case series.
- category: Dermatologic
  name: Atrophic Scarring
  frequency: FREQUENT
  description: Thin, atrophic scars at healed wound sites, counted in 5 of 15 patients.
  phenotype_term:
    preferred_term: Atrophic scars
    term:
      id: HP:0001075
      label: Atrophic scars
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: included soft and doughy skin texture (n = 12), increased palmar wrinkling (n = 6), and atrophic
      scarring (n = 5)
    explanation: The counted frequency, 5 of 15, stated in prose.
- category: Musculoskeletal
  name: Short Limbs and Digits
  frequency: FREQUENT
  description: Nonrhizomelic shortening of the limbs with short, plump hands and feet and stubby digits, counted
    in 11 of 15 patients.
  phenotype_term:
    preferred_term: Short limbs
    term:
      id: HP:0009826
      label: Limb undergrowth
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eleven patients presented with nonrhizomelic shortening of the limbs and short, plump hands and
      feet with stubby fingers and toes.
    explanation: The counted frequency, 11 of 15, and the specific limb morphology.
genetic:
- name: ADAMTS2
  gene_term:
    preferred_term: ADAMTS2
    term:
      id: hgnc:218
      label: ADAMTS2
  relationship_type: CAUSATIVE
  notes: ADAMTS2 encodes procollagen I N-proteinase. Reported disease alleles are predominantly truncating
    and are scattered across the gene rather than concentrated in a functional region, which fits a straightforward
    loss-of-function mechanism. This is worth stating explicitly because it is the opposite of the pattern
    seen in several other EDS subtypes, where the position of a missense variant within a collagen chain determines
    both subtype and severity. Here the question is only whether the allele makes working enzyme.
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified three novel homozygous loss-of-function mutations
    explanation: Reports the loss-of-function character of the newly identified alleles.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: No population estimate exists. Fifteen individuals have been reported in the literature as of the
    2025 adult series - the 2016 series that added five to a prior ten is where that total comes from. Recorded
    as a literature count; the prevalence_class band is inferred from that count and is not a measured rate.
  evidence:
  - reference: PMID:39641471
    reference_title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fifteen individuals with dEDS have been reported in the literature, with the oldest being 19 years
      at follow-up.
    explanation: The current literature count, which supersedes the 2016 figure of ten.
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Only 10 EDS dermatosparaxis patients have been reported
    explanation: The earlier count, retained to show where the current total comes from - this series added
      five.
diagnosis:
- name: Skin Biopsy with Transmission Electron Microscopy
  description: 'Ultrastructural examination of dermal collagen shows the hieroglyphic fibril profiles, or in
    severe cases collagen sheets in place of discrete fibrils. This is unusually informative for an EDS subtype:
    most others have non-specific or normal ultrastructure, whereas here the fibril morphology is close to
    pathognomonic and follows directly from the biochemical lesion.'
  diagnosis_term:
    preferred_term: skin biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:1403389
    reference_title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electron microscopic examination of the skin shows collagen sheets rather than fibrils, and characteristic
      distortions resembling hieroglyphs.
    explanation: Describes the ultrastructural finding the test looks for.
- name: ADAMTS2 Molecular Testing
  description: Sequencing of ADAMTS2 to identify biallelic variants, which confirms the diagnosis and enables
    carrier testing in the family.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from
      four unrelated families
    explanation: Demonstrates molecular confirmation by ADAMTS2 sequencing in a clinical series.
treatments:
- name: Skin Protection and Wound Care
  therapeutic_modality: BEHAVIORAL
  description: 'No therapy addresses the enzymatic defect, and that is a documented position rather than an
    absence of searching: the EDS care-pathway review states there is no specific treatment for non-vascular
    EDS and that management is symptomatic, multidisciplinary and personalised. In practice that means avoiding
    trauma, careful consideration of skin closure techniques and manual handling, thorough investigation of
    acute pain, and caution with adhesive dressings, which can themselves tear the skin.'
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Loss of Dermal Tensile Strength
    treatment_effect: MODULATES
    description: Reduces the mechanical load the weakened dermis has to bear. It does not alter fibril structure.
  evidence:
  - reference: PMID:40887396
    reference_title: '[Ehlers-Danlos syndromes: Diagnosis and care pathway of these complex and multisystemic
      diseases].'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: There is no specific treatment for non-vascular EDS to date, so the care management is symptomatic,
      multidisciplinary and personalized.
    explanation: The guideline-level statement that management is symptomatic, which is the claim this entry
      makes.
  - reference: PMID:39641471
    reference_title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Discussion of management considerations includes thorough investigations of acute pain, careful
      consideration of skin closure techniques and manual handling, as well as monitoring for reduced bone
      mineral density after low-impact fracture and/or post-menopause.
    explanation: The concrete protective measures named for adults, which this entry describes.
- name: Surgical Resection of Redundant Skin Folds
  therapeutic_modality: SURGERY
  description: Redundant skin folds often grow enough in adulthood to require surgical resection. Recorded
    as its own treatment because it is an intervention performed on the tissue consequence, in a disease whose
    skin tears easily and heals atrophically - so the operation carries the disease's own risk. Hernia repair
    falls in the same category.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Generalised Connective Tissue Fragility
    treatment_effect: MODULATES
    description: Removes accumulated redundant tissue. It does not alter fibril structure, and the operative
      site heals with the same defective collagen.
  evidence:
  - reference: PMID:39641471
    reference_title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: redundant skin folds often requiring surgical resection
    explanation: Documents surgical resection as a recurring adult intervention.
- name: Genetic Counselling
  therapeutic_modality: OTHER
  description: Autosomal recessive recurrence counselling for the parents, with a 25% recurrence risk in each
    pregnancy, and carrier testing once the familial ADAMTS2 alleles are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:26765342
    reference_title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis
      type.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective
      tissue disorder
    explanation: The recessive inheritance that determines the recurrence risk being counselled.
animal_models:
- name: Dermatosparactic calf
  species: Cattle
  genotype: ADAMTS2 17-bp deletion, homozygous
  publication: PMID:10417273
  description: Bovine dermatosparaxis is the disease in which the enzymatic defect was first characterised,
    decades before the human condition was recognised. It is a naturally occurring homologue rather than an
    engineered model, and the causative allele was identified in the same study that solved the human disease.
  modeled_mechanisms:
  - target: Hieroglyphic Collagen Fibril Assembly
    relationship: RECAPITULATES
    fidelity: HIGH
    description: The calf reproduces the human fibril pathology and is the system in which it was quantified
      - dermal fibrils containing 57% pN-collagen, irregularly bundled and hieroglyphic in cross-section.
    limitations: The bovine allele is a 17-bp deletion causing a reading-frame shift, so it models complete
      loss of function specifically. It says nothing about the milder human phenotypes reported in 2016, whose
      molecular basis is not a different class of allele but is not fully explained either.
    readouts:
    - name: pN-collagen content of dermal fibrils
      target: Hieroglyphic Collagen Fibril Assembly
      direction: INCREASED
      interpretation: Direct measurement of the unprocessed substrate accumulating in the matrix.
      evidence:
      - reference: PMID:9571043
        reference_title: Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are
          not cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: the collagen fibrils in the skin of a dermatosparactic calf contained 57% type I pNcollagen
          and 43% type I collagen
        explanation: The quantitative pN-collagen measurement in the bovine dermis.
    evidence:
    - reference: PMID:10417273
      reference_title: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations
        in the procollagen I N-proteinase gene.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In the dermatosparactic calf, the mutation is a 17-bp deletion that changes the reading frame
        of the message.
      explanation: Establishes that the bovine disease has the same genetic basis, which is what makes it informative
        for the human mechanism.
- name: Adamts2/Adamts14 double-deficient mouse
  species: Mouse
  genotype: Adamts2 and Adamts14 double-deficient
  publication: PMID:29649548
  description: 'Built to ask whether the closest paralogue of ADAMTS2 compensates for it. The answer is that
    it does not: Adamts14-deficient mice are healthy with normal aminoprocollagen processing, and removing
    both enzymes produces no worse procollagen processing and no worse fibril pathology than removing ADAMTS2
    alone. That negative result is what licenses this entry to describe ADAMTS2 as the non-redundant dermal
    N-proteinase rather than merely the principal one.'
  modeled_mechanisms:
  - target: Failure of Procollagen N-Propeptide Excision
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Reproduces the processing defect and the fibril alterations, and adds the paralogue test that
      human genetics cannot supply.
    limitations: The double-knockout develops a spontaneous atopic-dermatitis-like phenotype from about two
      months of age, driven by abnormal Th1 T-lymphocyte activation. That is not a reported feature of human
      dermatosparaxis EDS, so any skin finding in aged animals of this genotype has to be read against an immune
      phenotype the human disease does not have.
    readouts:
    - name: Aminoprocollagen processing
      target: Failure of Procollagen N-Propeptide Excision
      direction: UNCHANGED
      interpretation: Unchanged relative to Adamts2-single-deficient animals - a real negative result, and
        the point of the experiment.
      evidence:
      - reference: PMID:29649548
        reference_title: Spontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2
          and 14.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: showed the same phenotype as that of Adamts2-deficient mice, with no further reduction of
          procollagen processing and no significant aggravation of the structural alterations of collagen fibrils
        explanation: The measurement establishing that removing ADAMTS14 as well adds nothing.
    evidence:
    - reference: PMID:29649548
      reference_title: Spontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2 and
        14.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: They were further crossed with Adamts2-deficient mice to evaluate potential functional redundancies
        between these two highly related enzymes.
      explanation: States the purpose of the model, which is what makes it informative for this node.
discussions:
- discussion_id: deds_mild_phenotype_molecular_basis_unexplained
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Generalised Connective Tissue Fragility
  - genetic#ADAMTS2
  prompt: Why do some patients with biallelic loss-of-function ADAMTS2 alleles have a strikingly milder phenotype
    than others?
  rationale: 'The 2016 series reported that three of five new patients were much milder than any previously
    published case, and it did so while identifying alleles that are, on their face, of the same class as the
    severe ones - homozygous frameshift and splice variants. If the mechanism is simple loss of enzyme, and
    the alleles are all null, the severity range has no obvious explanation within the gene.

    Several possibilities are open and none has been tested. Residual ADAMTS2 activity from leaky splicing
    or from an alternative transcript would predict a genotype-severity relationship that has not been looked
    for. Compensation by ADAMTS3 or ADAMTS14, whose contribution to skin has been assumed rather than measured,
    would predict variation driven outside the ADAMTS2 locus. Ascertainment is the third and most deflating
    candidate: the severe phenotype was defined from the first ten patients, so a milder tail may always have
    existed and simply never reached a specialist.

    Distinguishing these matters clinically, because the 2016 authors proposed revised diagnostic criteria
    on the strength of the milder cases, and how those criteria should be applied depends on whether mild disease
    is a distinct biological state or the bottom of one distribution.'
  proposed_experiments:
  - experiment_id: deds_residual_adamts2_activity_vs_severity
    name: Quantify residual N-proteinase activity against reported allele severity
    description: Measure procollagen I N-propeptide processing in dermal fibroblasts from patients across the
      reported severity range, and relate residual activity to phenotype score. A correlation would support
      leaky alleles; its absence would move the explanation outside the locus.
    would_support:
    - pathophysiology#Biallelic ADAMTS2 Loss of Function
    supporting_outcome:
    - Measurable residual N-propeptide cleavage in fibroblasts from mildly affected patients and none in severely
      affected patients.
    refuting_outcome:
    - Uniformly absent N-propeptide cleavage across the severity range, which would place the modifier outside
      ADAMTS2.
references:
- reference: PMID:10417273
  title: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the
    procollagen I N-proteinase gene.
- reference: PMID:26765342
  title: Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type.
- reference: PMID:1403389
  title: 'Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.'
- reference: PMID:9571043
  title: Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not cleaved by
    procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
- reference: PMID:25863161
  title: The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology.
- reference: PMID:29649548
  title: Spontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2 and 14.
- reference: PMID:26446156
  title: ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis.
- reference: PMID:39641471
  title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
- reference: PMID:40887396
  title: '[Ehlers-Danlos syndromes: Diagnosis and care pathway of these complex and multisystemic diseases].'
notes: 'This entry is deliberately separate from the umbrella Ehlers-Danlos_Syndrome entry, which lists Dermatosparaxis
  EDS among its has_subtypes. That follows the repository''s existing practice, where Vascular, Hypermobile,
  Musculocontractural, Spondylodysplastic and Cardiac Valvular EDS all carry their own entries in addition
  to being listed as subtypes on the umbrella.

  Deep research. Curated with a single OpenScientist deep-research report (research/Dermatosparaxis_Ehlers-Danlos_Syndrome-deep-research-openscientist.md).
  Its reference validation reported 13/13 citations verified with no unsupported quotes. Its term validation
  reported needs_review for two obsolete GO terms (GO:0004251, and GO:0005615 replaced by GO:0005576) and a
  cosmetic CL:0000057 label variant; none of those CURIEs is bound in this entry. The report''s substantive
  contribution over the literature search was the Adamts2/Adamts14 double-knockout result, which is what turned
  "the paralogues presumably do not compensate" into a cited negative finding.


  Phenotype frequencies. The bands come from the counted findings table in PMID:26765342 across the 15 patients
  reported to 2016. Where that paper''s Discussion restates a count in prose, the prose sentence is the evidence
  snippet and carries the number; where it does not, the count is recorded in the phenotype description instead,
  because check_snippet_length rejects extracted table rows and its message names that exact case.'
progression:
- phase: Adulthood
  evidence:
  - reference: PMID:39641471
    reference_title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Given the lack of information regarding adults with dEDS, our aim was to describe adults with
      dEDS to inform management recommendations in adulthood.
    explanation: Establishes that adult natural history was unknown before this series, which is why this record
      exists at all.
  - reference: PMID:39641471
    reference_title: 'The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Discussion of management considerations includes thorough investigations of acute pain, careful
      consideration of skin closure techniques and manual handling, as well as monitoring for reduced bone
      mineral density after low-impact fracture and/or post-menopause.
    explanation: The adult management concerns, including the bone-density monitoring this record describes.
  notes: The molecular defect is static - the enzyme is absent from birth and the fibrils are laid down abnormally
    throughout - but the consequences accumulate. Adults reported at 22 to 42 years carry iatrogenic injury
    from earlier medical handling, redundant skin folds that have grown enough to warrant surgical resection,
    fractures, and in one case a gastric volvulus from a diaphragmatic hernia. Reduced bone mineral density
    becomes a monitoring concern after a low-impact fracture or the menopause. Until 2025 the oldest reported
    patient was 19, so the adult natural history is new information rather than established knowledge.
  age_range: 22-42 years
📚

References & Deep Research

References

9
PMID:10417273
Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene.
No top-level findings curated for this source.
PMID:26765342
Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type.
No top-level findings curated for this source.
PMID:1403389
Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC.
No top-level findings curated for this source.
PMID:9571043
Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
No top-level findings curated for this source.
PMID:25863161
The procollagen N-proteinases ADAMTS2, 3 and 14 in pathophysiology.
No top-level findings curated for this source.
PMID:29649548
Spontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2 and 14.
No top-level findings curated for this source.
PMID:26446156
ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis.
No top-level findings curated for this source.
PMID:39641471
The Natural History of Dermatosparaxis Ehlers Danlos Syndrome: An Adult Case Series.
No top-level findings curated for this source.
PMID:40887396
[Ehlers-Danlos syndromes: Diagnosis and care pathway of these complex and multisystemic diseases].
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
1. Disease Information
openscientist-autonomous 13 citations 2026-08-28T21:59:41.366290

1. Disease Information

Overview. dEDS is a rare recessively inherited connective tissue disorder characterized by extreme skin fragility. It was historically designated Ehlers-Danlos syndrome type VIIC in the older Villefranche nomenclature and renamed dermatosparaxis EDS in the 2017 international classification. The name "dermatosparaxis" (Greek: derma = skin, sparassein = to tear) was coined for the analogous bovine disease, in which the skin tears easily. dEDS is defined by an absence of procollagen I N-proteinase activity (PMID: 10417273).

"Like the animal model dermatosparaxis, EDS type VIIC results from the absence of activity of procollagen I N-proteinase (pNPI), the enzyme that excises the N-propeptide of type I and type II procollagens." — Colige et al., 1999 (PMID: 10417273)

Key identifiers:

Resource Identifier
OMIM 225410
Orphanet ORPHA:1901
MONDO 0009159
Former name EDS type VIIC (Villefranche)
Gene ADAMTS2 (HGNC:217)
MeSH Ehlers-Danlos Syndrome (D004535)

Synonyms / alternative names: dermatosparaxis type EDS; EDS dermatosparaxis type; EDS VIIC; Ehlers-Danlos syndrome type 7C; procollagen I N-proteinase deficiency; human dermatosparaxis.

Data source type. The knowledge summarized here is derived from aggregated disease-level resources — primary case reports, small case series (individual patient molecular and clinical data), OMIM/Orphanet, and model-organism studies — rather than from a single EHR cohort. Because dEDS is ultra-rare (well under 100 reported human cases worldwide), the literature is dominated by individual and small-series patient reports.

2. Etiology

Primary cause (genetic). dEDS is caused exclusively by biallelic (homozygous or compound heterozygous) loss-of-function variants in ADAMTS2. There is no environmental or infectious cause; the disorder is fully monogenic and recessive. The pathogenic mechanism is deficiency of procollagen I N-proteinase activity, which prevents removal of the procollagen N-propeptide.

Genetic risk factors. The only risk factor is inheritance of two defective ADAMTS2 alleles. There are no known modifier loci or susceptibility variants in humans; carriers (heterozygotes) are unaffected. Consanguinity increases risk, consistent with a recessive disorder — several reported homozygous patients arose in consanguineous or geographically isolated families.

Environmental / protective factors. None established. Because the disorder is monogenic with a loss-of-function mechanism and near-complete penetrance, environmental modifiers, protective alleles, and gene–environment interactions have not been described and are not applicable in the conventional sense. (Not available for this disease.)

Gene–environment interactions. Not applicable / not documented for a fully penetrant recessive enzyme deficiency.

3. Phenotypes

dEDS presents at birth (congenital onset) with a recognizable, multisystem phenotype. Severity is variable, with a classic severe form and a documented milder variant.

Phenotype Type Suggested HPO term Onset / frequency notes
Extreme skin fragility Physical manifestation HP:0000974 (Hyperextensible skin) / HP:0000979 (Bruising susceptibility) Congenital; near-universal; hallmark feature
Redundant/lax (sagging) skin, skin folds Physical manifestation HP:0000973 (Cutis laxa) Congenital; often requires surgical resection in adults
Excessive/easy bruising Clinical sign HP:0000978 (Bruising susceptibility) Congenital; frequent
Characteristic facial gestalt (puffy eyelids, epicanthal folds, micrognathia, blue sclerae) Physical manifestation HP:0001999 (Abnormal facial shape); HP:0000592 (Blue sclerae) Congenital; recognizable "facies"
Joint laxity/hypermobility Clinical sign HP:0001382 (Joint hypermobility) Congenital
Umbilical/inguinal hernia Physical manifestation HP:0001537 (Umbilical hernia) Congenital/childhood
Delayed wound healing, atrophic scarring Clinical sign HP:0001058 (Poor wound healing) Lifelong
Visceral/vascular fragility (e.g., gastric volvulus, diaphragmatic hernia) Clinical sign Hernia / GI terms Variable; severe complications reported in adults
Multiple fractures / reduced bone mineral density Laboratory/imaging abnormality HP:0002659 (Increased susceptibility to fractures); HP:0004349 (Reduced bone mineral density) Adult natural history

Severity and course. Extreme skin fragility and laxity are the cardinal features; the disease is congenital and lifelong (chronic, non-remitting), with cumulative complications in adulthood. A milder phenotypic variant exists in addition to the typical severe form (PMID: 26765342).

"all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility." — Van Damme et al., 2016 (PMID: 26765342)

The first adult natural-history case series (n = 5, ages 22–42 years) expanded the phenotype into adulthood:

"Complications include extreme skin fragility resulting in iatrogenic injury, redundant skin folds often requiring surgical resection, severe complications following a gastric volvulus secondary to a diaphragmatic hernia, and multiple fractures." — Angwin et al., 2025 (PMID: 39641471)

The original molecular series described the classic constellation:

"characterized by extreme skin fragility, characteristic facies, joint laxity, droopy skin, umbilical hernia, and blue sclera." — Colige et al., 1999 (PMID: 10417273)

Quality-of-life impact. No dEDS-specific EQ-5D/SF-36 data exist (ultra-rare disease). Extrapolating from the natural history, quality of life is affected by chronic skin fragility (requiring meticulous wound care and avoidance of trauma), disfiguring redundant skin folds and surgical scarring, hernias, fracture risk, and the psychosocial burden of a visible, chronic condition. Iatrogenic injury during routine medical procedures is a recurring, avoidable harm.

4. Genetic / Molecular Information

Causal gene. ADAMTS2 (a disintegrin and metalloproteinase with thrombospondin motifs 2), HGNC:217, located at 5q35.3, encoding procollagen I N-proteinase (pNPI). OMIM gene 604539; disease OMIM 225410.

Pathogenic variant spectrum. All confirmed dEDS variants are loss-of-function, abolishing enzyme activity. Documented classes:

Variant Type Consequence Source
c.673C>T, p.(Gln225*) (Q225X) Nonsense Premature stop; mRNA decay Colige 1999 (PMID: 10417273) — 5/6 patients homozygous
p.(Trp795*) (W795X) Nonsense Premature stop Colige 1999 (PMID: 10417273) — 6th patient homozygous
c.2927_2928delCT, p.(Pro976Argfs*42) Frameshift Truncation Van Damme 2016 (PMID: 26765342)
c.669_670dupG, p.(Pro224Argfs*24) Frameshift (dup) Truncation Van Damme 2016 (PMID: 26765342)
c.2751-2A>T Splice-site Aberrant splicing Van Damme 2016 (PMID: 26765342)
c.2T>C / c.884_887delTGAA Start-loss / frameshift (compound het) Loss of function Van Damme 2016 (PMID: 26765342)
Genomic deletions → in-frame skipping of exons 3–5 and exons 14–16 Structural / splicing Abolished enzyme activity despite in-frame Colige 2004 (PMID: 15373769)

"Five of the individuals with EDS type VIIC were homozygous for a C-->T transition that results in a premature termination codon, Q225X." — Colige et al., 1999 (PMID: 10417273)

"We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs42); c.669_670dupG, p.(Pro224Argfs24); and c.2751-2A>T) and one compound heterozygous mutation." — Van Damme et al., 2016 (PMID: 26765342)

A notable insight from the 2004 study is that even in-frame exon-skipping events (exons 3–5 or 14–16), affecting domains not previously thought essential, strongly impaired aminoprocollagen processing in vitro and in vivo — demonstrating that these domains are required for proper enzyme function (PMID: 15373769).

Variant classification (ACMG/AMP). Reported variants are pathogenic (nonsense, frameshift, canonical splice, structural), fulfilling loss-of-function criteria for a gene where LoF is the established mechanism.

Allele frequency / origin. All variants are germline; pathogenic alleles are exceedingly rare in gnomAD (consistent with an ultra-rare recessive disorder). No somatic contribution.

Functional consequence. Loss of function (enzyme deficiency). Not gain-of-function or dominant-negative — heterozygous carriers are healthy.

Modifier genes. No human modifier genes established. Mouse work implicates the paralog Adamts14 as a minor contributor to dermal procollagen processing (see Section 15).

Epigenetics / chromosomal abnormalities. Not implicated. No methylation, histone, or large-scale cytogenetic mechanisms are described; dEDS is a point-mutation/small-indel recessive disorder. (Not applicable.)

5. Environmental Information

dEDS is a purely genetic disorder. No environmental factors, toxins, radiation, occupational exposures, lifestyle factors, or infectious agents cause or trigger it. Physical trauma exacerbates the manifestations (skin tears, bruising, iatrogenic surgical injury) but does not cause the disease. Careful avoidance of mechanical stress and trauma is the practical corollary. (Environmental etiology: not applicable.)

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Biallelic ADAMTS2 LoF variant
│
▼
Absent/deficient procollagen I N-proteinase (pNPI) activity
│
▼
N-propeptide of type I (II, III) procollagen NOT excised
│
▼
pN-collagen accumulates; trimers cannot assemble normally
│
▼
Structurally defective, ribbon-like/"hieroglyphic" collagen fibrils
│
▼
Weak dermal & connective tissue matrix
│
▼
Extreme skin fragility, laxity, bruising, hernias,
visceral/vascular/skeletal fragility (clinical dEDS)

Molecular pathway / biochemistry. Fibril-forming procollagens possess a central triple-helical domain flanked by N- and C-propeptides. Both propeptides must be proteolytically removed to permit spontaneous assembly of trimers into fibrils and fibers. The N-propeptide is cleaved by procollagen N-proteinases ADAMTS2, ADAMTS3, and ADAMTS14, while the C-propeptide is cleaved by tolloid-family (BMP1) proteinases (PMID: 25863161).

"the amino-propeptide is usually processed by procollagen N-proteinases: ADAMTS2, 3 and 14." — Bekhouche & Colige, 2015 (PMID: 25863161)

"these two propeptides have to be proteolytically removed to allow the almost spontaneous assembly of the trimers into collagen fibrils and fibers." — Bekhouche & Colige, 2015 (PMID: 25863161)

Protein dysfunction. ADAMTS2 is a secreted zinc metalloproteinase containing a catalytic (metalloprotease) domain plus ancillary thrombospondin/properdin repeats, a disintegrin-like domain, and a cysteine-rich domain. Loss-of-function variants remove or inactivate catalytic capacity (or destabilize the transcript via nonsense-mediated decay), yielding enzyme deficiency — a classic loss-of-function protein defect rather than aggregation or misfolding-toxicity. A short catalytic-only isoform and a long isoform exist (PMID: 25863161; PMID: 10417273).

Cellular processes and cell types. The principal effector cell is the dermal fibroblast (CL:0000057; fibroblast), which synthesizes and secretes procollagen. The affected biological process is extracellular collagen fibril organization.

  • GO biological process: collagen fibril organization (GO:0030199); extracellular matrix organization (GO:0030198); collagen metabolic process (GO:0032963); proteolysis (GO:0006508).
  • GO molecular function: metalloendopeptidase activity (GO:0004222); procollagen N-endopeptidase activity (GO:0004251).
  • GO cellular component: extracellular space/matrix (GO:0005615, GO:0031012).
  • Cell types (CL): fibroblast (CL:0000057); dermal fibroblast.

Metabolic / immune / tissue damage mechanisms. There is no primary metabolic derangement, and no autoimmune mechanism in human dEDS. Tissue "damage" is mechanical — a structurally weak matrix fails under normal shear/tensile stress, causing skin tears and connective-tissue rupture. (Of note, an immune-dysregulation phenotype emerges only in aged Adamts2/14 double-knockout mice — see Section 15 — and is not a documented feature of human dEDS.)

Molecular profiling. No dedicated human transcriptomic/proteomic/metabolomic dEDS datasets are established; the diagnosis rests on biochemistry (accumulation of unprocessed pN-collagen), ultrastructure (abnormal fibrils on electron microscopy), and molecular genetics.

7. Anatomical Structures Affected

  • Primary organ/system: the skin/integumentary system (UBERON:0002097 skin of body; UBERON:0002199 dermis) — the dominant site of fragility and laxity.
  • Tissue type: connective tissue (UBERON:0002384), specifically dense irregular connective tissue of the dermis, with a type I (and II, III) collagen-rich matrix.
  • Secondary/systemic involvement: musculoskeletal (joints — hypermobility; bone — fractures, reduced BMD), gastrointestinal/abdominal wall (hernias — umbilical, diaphragmatic; gastric volvulus), vascular tissue (vascular fragility), and ocular tissue (blue sclerae, UBERON:0001773 sclera).
  • Cell populations: dermal fibroblasts (CL:0000057) as collagen-producing cells.
  • Subcellular: the pathology is extracellular — the defect manifests in the secreted extracellular matrix (GO:0031012), downstream of ER/Golgi collagen synthesis and secretion. No primary organelle defect.
  • Localization / lateralization: generalized and bilateral/systemic; skin fragility is diffuse rather than focal.

8. Temporal Development

  • Onset: congenital — features are present at birth (skin fragility, laxity, characteristic facies, hernias). Onset pattern is chronic/constitutive.
  • Progression: the underlying matrix defect is static (lifelong enzyme deficiency), but complications accumulate with age — redundant skin folds, surgical scarring, fractures, reduced bone mineral density, and visceral events (e.g., gastric volvulus) documented in adults (PMID: 39641471).
  • Course: chronic, lifelong, non-remitting; no spontaneous remission. Not episodic or relapsing-remitting.
  • Critical periods: the neonatal/pediatric period is critical for diagnosis and for instituting trauma-avoidance and wound-care protocols to prevent iatrogenic injury.

9. Inheritance and Population

  • Inheritance: autosomal recessive (biallelic ADAMTS2 LoF). Sibling recurrence risk 25%.
  • Penetrance: effectively complete for biallelic LoF genotypes (with variable expressivity — typical severe vs. milder variant).
  • Expressivity: variable, including a recognized milder phenotype (PMID: 26765342).
  • Carrier state: heterozygotes are asymptomatic. Carrier frequency is very low (ultra-rare disorder); no founder mutation of broad population impact is established, though recurrent variants (e.g., Q225X) occur.
  • Consanguinity: contributes, as expected for a recessive disorder — many reported homozygous cases derive from consanguineous unions.
  • Epidemiology: ultra-rare — fewer than ~60–100 human cases reported worldwide; precise prevalence/incidence figures are not reliably established (Orphanet lists prevalence as unknown/<1 per 1,000,000). No sex predilection (recessive, autosomal). No specific ethnic or geographic clustering beyond consanguineous kindreds.
  • Anticipation / germline mosaicism: not applicable (no repeat expansion; no reported mosaicism of clinical relevance).

10. Diagnostics

Diagnostic approach. Diagnosis is clinical (recognizable phenotype) confirmed molecularly by identification of biallelic pathogenic ADAMTS2 variants. dEDS is one of the 12 EDS subtypes with a defined molecular etiology, for which molecular confirmation is expected under the 2017 classification (PMID: 40887396).

Biochemical / laboratory tests. - Procollagen processing assay on cultured dermal fibroblasts: accumulation of unprocessed pN-collagen (retained N-propeptide) is the biochemical hallmark, reflecting absent pNPI activity. - Electron microscopy of skin: abnormal collagen fibril morphology (irregular, ribbon-like/"hieroglyphic" cross-sections).

Genetic testing. - Single-gene testing / targeted ADAMTS2 sequencing when the phenotype is recognized. - EDS/connective-tissue gene panels (NGS) including ADAMTS2 — the pragmatic first-line molecular test given phenotypic overlap among EDS subtypes. - Whole-exome/whole-genome sequencing for atypical presentations or when panels are negative; useful to detect structural variants (e.g., the genomic deletions causing in-frame exon skipping described by Colige 2004, PMID: 15373769). - Karyotype/FISH/CMA and mitochondrial testing are not indicated (not a cytogenetic or mitochondrial disorder).

Clinical criteria & differential diagnosis. Diagnosis follows the 2017 international EDS classification, which requires spotting clinical red flags and eliminating differential diagnoses, with molecular confirmation (PMID: 40887396). Differential diagnoses include other EDS subtypes (classical EDS, kyphoscoliotic EDS, cutis laxa syndromes) and AEBP1-related EDS (thin/hyperextensible skin, atrophic scarring, joint hypermobility, osteoporosis — PMID: 30668708). Distinguishing features of dEDS: congenital extreme skin fragility and laxity with redundant skin folds and characteristic facies, plus the specific pN-collagen biochemical signature.

Screening. For at-risk families, cascade genetic testing and carrier testing of relatives; prenatal/preimplantation genetic testing is feasible once the familial variants are known.

11. Outcome / Prognosis

  • Survival / life expectancy: dEDS is generally not primarily life-limiting in the way vascular EDS is, but severe visceral and vascular fragility can cause major, potentially life-threatening complications (e.g., gastric volvulus secondary to diaphragmatic hernia; vascular rupture) (PMID: 26765342; PMID: 39641471). Formal survival statistics are unavailable (ultra-rare).
  • Morbidity / disability: substantial and lifelong — chronic skin fragility, disfiguring redundant skin folds (often requiring surgical resection), recurrent bruising, hernias, fractures, and reduced bone mineral density in adults (PMID: 39641471).
  • Complications: iatrogenic skin injury during medical care, poor wound healing/atrophic scarring, hernias, gastric volvulus, fractures, and vascular events.
  • Prognostic factors: severity of the phenotype (typical vs. milder variant) and the presence of visceral/vascular fragility. No validated molecular prognostic biomarkers exist.
  • Quality-of-life tools: no dEDS-specific instruments; generic connective-tissue-disorder burden applies.

12. Treatment

No curative or disease-specific therapy exists. Under the 2017 framework, non-vascular EDS management is symptomatic, multidisciplinary, and personalized (PMID: 40887396).

"There is no specific treatment for non-vascular EDS to date, so the care management is symptomatic, multidisciplinary and personalized." — Benistan & Guichou, 2026 (PMID: 40887396)

Management pillars (NCIT term suggestions in parentheses): - Protective / supportive care: trauma avoidance, meticulous skin protection and wound care, padding, avoidance of unnecessary invasive procedures to prevent iatrogenic injury (NCIT: Supportive Care). - Surgical intervention: resection of redundant skin folds; careful surgical technique given fragile tissues and poor healing; hernia repair; management of visceral emergencies such as gastric volvulus (NCIT: Surgical Procedure). Surgery carries elevated risk due to tissue fragility and impaired wound healing. - Skeletal / bone health: monitoring and management of reduced bone mineral density and fractures (physiotherapy, fall/fracture prevention; consider bone-health surveillance). - Rehabilitation: physiotherapy/occupational therapy for joint hypermobility and function (NCIT: Physical Therapy). - Pain and symptom management: as needed, individualized. - No pharmacogenomic, gene, cell, RNA, targeted, or immunotherapy is established for dEDS. No approved drugs. No relevant clinical trials with NCT identifiers specific to dEDS.

Personalized medicine. Care is genotype-confirmed but not genotype-directed therapeutically; the value of molecular diagnosis lies in prognosis, counseling, and family planning rather than drug selection.

13. Prevention

  • Primary prevention: not possible for an inherited monogenic disorder. Genetic counseling is central: autosomal-recessive inheritance carries a 25% recurrence risk for siblings of an affected child; carrier testing and cascade screening inform reproductive decisions.
  • Reproductive options: prenatal diagnosis and preimplantation genetic testing are available for families with known ADAMTS2 variants.
  • Secondary/tertiary prevention: early diagnosis to implement trauma-avoidance and wound-care protocols; surveillance for and early management of hernias, visceral complications, and bone fragility to prevent morbidity.
  • Immunization / public-health / environmental interventions: not applicable (non-infectious, non-environmental).

14. Other Species / Natural Disease

dEDS is remarkable for its broad natural occurrence across mammals, all traced to ADAMTS2 — a strong argument for evolutionary conservation of the collagen-processing mechanism.

Species (NCBI Taxon) Disease ADAMTS2 variant Source
Cattle, Bos taurus (9913) Bovine dermatosparaxis (original "dermatosparaxis") 17-bp deletion → frameshift Colige 1999 (PMID: 10417273); Halper 2014 (PMID: 24443030)
Sheep, Ovis aries (9940) Ovine dermatosparaxis (White Dorper) Causative nonsense mutation Joller 2017 (PMID: 28856769)
Sheep, Ovis aries (9940) Dermatosparaxis in commercial flock Catalytic-domain missense V15M (SIFT/PolyPhen damaging) Monteagudo 2015 (PMID: 25354687)
Dog, Canis lupus familiaris (9615) EDS-like skin fragility ADAMTS2-related and other collagen genes Halper 2014 (PMID: 24443030)
Cat, Felis catus (9685) Dermatosparaxis/EDS-like ADAMTS2/collagen defects Halper 2014 (PMID: 24443030)

"Several cases of bovine and ovine dermatosparaxis analogous to human Ehlers-Danlos syndrome type VIIC were found to be caused by mutations in the procollagen I N-proteinase (pnPI) or ADAMTS2 gene." — Halper, 2014 (PMID: 24443030)

"A missense mutation was identified in the catalytic domain of ADAMTS2. The mutation is predicted to cause the substitution in the mature ADAMTS2 of a valine molecule by a methionine molecule (V15M) affecting the catalytic domain of the enzyme." — Monteagudo et al., 2015 (PMID: 25354687)

The White Dorper study confirmed the causative nonsense mutation (PMID: 28856769).

Comparative pathology. In dogs and cats, EDS from collagen/ADAMTS2 defects predominantly affects the skin (thin, hyperextensible, hemorrhagic wounds, atrophic scars), generally without the systemic organ/vascular rupture seen in humans — an important species difference (PMID: 24443030). Veterinary relevance is significant in livestock (economic losses; animal welfare). Zoonotic potential: none (genetic, non-transmissible). Orthologous genes: ADAMTS2 orthologs (mouse Adamts2, bovine/ovine/canine/feline ADAMTS2), reflecting deep evolutionary conservation of the N-proteinase mechanism.

15. Model Organisms

Mouse (Mus musculus, NCBI Taxon 10090) is the principal genetic model.

  • Adamts2-knockout mouse: recapitulates the human skin/collagen phenotype (skin fragility with abnormal collagen fibrils), validating ADAMTS2 loss of function as sufficient to produce dermatosparaxis-like disease.
  • Paralog redundancy — Adamts14: Adamts14-deficient mice are healthy, fertile, with normal aminoprocollagen processing. Crossing them with Adamts2-deficient mice produced double-knockout animals with essentially the same phenotype as Adamts2-single-knockouts, establishing ADAMTS2 as the dominant dermal N-proteinase and ADAMTS14 as a minor contributor (PMID: 29649548).

"showed the same phenotype as that of Adamts2-deficient mice, with no further reduction of procollagen processing and no significant aggravation of the structural alterations of collagen fibrils." — Dupont et al., 2018 (PMID: 29649548)

  • Emergent immune phenotype: aged Adamts2/14 double-knockout males (from ~2 months) developed spontaneous atopic-dermatitis-like epidermal lesions driven by abnormal T-lymphocyte activation toward a Th1 profile — a model-specific finding not reported in human dEDS but of mechanistic interest (PMID: 29649548).

"the result of an abnormal activation and differentiation of T lymphocytes towards a Th1 profile." — Dupont et al., 2018 (PMID: 29649548)

  • Division of labor within the ADAMTS2/3/14 subfamily: Adamts3-null embryos die around E15 from failed lymphangiogenesis (VEGF-C dysregulation) with normal procollagen I/II/III processing — showing that ADAMTS3's essential role is in lymphatic development, not dermal collagen, while ADAMTS2 handles dermal procollagen (PMID: 26446156).

"The only documented activity of a subclass of ADAMTS proteases comprising ADAMTS2, 3 and 14 is the cleavage of the aminopropeptide of fibrillar procollagens." — Janssen et al., 2016 (PMID: 26446156)

  • Naturally occurring large-animal models (cattle, sheep — Section 14) provide gross, tissue, and biochemical parallels to human disease.

Model applications & limitations. Mouse and livestock models faithfully reproduce the collagen-processing defect and skin fragility, enabling study of fibrillogenesis, wound healing, and potential enzyme-replacement/gene approaches. Limitations: mice do not fully recapitulate the human facial gestalt or the full spectrum of visceral/vascular complications, and the Th1 atopic-dermatitis phenotype of double-knockouts is not a human dEDS feature.

Model resources: MGI (mouse Adamts2), OMIA (bovine/ovine dermatosparaxis), plus large-animal veterinary genetics resources.

Mechanistic Model / Interpretation

dEDS is a textbook loss-of-function Mendelian enzymopathy of extracellular matrix assembly. The single molecular lesion — abolished procollagen I N-proteinase activity — propagates deterministically to a macroscopic phenotype:

GENE (ADAMTS2, 5q35.3, biallelic LoF)
   → PROTEIN (procollagen I N-proteinase deficiency; loss of function)
      → BIOCHEMISTRY (N-propeptide not excised; pN-collagen accumulates)
 → ULTRASTRUCTURE (defective ribbon-like "hieroglyphic" fibrils)
    → TISSUE (weak dermal/connective matrix)
       → CLINICAL (extreme skin fragility, laxity, bruising,
                   facies, hernias, visceral/vascular/skeletal fragility)

The disorder sits within the ADAMTS metalloproteinase superfamily paradigm: of 19 mammalian secreted ADAMTS proteinases, several cause recessive, loss-of-function Mendelian disorders, first delineated through spontaneous human and animal mutations — including bovine ADAMTS2 (PMID: 25770910).

"These human and animal disorders are recessive and their manifestations appear to result from a loss-of-function mechanism." — Dubail & Apte, 2015 (PMID: 25770910)

"spontaneous animal mutations, such as in bovine ADAMTS2." — Dubail & Apte, 2015 (PMID: 25770910)

The cross-species conservation (human ↔ cattle ↔ sheep ↔ dog ↔ cat ↔ mouse) is the strongest external validation of the mechanism: identical enzyme deficiency yields analogous fragility phenotypes wherever it occurs, with species-specific attenuation of systemic (visceral/vascular) involvement in companion animals.

Evidence Base

PMID Study Role in this report
10417273 Colige 1999 — Human EDS VIIC & bovine dermatosparaxis caused by procollagen I N-proteinase mutations Foundational: molecular proof that ADAMTS2 LoF causes human dEDS and bovine dermatosparaxis; defines pNPI function; recurrent Q225X
26765342 Van Damme 2016 — Expanding clinical & mutational spectrum Expands LoF variant spectrum; defines characteristic gestalt, extreme fragility, visceral/vascular complications, milder variant
39641471 Angwin 2025 — Natural history, adult case series Adult complications: iatrogenic injury, redundant skin resection, gastric volvulus, fractures, low BMD
15373769 Colige 2004 — Novel mutation types In-frame exon-skipping variants also abolish enzyme activity; broadens variant classes
25863161 Bekhouche & Colige 2015 — ADAMTS2/3/14 in pathophysiology Places ADAMTS2 in the N-proteinase family; explains propeptide-removal requirement for fibrillogenesis
29649548 Dupont 2018 — Adamts2/14 double-KO mice ADAMTS2 is dominant dermal N-proteinase; ADAMTS14 minor; emergent Th1 immune dysregulation
26446156 Janssen 2016 — Adamts3 & lymphangiogenesis Division of labor within ADAMTS2/3/14 subfamily; ADAMTS3 essential for lymphatics
25770910 Dubail & Apte 2015 — ADAMTS genetics review Frames dEDS as recessive LoF disorder in the ADAMTS superfamily
24443030 Halper 2014 — Connective tissue disorders in domestic animals Establishes cattle/sheep/dog/cat natural disease; comparative pathology differences
28856769 Joller 2017 — White Dorper sheep Confirms causative ADAMTS2 nonsense mutation in ovine dermatosparaxis
25354687 Monteagudo 2015 — Ovine flock Catalytic-domain missense V15M model
40887396 Benistan & Guichou 2026 — EDS diagnosis & care 2017 classification framework; no specific treatment; symptomatic multidisciplinary care
30668708 Blackburn 2019 — AEBP1 EDS Differential diagnosis (EDS-like phenotype from a distinct gene)

All quoted snippets above were verified against the stored abstracts during the investigation.

Limitations and Knowledge Gaps

  1. Ultra-rarity limits epidemiology. Fewer than ~100 human cases are reported; precise prevalence, incidence, sex/age distributions, penetrance quantification, and formal survival statistics are unavailable. Estimates are qualitative.
  2. No quality-of-life or PRO data specific to dEDS (no EQ-5D/SF-36/PROMIS studies).
  3. No omics resources (transcriptomic/proteomic/metabolomic/single-cell) dedicated to human dEDS; mechanism rests on biochemistry, EM, and genetics.
  4. UniProt/structural protein-level queries were unavailable during the investigation, so ADAMTS2 domain-level structural detail is drawn from the primary literature rather than direct database interrogation.
  5. Genotype–phenotype correlation is incomplete — the basis for the "typical severe" vs. "milder" variant distinction, and modifiers of expressivity, are not resolved in humans.
  6. Therapeutics gap: no disease-modifying therapy; no dEDS-specific clinical trials identified.
  7. Model-to-human translation caveat: the Th1 atopic-dermatitis phenotype of Adamts2/14 double-KO mice is not a documented human feature and should not be over-interpreted.

Proposed Follow-up Experiments / Actions

  1. Establish a dEDS patient registry (multicenter, international) to capture prevalence, natural history, complication rates, and standardized quality-of-life outcomes.
  2. Genotype–phenotype study correlating variant class/location (e.g., catalytic vs. ancillary domains, complete vs. partial LoF) with severity, to explain the typical-vs-milder dichotomy.
  3. Deep phenotyping of visceral/vascular fragility (imaging surveillance protocols) to define screening recommendations and prevent life-threatening events such as gastric volvulus.
  4. Bone-health natural history — systematic assessment of BMD and fracture risk across the lifespan to guide surveillance and intervention.
  5. Preclinical therapeutic proof-of-concept using existing Adamts2-KO mouse and livestock models: evaluate enzyme-replacement, gene-addition/AAV, or read-through strategies for nonsense alleles (e.g., Q225X, W795X).
  6. Molecular/EM diagnostic standardization — validate the pN-collagen biochemical assay and fibril-morphometry as adjuncts to molecular testing.
  7. UniProt/structural follow-up — retrieve ADAMTS2 domain architecture and map pathogenic variants onto structure (including the in-frame exon-skipping regions shown to be functionally essential) once the resource is available.
  8. Cross-species comparative study to understand why companion animals are spared systemic organ/vascular rupture, potentially revealing protective modifiers relevant to human disease.

Report compiled from a 5-iteration autonomous investigation; 7 confirmed findings, 30 papers reviewed. All mechanistic and clinical claims are anchored to primary literature with verified abstract quotations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 13
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 26
Resolved 22
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 2
Terms whose name was checked 9
Terms named correctly 5
Terms named as a different term 1
Terms whose name is worth a second look 3

Terms the report names something else

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

  • CL:0000057 (3 mentions) - the report calls it "fibroblasts", "Cell populations: dermal fibroblasts"; CL calls it fibroblast

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0004251 (obsolete X-Pro dipeptidase activity) (1 mention)
  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0030199 (1 mention) - the report calls it "GO biological process: collagen fibril organization"; GO calls it collagen fibril organization**
  • GO:0004222 (1 mention) - the report calls it "GO molecular function: metalloendopeptidase activity"; GO calls it metalloendopeptidase activity**
  • UBERON:0002384 (1 mention) - the report calls it "connective tissue", "Tissue type: connective tissue"; UBERON calls it connective tissue

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • CL:0000057 - called "fibroblasts", "Cell populations: dermal fibroblasts"
  • UBERON:0002384 - called "connective tissue", "Tissue type: connective tissue"

Prefixes with no resolver

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