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Definitions

1

2016 revised clinical diagnostic criteria for dermatosparaxis EDS

The 1997 Villefranche criteria were drawn from initial observations in a small number of patients and had not been revisited since. Table 2 of the 2016 series proposes four major criteria. Severe skin fragility and sagging, redundant skin carry over unchanged from Villefranche; bruising easily is promoted from the Villefranche minor list to major; and a typical facial gestalt - congenital and/or postnatal, progressive, comprising periorbital soft-tissue swelling, blue sclerae, down-slanting palpebral fissures, epicanthic folds, micrognathia, delayed fontanel closure and dental anomalies - is added as a fourth major criterion. The minor list is replaced rather than extended. Postnatal growth restriction, short limbs/hands/feet, joint hypermobility and visceral/vascular fragility are new criteria with no Villefranche antecedent; umbilical hernia narrows the Villefranche criterion "large hernias (umbilical, inguinal)"; and two Villefranche minor criteria, soft doughy skin texture and premature rupture of fetal membranes, are dropped.

DIAGNOSTIC_CRITERIA Proposed update to the 1997 Villefranche criteria, given in Table 2 of the 2016 five-patient case series

Proposed updated major criteria

The four major criteria of the 2016 proposed updated set (Table 2). The source states no minimum count, so minimum_required is deliberately left unset.

Core clinical characteristics

Severe skin fragility
Sagging, redundant skin
Bruising easily Promoted from a Villefranche minor criterion to a major criterion in the 2016 proposed set.
Typical facial gestalt, congenital and/or postnatal, progressive (periorbital soft-tissue swelling, blue sclerae, down-slanting palpebral fissures, epicanthic folds, micrognathia, delayed fontanel closure, dental anomalies) Left unbound. The criterion is a composite gestalt of seven separately codeable findings rather than a single phenotype, and no HP term names the composite. Three of its components - blue sclerae, micrognathia and delayed fontanel closure - are bound individually in this entry's phenotypes.

Show evidence (1 reference)

PMID:26765342 SUPPORT Human Clinical

"Typical facial gestalt, congenital and/or postnatal, progressive, with swelling of the periorbital soft tissues, blue sclerae, down-slanting palpebral fissures, epicanthic folds, micrognathia, delayed fontanel closure, and dental anomalies"

The fourth major criterion of the proposed updated set, quoted from the Table 2 major-criteria column.

Proposed updated minor criteria

The five minor criteria of the 2016 proposed updated set (Table 2). Four are new; umbilical hernia narrows a Villefranche criterion. The source states no minimum count.

Core clinical characteristics

Postnatal growth restriction
Short limbs, hands, and feet
Joint hypermobility
Umbilical hernia Narrowed from the Villefranche criterion "Large hernias (umbilical, inguinal)".
Visceral and vascular fragility, congenital or postnatal Left unbound. The criterion covers fragility of two distinct organ systems and no single HP term names it.

Show evidence (1 reference)

PMID:26765342 SUPPORT Human Clinical

"Visceral and vascular fragility, congenital or postnatal"

One of the five minor criteria of the proposed updated set, quoted from the Table 2 minor-criteria column.

Show evidence (1 reference)

PMID:26765342 SUPPORT Human Clinical

"The current criteria, established in 1997 ... were based on initial observations in a few patients, but these are no longer up-to-date with current knowledge."

States why the case series proposed a revised criteria set.

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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. A 2022 canine report (see animal_models) adds a cross-species data point without settling the question. Six dogs homozygous for a truncating ADAMTS2 allele were all euthanized for severe skin fragility by 13 weeks of age, while a dog homozygous for a distinct catalytic-domain missense allele survived at least nine years with a milder course - superficially the same allele-class-versus-severity pattern seen in the human series. But the paper is explicit that this is not a controlled comparison: the truncating-allele puppies were euthanized at owner discretion once fragility became apparent, so whether they would have gone on to a longer, milder course like the missense dog is unknown. The ascertainment candidate explanation above therefore has a direct veterinary analogue, not just a human one.

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

Mechanism confidence: Established

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

Genetic context ADAMTS2 hgnc:218 functional_impact_category: LOSS_OF_FUNCTION

procollagen I N-proteinase activity GO:0004222 ⇓ LOSS OF FUNCTION

Animal models

Ovine ADAMTS2 catalytic-domain missense model (V15M) Sheep recapitulates A catalytic-domain missense allele, complementing the null alleles carried by the bovine and mouse models. The source does not claim priority for it, so none is asserted here.

Dermatosparactic White Dorper sheep (ADAMTS2 nonsense allele) Sheep recapitulates A naturally occurring ovine ADAMTS2 nonsense allele, independently confirming loss-of-function ADAMTS2 mutation as causative outside the bovine and canine truncating-allele models.

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

Mechanism confidence: Established

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 ⇓ LOSS OF FUNCTION collagen biosynthetic process GO:0032964 ⚠ 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

Mechanism confidence: Established

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 ⚠ ABNORMAL extracellular matrix organization GO:0030198 ⚠ ABNORMAL

dermis UBERON:0002067

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.

Canine dermatosparaxis (ADAMTS2 c.10delC truncating allele) Dog recapitulates Post-mortem dermal, tendon, and ligament collagen from affected puppies showed the same abnormal fibril cross-sectional ultrastructure as the human and bovine disease, extending the ultrastructural phenotype beyond dermis to tendon and ligament.

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

Mechanism confidence: Established

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 ⚠ ABNORMAL

skin of body UBERON:0002097

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

Mechanism confidence: Established

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 ⚠ 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.

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Phenotypes

15

Blood 2

Excessive Bruising FREQUENT Bruising susceptibility HP:0000978

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

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.

Digestive 1

Umbilical Hernia VERY_FREQUENT HP:0001537

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.

Eye 1

Blue Sclerae VERY_FREQUENT HP:0000592

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

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

Show evidence (1 reference)

PMID:1403389 SUPPORT Human Clinical

"blue sclerae, micrognathia, and umbilical hernia"

Names micrognathia in the original human clinical description.

Integument 4

Extreme Skin Fragility VERY_FREQUENT Fragile skin HP:0001030

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

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.

Soft Doughy Skin Texture VERY_FREQUENT Soft skin HP:0000977

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.

Atrophic Scarring FREQUENT Atrophic scars HP:0001075

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

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 3

Joint Hypermobility FREQUENT HP:0001382

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.

Fractures OCCASIONAL Increased susceptibility to fractures HP:0002659

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

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.

Growth 1

Postnatal Growth Failure VERY_FREQUENT Short stature HP:0004322

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.

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Genetic Associations

1

ADAMTS2

Gene: ADAMTS2 hgnc:218 gene page 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.

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Variants

1

In-frame exon-skipping genomic deletions (exons 3-5, exons 14-16) Pathogenic

Gene: ADAMTS2 hgnc:218 in-frame deletion (exon skipping)

A distinct allele class alongside the predominant truncating (nonsense/frameshift/splice) alleles. Genomic deletions remove exons 3-5 or exons 14-16 from the transcript without shifting the reading frame, so the resulting ADAMTS2 protein is missing an internal domain rather than being absent or grossly truncated. Neither deleted region had previously been recognised as functionally critical, but aminoprocollagen processing was still strongly impaired, so this class extends the requirement for intact enzyme structure beyond the domains already implicated by nonsense alleles.

Functional effects

procollagen I N-proteinase (aminoprocollagen) processing loss-of-function

Removing exons 3-5 or exons 14-16 leaves the reading frame intact, so the protein is internally shortened rather than truncated or absent, yet aminoprocollagen processing is still strongly impaired both in vitro and in vivo. The affected domains had not previously been recognised as crucial for ADAMTS-2 activity.

Show evidence (2 references)

PMID:15373769 SUPPORT Human Clinical

"The first patient was homozygous for a genomic deletion causing an in-frame skipping of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic deletion resulting in an..."

Reports both in-frame-skipping alleles - a homozygous exon 3-5 deletion in one patient, and a compound-heterozygous exon 14-16 deletion paired with an exon-3-loss nonsense allele in the second.

PMID:15373769 SUPPORT Human Clinical

"Although the exons 3-5 or 14-16 encode protein domains that have not been previously recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly impaired in vitro and in vivo, providing evidence for the requirement of these domains for proper enzyme function."

Establishes that this in-frame, non-truncating allele class still abolishes enzyme function, extending the functionally required region of ADAMTS2 beyond what nonsense alleles alone had implicated.

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Medical Actions

3

Skin Protection and Wound Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

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 procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

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 counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

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.

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Biochemical Markers

1

pNalpha1(I) and pNalpha2(I) procollagen accumulation in dermal fibroblasts (INCREASED)

Context: The biochemical hallmark of the disease and the basis of the collagen-processing diagnostic assay. Pulse-labelled fibrillar (pro)collagen chains secreted by cultured dermal fibroblasts are separated by SDS-PAGE and visualised by fluorography; because ADAMTS2 cannot excise the aminopropeptide, the pN-collagen bands accumulate while the fully processed pC-collagen and mature collagen bands are reduced or absent. This is a processing signature rather than a quantity signature - overall pepsin-digested collagen content is normal.

Pathograph Readouts

Readout Of Failure of Procollagen N-Propeptide Excision Positive Diagnostic

Direct biochemical demonstration, in patient-derived cells, of the unprocessed procollagen species that the enzymatic defect is predicted to leave behind.

Show evidence (1 reference)

PMID:26765342 SUPPORT Human Clinical

"Procollagen analysis showed the characteristic accu- mulation of the bands representing pNα 1(I) and pNα 2(I) procollagen chains, although the accumulation was variable between patients"

The biochemical finding in cultured dermal fibroblasts from the four patients who underwent skin biopsy - P2, P3, P4 and P5, who between them come from four unrelated families - and the direct evidentiary basis for the diagnostic collagen-processing assay.

Show evidence (2 references)

PMID:26765342 SUPPORT Human Clinical

"Procollagen analysis showed the characteristic accu- mulation of the bands representing pNα 1(I) and pNα 2(I) procollagen chains, although the accumulation was variable between patients"

Directly supports the pN-chain accumulation this marker is named for, and records that its magnitude varied between patients.

PMID:26765342 SUPPORT Human Clinical

"Sodium dodecyl sulfate-polyacrylamide analysis of pepsin- digested fibrillar collagens retained in the cells and secreted in the medium was normal in all affected siblings"

Scoped to the context claim rather than to the accumulation - total pepsin-digested fibrillar collagen was normal, which is what makes the defect qualitative (processing) rather than quantitative (synthesis).

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Diagnosis

3

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

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

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.

Coagulation Studies Can Be Normal Despite Clinically Significant Bleeding

Routine coagulation testing is not a reliable way to rule out or explain the bleeding complications seen in this disease, because the underlying defect is structural (connective-tissue and vascular fragility) rather than a disorder of the coagulation cascade itself. A negative coagulation workup should not be read as evidence against a bleeding complication being disease-related.

coagulation testing NCIT:C112239

Show evidence (1 reference)

PMID:42261541 SUPPORT Human Clinical

"Complete blood count, basic metabolic panel, lipid panel, and coagulation profile were normal. Factor assay and rotational thromboelastometry were within normal limits."

An adolescent with dEDS presenting with persistent hematemesis and mucocutaneous bleeding had entirely normal coagulation studies, including factor assay and rotational thromboelastometry, illustrating that a normal coagulation workup does not exclude disease-related bleeding.

📈

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.

📊

Related Datasets

1

A Patient-Analog Adamts2 Knock-In Murine Model Reveals Fibroblast-Centered Extracellular Matrix Failure in Dermatosparaxis Ehlers–Danlos Syndrome (dEDS) geo:GSE343646

Single-nucleus RNA sequencing and digital pathology of skin from a patient-analog Adamts2 Q226* knock-in mouse, the first genetically faithful (patient-allele) mouse model of dermatosparaxis EDS. Identifies dermal fibroblasts as the cell population most transcriptionally disrupted by ADAMTS2 loss and quantifies collagen architecture defects beyond what the earlier bovine, double-knockout mouse, and sheep models captured.

mouse SINGLE CELL RNA SEQ n=4

No associated peer-reviewed publication (PMID) was found for this 2026 GEO deposit at the time of curation; PubMed searches for the study title and the Adamts2 Q226* knock-in allele returned no hits. Cited here as a dataset record per the geo: reference workflow rather than as a full animal_models entry, since AnimalModel.publication requires a PMID. If a manuscript is later published, this dataset and its findings should be promoted to a full animal_models entry with modeled_mechanisms links.

Show evidence (2 references)

GEO:GSE343646 SUPPORT Model Organism

"we generated a patient-analog Adamts2Q226*/Q226* knock-in mouse model and used histologic, ultrastructural, biochemical, digital pathology, and single-nucleus transcriptomic approaches to define the consequences of ADAMTS2 loss in skin"

Establishes the model as carrying the actual patient nonsense allele (Q226*) rather than an engineered null, distinguishing it from the frameshift/deletion alleles in the calf and double-knockout mouse models already in this entry.

GEO:GSE343646 SUPPORT Model Organism

"Single-nucleus RNA sequencing identified fibroblasts as the cell population most strongly affected by Adamts2 deficiency, with coordinated downregulation of collagen, microfibrillar, and other ECM-associated genes."

Reports the study's central novel finding -- fibroblasts as the transcriptionally dominant affected cell population -- which is not established by any of the entry's existing animal models.

🐁

Animal Models

5

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.

Ovine ADAMTS2 catalytic-domain missense model (V15M)

A naturally occurring missense allele identified in a commercial sheep flock with clinical dermatosparaxis. Unlike the bovine and mouse models already in this entry, both of which are null alleles, this substitution falls within the catalytic domain itself, and its damaging effect is predicted computationally rather than shown by a direct enzymatic assay.

Species

Sheep

Genotype

ADAMTS2 p.Val15Met (catalytic-domain missense)

Publication

PMID:25354687

Pathograph links

Biallelic ADAMTS2 Loss of Function recapitulates fidelity: moderate A catalytic-domain missense allele, complementing the null alleles carried by the bovine and mouse models. The source does not claim priority for it, so none is asserted here.

Limitations: Pathogenicity rests on SIFT/PolyPhen-2 prediction and three-dimensional structural modelling rather than a measured enzymatic or fibril-ultrastructure readout, making this a weaker evidentiary class than the bovine and mouse models, both of which have direct biochemical or histological confirmation.

Readouts

In silico structural impact of the V15M substitution

Direction: ALTERED

Interpretation: A computational prediction that the substitution destabilises protein folding or distorts structure, rather than a measured functional consequence.

Show evidence (1 reference)

PMID:25354687 SUPPORT Computational

"Three-dimensional modelling suggested that this mutation may alter the stability of the protein folding or distort the structure, causing the protein to malfunction."

The computational structural prediction behind the pathogenicity call, since no direct enzymatic assay is reported for this allele.

Show evidence (1 reference)

PMID:25354687 SUPPORT Model Organism

"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."

Identifies the naturally occurring catalytic-domain missense allele in the affected sheep flock.

Canine dermatosparaxis (ADAMTS2 c.10delC truncating allele)

A naturally occurring truncating allele found in six Alapaha Blue Blood Bulldog and Pit Bull Terrier puppies, all euthanized for severe skin fragility by 13 weeks of age. The same report also describes an adult Catahoula Leopard Dog homozygous for a distinct catalytic-domain missense allele (p.Arg966His) with a much milder course, surviving at least 9 years -- a within-species severity contrast the paper itself declines to attribute conclusively to residual enzyme activity, since euthanasia timing for the truncating-allele puppies also reflected owner decision-making rather than a measured biological endpoint.

Species

Dog

Genotype

ADAMTS2 c.10delC, p.(Pro4ArgfsTer175), homozygous

Publication

PMID:36421833

Pathograph links

Hieroglyphic Collagen Fibril Assembly recapitulates fidelity: high Post-mortem dermal, tendon, and ligament collagen from affected puppies showed the same abnormal fibril cross-sectional ultrastructure as the human and bovine disease, extending the ultrastructural phenotype beyond dermis to tendon and ligament.

Limitations: The truncating-allele dogs were all euthanized in early puppyhood at owner discretion once skin fragility became apparent, so the natural adult course of this specific genotype is unknown; the paper explicitly states it is unclear whether these puppies would have eventually developed life-threatening injuries or continued to accrue manageable wounds. The milder missense-allele dog's long survival is presented as a plausible but unproven case for residual enzyme activity as a severity determinant.

Readouts

Dermal, tendon, and ligament collagen fibril ultrastructure

Direction: ALTERED

Interpretation: Direct ultrastructural confirmation of abnormal fibrillogenesis in a second connective-tissue compartment (tendon/ligament) beyond the dermis already characterized in the bovine model.

Show evidence (2 references)

PMID:36421833 SUPPORT Model Organism

"the dermal collagen fibrils of the affected puppies had curved linear profiles in cross-section"

The ultrastructural finding in dermis, described elsewhere in the paper as hieroglyphic-like.

+ 1 more reference

Show evidence (1 reference)

PMID:36421833 SUPPORT Model Organism

"Cross sections of collagen fibrils in post-mortem dermal tissues from 2 of these dogs showed hieroglyphic-like figures similar to those from cases of severe dermatosparaxis in other species."

Establishes this natural canine allele as a fourth species (alongside human, bovine, and ovine) reproducing the hieroglyphic fibril phenotype.

Reported by the same group that authored the sheep V15M report above. Genotyping of archived DNA found the truncating deletion allele at a frequency of 0.27 in a tested Alapaha Blue Blood Bulldog cohort, indicating the allele is not vanishingly rare within that breed.

Dermatosparactic White Dorper sheep (ADAMTS2 nonsense allele)

A naturally occurring ADAMTS2 nonsense allele reported in a White Dorper flock in Switzerland. It is a second, independent ovine allele alongside the V15M catalytic-domain missense model above, and a null rather than a missense one -- so the two together give a within-species contrast between a null allele and a catalytic-domain missense one.

Species

Sheep

Genotype

ADAMTS2 nonsense variant (zygosity not recorded in the available source)

Publication

PMID:28856769

Pathograph links

Biallelic ADAMTS2 Loss of Function recapitulates fidelity: unknown A naturally occurring ovine ADAMTS2 nonsense allele, independently confirming loss-of-function ADAMTS2 mutation as causative outside the bovine and canine truncating-allele models.

Limitations: No abstract is available for this record, so nothing beyond the title and indexed subject terms could be verified. No phenotypic, biochemical, or ultrastructural detail is recorded here, no evidence quote is attached to this link, and `fidelity` is left UNKNOWN rather than asserted. The breed-level phenotype is therefore not established from this entry's sources, and the link records only the causative allele class.

Notes

Carried at title-and-MeSH level only. `references_cache/PMID_28856769.md` has no abstract, so per the evidence SOP no snippet was manufactured from the title; the model is recorded with its limitation disclosed instead of being dropped, since the allele class it contributes is not otherwise represented in the ovine models here. Zygosity is unsourced. Dermatosparaxis EDS is autosomal recessive, so a homozygous nonsense genotype is the expected finding, but neither the title nor the indexed MeSH terms state it, so `genotype` records the allele class only rather than asserting a zygosity this entry's sources cannot support. Opposing view on record. PR #10177 deliberately omitted this model, on the grounds that a model with no quotable evidence should wait until someone can quote it. That argument is recorded here so a future curator can act on it by deleting this one list entry, rather than having to re-derive it.

{ }

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.
biochemical:
- name: pNalpha1(I) and pNalpha2(I) procollagen accumulation in dermal fibroblasts
  presence: INCREASED
  context: The biochemical hallmark of the disease and the basis of the collagen-processing
    diagnostic assay. Pulse-labelled fibrillar (pro)collagen chains secreted by cultured
    dermal fibroblasts are separated by SDS-PAGE and visualised by fluorography; because
    ADAMTS2 cannot excise the aminopropeptide, the pN-collagen bands accumulate while
    the fully processed pC-collagen and mature collagen bands are reduced or absent.
    This is a processing signature rather than a quantity signature - overall pepsin-digested
    collagen content is normal.
  readouts:
  - target: Failure of Procollagen N-Propeptide Excision
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Direct biochemical demonstration, in patient-derived cells, of the
      unprocessed procollagen species that the enzymatic defect is predicted to leave
      behind.
    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: Procollagen analysis showed the characteristic accu- mulation of the bands
        representing pNα 1(I) and pNα 2(I) procollagen chains, although the
        accumulation was variable between patients
      explanation: The biochemical finding in cultured dermal fibroblasts from the four
        patients who underwent skin biopsy - P2, P3, P4 and P5, who between them come from
        four unrelated families - and the direct evidentiary basis for the diagnostic
        collagen-processing assay.
  cell_types:
  - preferred_term: cultured dermal fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  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: Procollagen analysis showed the characteristic accu- mulation of the bands
      representing pNα 1(I) and pNα 2(I) procollagen chains, although the
      accumulation was variable between patients
    explanation: Directly supports the pN-chain accumulation this marker is named for, and
      records that its magnitude varied between 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: Sodium dodecyl sulfate-polyacrylamide analysis of pepsin- digested fibrillar
      collagens retained in the cells and secreted in the medium was normal in all affected
      siblings
    explanation: Scoped to the context claim rather than to the accumulation - total
      pepsin-digested fibrillar collagen was normal, which is what makes the defect
      qualitative (processing) rather than quantitative (synthesis).
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.
variants:
- name: In-frame exon-skipping genomic deletions (exons 3-5, exons 14-16)
  description: A distinct allele class alongside the predominant truncating (nonsense/frameshift/splice)
    alleles. Genomic deletions remove exons 3-5 or exons 14-16 from the transcript without shifting
    the reading frame, so the resulting ADAMTS2 protein is missing an internal domain rather than
    being absent or grossly truncated. Neither deleted region had previously been recognised as
    functionally critical, but aminoprocollagen processing was still strongly impaired, so this
    class extends the requirement for intact enzyme structure beyond the domains already implicated
    by nonsense alleles.
  gene:
    preferred_term: ADAMTS2
    term:
      id: hgnc:218
      label: ADAMTS2
  clinical_significance: PATHOGENIC
  type: in-frame deletion (exon skipping)
  functional_effects:
  - function: procollagen I N-proteinase (aminoprocollagen) processing
    description: >-
      Removing exons 3-5 or exons 14-16 leaves the reading frame intact, so the protein is
      internally shortened rather than truncated or absent, yet aminoprocollagen processing is
      still strongly impaired both in vitro and in vivo. The affected domains had not previously
      been recognised as crucial for ADAMTS-2 activity.
    type: loss-of-function
  evidence:
  - reference: PMID:15373769
    reference_title: Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos
      syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The first patient was homozygous for a genomic deletion causing an in-frame skipping
      of exons 3-5 in the transcript. In the second patient, the allele inherited from the mother
      lacks exon 3, generating a premature stop codon, whereas the paternal allele has a genomic
      deletion resulting in an in-frame skipping of exons 14-16 at the mRNA level.
    explanation: Reports both in-frame-skipping alleles - a homozygous exon 3-5 deletion in one
      patient, and a compound-heterozygous exon 14-16 deletion paired with an exon-3-loss nonsense
      allele in the second.
  - reference: PMID:15373769
    reference_title: Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos
      syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Although the exons 3-5 or 14-16 encode protein domains that have not been previously
      recognized as crucial for ADAMTS-2 activity, the aminoprocollagen processing was strongly
      impaired in vitro and in vivo, providing evidence for the requirement of these domains for
      proper enzyme function.
    explanation: Establishes that this in-frame, non-truncating allele class still abolishes enzyme
      function, extending the functionally required region of ADAMTS2 beyond what nonsense alleles
      alone had implicated.
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.
- name: Coagulation Studies Can Be Normal Despite Clinically Significant Bleeding
  description: >-
    Routine coagulation testing is not a reliable way to rule out or explain the bleeding
    complications seen in this disease, because the underlying defect is structural
    (connective-tissue and vascular fragility) rather than a disorder of the coagulation cascade
    itself. A negative coagulation workup should not be read as evidence against a bleeding
    complication being disease-related.
  diagnosis_term:
    preferred_term: coagulation testing
    term:
      id: NCIT:C112239
      label: Coagulation Index Measurement
  evidence:
  - reference: PMID:42261541
    reference_title: 'Exploring the Hemorrhagic Manifestations of an Adolescent With
      Dermatosparaxis-Type Ehlers-Danlos Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Complete blood count, basic metabolic panel, lipid panel, and coagulation profile
      were normal. Factor assay and rotational thromboelastometry were within normal limits.
    explanation: An adolescent with dEDS presenting with persistent hematemesis and mucocutaneous
      bleeding had entirely normal coagulation studies, including factor assay and rotational
      thromboelastometry, illustrating that a normal coagulation workup does not exclude
      disease-related bleeding.
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.
- name: Ovine ADAMTS2 catalytic-domain missense model (V15M)
  species: Sheep
  genotype: ADAMTS2 p.Val15Met (catalytic-domain missense)
  publication: PMID:25354687
  description: A naturally occurring missense allele identified in a commercial sheep flock with
    clinical dermatosparaxis. Unlike the bovine and mouse models already in this entry, both of
    which are null alleles, this substitution falls within the catalytic domain itself, and its
    damaging effect is predicted computationally rather than shown by a direct enzymatic assay.
  modeled_mechanisms:
  - target: Biallelic ADAMTS2 Loss of Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: A catalytic-domain missense allele, complementing the null alleles carried by the
      bovine and mouse models. The source does not claim priority for it, so none is asserted here.
    limitations: Pathogenicity rests on SIFT/PolyPhen-2 prediction and three-dimensional structural
      modelling rather than a measured enzymatic or fibril-ultrastructure readout, making this a
      weaker evidentiary class than the bovine and mouse models, both of which have direct
      biochemical or histological confirmation.
    readouts:
    - name: In silico structural impact of the V15M substitution
      target: Biallelic ADAMTS2 Loss of Function
      direction: ALTERED
      interpretation: A computational prediction that the substitution destabilises protein folding
        or distorts structure, rather than a measured functional consequence.
      evidence:
      - reference: PMID:25354687
        reference_title: In silico identification and three-dimensional modelling of the missense
          mutation in ADAMTS2 in a sheep flock with dermatosparaxis.
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: Three-dimensional modelling suggested that this mutation may alter the stability
          of the protein folding or distort the structure, causing the protein to malfunction.
        explanation: The computational structural prediction behind the pathogenicity call, since
          no direct enzymatic assay is reported for this allele.
    evidence:
    - reference: PMID:25354687
      reference_title: In silico identification and three-dimensional modelling of the missense
        mutation in ADAMTS2 in a sheep flock with dermatosparaxis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 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.
      explanation: Identifies the naturally occurring catalytic-domain missense allele in the
        affected sheep flock.
- name: Canine dermatosparaxis (ADAMTS2 c.10delC truncating allele)
  species: Dog
  genotype: ADAMTS2 c.10delC, p.(Pro4ArgfsTer175), homozygous
  publication: PMID:36421833
  description: >-
    A naturally occurring truncating allele found in six Alapaha Blue Blood
    Bulldog and Pit Bull Terrier puppies, all euthanized for severe skin
    fragility by 13 weeks of age. The same report also describes an adult
    Catahoula Leopard Dog homozygous for a distinct catalytic-domain missense
    allele (p.Arg966His) with a much milder course, surviving at least 9
    years -- a within-species severity contrast the paper itself declines to
    attribute conclusively to residual enzyme activity, since euthanasia
    timing for the truncating-allele puppies also reflected owner
    decision-making rather than a measured biological endpoint.
  modeled_mechanisms:
  - target: Hieroglyphic Collagen Fibril Assembly
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Post-mortem dermal, tendon, and ligament collagen from affected puppies showed
      the same abnormal fibril cross-sectional ultrastructure as the human and bovine disease,
      extending the ultrastructural phenotype beyond dermis to tendon and ligament.
    limitations: >-
      The truncating-allele dogs were all euthanized in early puppyhood at owner discretion once
      skin fragility became apparent, so the natural adult course of this specific genotype is
      unknown; the paper explicitly states it is unclear whether these puppies would have
      eventually developed life-threatening injuries or continued to accrue manageable wounds.
      The milder missense-allele dog's long survival is presented as a plausible but unproven
      case for residual enzyme activity as a severity determinant.
    readouts:
    - name: Dermal, tendon, and ligament collagen fibril ultrastructure
      target: Hieroglyphic Collagen Fibril Assembly
      direction: ALTERED
      interpretation: Direct ultrastructural confirmation of abnormal fibrillogenesis in a second
        connective-tissue compartment (tendon/ligament) beyond the dermis already characterized
        in the bovine model.
      evidence:
      - reference: PMID:36421833
        reference_title: Novel Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in
          Dogs with Dermatosparactic Ehlers-Danlos Syndrome.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: the dermal collagen fibrils of the affected puppies had curved linear profiles
          in cross-section
        explanation: The ultrastructural finding in dermis, described elsewhere in the paper as
          hieroglyphic-like.
      - reference: PMID:36421833
        reference_title: Novel Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in
          Dogs with Dermatosparactic Ehlers-Danlos Syndrome.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: the collagen fibrils in tendons and ligaments from the two affected puppies that
          were markedly smaller in diameter and irregularly shaped
        explanation: Extends the fibril-ultrastructure defect to tendon and ligament, tissues not
          examined in the other animal models in this entry.
    evidence:
    - reference: PMID:36421833
      reference_title: Novel Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in
        Dogs with Dermatosparactic Ehlers-Danlos Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Cross sections of collagen fibrils in post-mortem dermal tissues from 2 of these
        dogs showed hieroglyphic-like figures similar to those from cases of severe dermatosparaxis
        in other species.
      explanation: Establishes this natural canine allele as a fourth species (alongside human,
        bovine, and ovine) reproducing the hieroglyphic fibril phenotype.
  notes: >-
    Reported by the same group that authored the sheep V15M report above. Genotyping of archived
    DNA found the truncating deletion allele at a frequency of 0.27 in a tested Alapaha Blue Blood
    Bulldog cohort, indicating the allele is not vanishingly rare within that breed.
- name: Dermatosparactic White Dorper sheep (ADAMTS2 nonsense allele)
  species: Sheep
  genotype: ADAMTS2 nonsense variant (zygosity not recorded in the available source)
  publication: PMID:28856769
  description: >-
    A naturally occurring ADAMTS2 nonsense allele reported in a White Dorper
    flock in Switzerland. It is a second, independent ovine allele alongside the
    V15M catalytic-domain missense model above, and a null rather than a
    missense one -- so the two together give a within-species contrast between
    a null allele and a catalytic-domain missense one.
  modeled_mechanisms:
  - target: Biallelic ADAMTS2 Loss of Function
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    description: >-
      A naturally occurring ovine ADAMTS2 nonsense allele, independently
      confirming loss-of-function ADAMTS2 mutation as causative outside the
      bovine and canine truncating-allele models.
    limitations: >-
      No abstract is available for this record, so nothing beyond the title and
      indexed subject terms could be verified. No phenotypic, biochemical, or
      ultrastructural detail is recorded here, no evidence quote is attached to
      this link, and `fidelity` is left UNKNOWN rather than asserted. The
      breed-level phenotype is therefore not established from this entry's
      sources, and the link records only the causative allele class.
  notes: >-
    Carried at title-and-MeSH level only. `references_cache/PMID_28856769.md`
    has no abstract, so per the evidence SOP no snippet was manufactured from
    the title; the model is recorded with its limitation disclosed instead of
    being dropped, since the allele class it contributes is not otherwise
    represented in the ovine models here.

    Zygosity is unsourced. Dermatosparaxis EDS is autosomal recessive, so a
    homozygous nonsense genotype is the expected finding, but neither the title
    nor the indexed MeSH terms state it, so `genotype` records the allele class
    only rather than asserting a zygosity this entry's sources cannot support.

    Opposing view on record. PR #10177 deliberately omitted this model, on the
    grounds that a model with no quotable evidence should wait until someone can
    quote it. That argument is recorded here so a future curator can act on it by
    deleting this one list entry, rather than having to re-derive it.
definitions:
- name: 2016 revised clinical diagnostic criteria for dermatosparaxis EDS
  definition_type: DIAGNOSTIC_CRITERIA
  scope: Proposed update to the 1997 Villefranche criteria, given in Table 2 of the 2016 five-patient
    case series
  description: The 1997 Villefranche criteria were drawn from initial observations in a small
    number of patients and had not been revisited since. Table 2 of the 2016 series proposes four
    major criteria. Severe skin fragility and sagging, redundant skin carry over unchanged from
    Villefranche; bruising easily is promoted from the Villefranche minor list to major; and a
    typical facial gestalt - congenital and/or postnatal, progressive, comprising periorbital
    soft-tissue swelling, blue sclerae, down-slanting palpebral fissures, epicanthic folds,
    micrognathia, delayed fontanel closure and dental anomalies - is added as a fourth major
    criterion. The minor list is replaced rather than extended. Postnatal growth restriction,
    short limbs/hands/feet, joint hypermobility and visceral/vascular fragility are new criteria
    with no Villefranche antecedent; umbilical hernia narrows the Villefranche criterion "large
    hernias (umbilical, inguinal)"; and two Villefranche minor criteria, soft doughy skin texture
    and premature rupture of fetal membranes, are dropped.
  criteria_sets:
  - name: Proposed updated major criteria
    description: The four major criteria of the 2016 proposed updated set (Table 2). The source
      states no minimum count, so minimum_required is deliberately left unset.
    core_clinical_characteristics:
    - preferred_term: Severe skin fragility
      term:
        id: HP:0001030
        label: Fragile skin
      severity: SEVERE
    - preferred_term: Sagging, redundant skin
      term:
        id: HP:0001582
        label: Redundant skin
    - preferred_term: Bruising easily
      description: Promoted from a Villefranche minor criterion to a major criterion in the 2016
        proposed set.
      term:
        id: HP:0000978
        label: Bruising susceptibility
    - preferred_term: Typical facial gestalt, congenital and/or postnatal, progressive (periorbital
        soft-tissue swelling, blue sclerae, down-slanting palpebral fissures, epicanthic folds,
        micrognathia, delayed fontanel closure, dental anomalies)
      description: Left unbound. The criterion is a composite gestalt of seven separately codeable
        findings rather than a single phenotype, and no HP term names the composite. Three of its
        components - blue sclerae, micrognathia and delayed fontanel closure - are bound
        individually in this entry's phenotypes.
    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: Typical facial gestalt, congenital and/or postnatal, progressive, with swelling of the
        periorbital soft tissues, blue sclerae, down-slanting palpebral fissures, epicanthic folds,
        micrognathia, delayed fontanel closure, and dental anomalies
      explanation: The fourth major criterion of the proposed updated set, quoted from the Table 2
        major-criteria column.
  - name: Proposed updated minor criteria
    description: The five minor criteria of the 2016 proposed updated set (Table 2). Four are new;
      umbilical hernia narrows a Villefranche criterion. The source states no minimum count.
    core_clinical_characteristics:
    - preferred_term: Postnatal growth restriction
      term:
        id: HP:0004322
        label: Short stature
    - preferred_term: Short limbs, hands, and feet
      term:
        id: HP:0009826
        label: Limb undergrowth
    - preferred_term: Joint hypermobility
      term:
        id: HP:0001382
        label: Joint hypermobility
    - preferred_term: Umbilical hernia
      description: Narrowed from the Villefranche criterion "Large hernias (umbilical, inguinal)".
      term:
        id: HP:0001537
        label: Umbilical hernia
    - preferred_term: Visceral and vascular fragility, congenital or postnatal
      description: Left unbound. The criterion covers fragility of two distinct organ systems and
        no single HP term names it.
    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: Visceral and vascular fragility, congenital or postnatal
      explanation: One of the five minor criteria of the proposed updated set, quoted from the
        Table 2 minor-criteria column.
  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 current criteria, established in 1997 ... were based on initial observations
      in a few patients, but these are no longer up-to-date with current knowledge.
    explanation: States why the case series proposed a revised criteria set.
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.

    A 2022 canine report (see animal_models) adds a cross-species data point without settling the question.
    Six dogs homozygous for a truncating ADAMTS2 allele were all euthanized for severe skin fragility by 13
    weeks of age, while a dog homozygous for a distinct catalytic-domain missense allele survived at least
    nine years with a milder course - superficially the same allele-class-versus-severity pattern seen in the
    human series. But the paper is explicit that this is not a controlled comparison: the truncating-allele
    puppies were euthanized at owner discretion once fragility became apparent, so whether they would have
    gone on to a longer, milder course like the missense dog is unknown. The ascertainment candidate explanation
    above therefore has a direct veterinary analogue, not just a human one.'
  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].'
- reference: PMID:15373769
  title: Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type
    VIIC) and common polymorphisms in the ADAMTS2 gene.
- reference: PMID:25354687
  title: In silico identification and three-dimensional modelling of the missense mutation in ADAMTS2 in
    a sheep flock with dermatosparaxis.
- reference: PMID:28856769
  title: 'Dermatosparaxis in White Dorper sheep: confirmation of a causative nonsense mutation in ADAMTS2.'
- reference: PMID:36421833
  title: Novel Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in Dogs with Dermatosparactic
    Ehlers-Danlos Syndrome.
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
datasets:
- accession: geo:GSE343646
  title: "A Patient-Analog Adamts2 Knock-In Murine Model Reveals Fibroblast-Centered Extracellular Matrix Failure in Dermatosparaxis Ehlers–Danlos Syndrome (dEDS)"
  description: >-
    Single-nucleus RNA sequencing and digital pathology of skin from a
    patient-analog Adamts2 Q226* knock-in mouse, the first genetically
    faithful (patient-allele) mouse model of dermatosparaxis EDS. Identifies
    dermal fibroblasts as the cell population most transcriptionally
    disrupted by ADAMTS2 loss and quantifies collagen architecture defects
    beyond what the earlier bovine, double-knockout mouse, and sheep models
    captured.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 4
  genes:
  - preferred_term: ADAMTS2
    term:
      id: hgnc:218
      label: ADAMTS2
  evidence:
  - reference: GEO:GSE343646
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we generated a patient-analog Adamts2Q226*/Q226* knock-in mouse model and used histologic, ultrastructural, biochemical, digital pathology, and single-nucleus transcriptomic approaches to define the consequences of ADAMTS2 loss in skin"
    explanation: Establishes the model as carrying the actual patient nonsense allele (Q226*) rather than an engineered null, distinguishing it from the frameshift/deletion alleles in the calf and double-knockout mouse models already in this entry.
  - reference: GEO:GSE343646
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Single-nucleus RNA sequencing identified fibroblasts as the cell population most strongly affected by Adamts2 deficiency, with coordinated downregulation of collagen, microfibrillar, and other ECM-associated genes."
    explanation: Reports the study's central novel finding -- fibroblasts as the transcriptionally dominant affected cell population -- which is not established by any of the entry's existing animal models.
  notes: >-
    No associated peer-reviewed publication (PMID) was found for this 2026
    GEO deposit at the time of curation; PubMed searches for the study title
    and the Adamts2 Q226* knock-in allele returned no hits. Cited here as a
    dataset record per the geo: reference workflow rather than as a full
    animal_models entry, since AnimalModel.publication requires a PMID. If a
    manuscript is later published, this dataset and its findings should be
    promoted to a full animal_models entry with modeled_mechanisms links.

📚

References & Deep Research

References

13

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.

PMID:15373769

Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.

No top-level findings curated for this source.

PMID:25354687

In silico identification and three-dimensional modelling of the missense mutation in ADAMTS2 in a sheep flock with dermatosparaxis.

No top-level findings curated for this source.

PMID:28856769

Dermatosparaxis in White Dorper sheep: confirmation of a causative nonsense mutation in ADAMTS2.

No top-level findings curated for this source.

PMID:36421833

Novel Homozygous ADAMTS2 Variants and Associated Disease Phenotypes in Dogs with Dermatosparactic Ehlers-Danlos Syndrome.

No top-level findings curated for this source.

Deep Research

2

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

Evaluations and curation notes (3)

Record 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.

Augment: Dermatosparaxis Ehlers-Danlos Syndrome (deep-research cross-check) · 2026-09-15T22:55:17Z · View source

This entry already existed as an exceptionally mature, actively-maintained curation (91.0% compliance, 1277 lines, animal_models/definitions/discussions/progression sections all present, its own prior OpenScientist deep-research pass documented in notes:) -- so this session's task was augmentation, not creation. Per /curate instructions, a fresh deep-research pass was run via 'just dr_fallback=--fallback research-disorder falcon Dermatosparaxis_Ehlers-Danlos_Syndrome' (falcon/Edison Scientific ran successfully this time, 628s, 34 citations, 11/11 references resolved, 0 confabulated; needs_review:true was driven only by a harmless template-placeholder artifact ('if available' leaking into the MONDO label field) plus one pre-existing obsolete GO term not used in this entry). Before running deep research, just discover-datasets surfaced a highly relevant, previously-uncited 2026 GEO dataset (geo:GSE343646, a patient-analog Adamts2 Q226* knock-in mouse with single-nucleus RNA-seq identifying fibroblasts as the most transcriptionally disrupted cell population) which was verified via just verify-datasets and added as a datasets: entry -- not as a full animal_models entry, since AnimalModel.publication requires a PMID and no peer-reviewed publication for this 2026 GEO deposit could be found via PubMed search. Cross-checking the fresh deep-research report's body against the existing entry found it substantially corroborated already-cited content, but surfaced two genuinely new, previously-uncited primary sources (fetched and verified before use, both full-text): PMID:36421833 (Jaffey et al. 2022, a natural canine dermatosparaxis model reporting two ADAMTS2 genotypes with strikingly different severity -- a truncating allele in 6 dogs all euthanized by 13 weeks vs. a catalytic-domain missense allele in a dog surviving 9+ years) and PMID:42261541 (a 2026 case report of an adolescent with dEDS presenting with hemorrhagic complications despite entirely normal coagulation studies). Added the canine model as a new animal_models entry (modeled_mechanisms -> Hieroglyphic Collagen Fibril Assembly, extending the ultrastructural phenotype to tendon/ligament beyond the dermis already characterized in the bovine model), explicitly preserving the source paper's own hedging that euthanasia timing for the truncating-allele puppies reflected owner discretion rather than a measured biological endpoint -- this was then woven into the existing deds_mild_phenotype_molecular_basis_unexplained discussion's rationale as a cross-species data point that parallels but does not resolve the human ascertainment-vs-biology question. Added the case report's coagulation-testing nuance as a new diagnosis: entry (normal coagulation panel/factor assay/thromboelastometry does not exclude disease-related bleeding). Considered and declined the report's large phenotype-frequency table (hypertrichosis, pes planus, additional ocular/dental findings, etc.) since it draws from the same underlying source (Van Damme et al. 2016 = PMID:26765342) already exhaustively and deliberately mined by the entry's existing curator with documented methodology in its notes: field: re-deriving frequency bands from a table the falcon report merely re-quotes would not add information and risked contradicting the existing curator's already-careful frequency-sourcing decisions. Revalidated with: just validate (schema/term/reference, 73/73 snippets verified), just validate-disorders (CI-authoritative batched gate, passed), just check-causal-targets (0 new dangling targets), just check-entity-refs, just check-duplicate-keys, just check-enum-values, just check-snippet-length (whole-KB, exit 0), and just list-gene-term-mismatches (0 mismatches across 4 gene bindings). Compliance (just compliance): 90.6% global / 90.4% weighted (essentially unchanged from the pre-existing 91.0%/91.5%, since most additions populated previously-empty optional slots such as datasets: alongside new required fields). Note: an unrelated, unexplained stray file references_cache/GEO_GSE130749.md (a testis-development CBX2/Wnt dataset with no connection to EDS or this session's work) appeared in the working tree during this session; it was not referenced by either deep-research report and was left uncommitted/unstaged rather than included here.

Create: Dermatosparaxis_Ehlers-Danlos_Syndrome · 2026-08-28T22:08:36Z · View source

De novo curation of dermatosparaxis Ehlers-Danlos syndrome, MONDO:0009161, claimed via issue #9938. One OpenScientist deep-research report was run: research/Dermatosparaxis_Ehlers-Danlos_Syndrome-deep-research-openscientist.md. Its reference validation reported 13/13 verified with no unsupported quotes; its term validation flagged two obsolete GO terms and a cosmetic CL label variant, none of which are bound in this entry. Evidence was drawn from independently fetched PubMed abstracts rather than from report-supplied quotes. The report's substantive contribution was the Adamts2/Adamts14 double-knockout result, which substantiates the non-compensation claim. Validated with just validate at 57/57 snippets verified after review rounds, plus check-duplicate-keys and check-entity-refs.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 34 citations 2026-09-15T22:46:03.890319

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

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

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

Disease Characteristics Research Template

Target Disease

Disease Name: Dermatosparaxis Ehlers-Danlos Syndrome
MONDO ID: MONDO:0009161 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Dermatosparaxis Ehlers-Danlos Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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

5. Environmental Information

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

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

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

6. Mechanism / Pathophysiology

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

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

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

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

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

7. Anatomical Structures Affected

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

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

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

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

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

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

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

10. Diagnostics

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

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

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

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

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

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Dermatosparaxis Ehlers–Danlos syndrome: disease-characteristics report

Executive summary and evidence scope

Dermatosparaxis Ehlers–Danlos syndrome (dEDS) is an ultra-rare, autosomal-recessive connective-tissue disorder caused by biallelic pathogenic variants in ADAMTS2. Deficient ADAMTS-2-mediated removal of amino-terminal propeptides from fibrillar procollagens—especially types I and III in skin—produces abnormally organized collagen fibrils and extreme tissue fragility. Hallmarks are congenital or early-childhood skin fragility, easy bruising, soft/doughy or redundant skin, characteristic craniofacial findings, joint hypermobility, umbilical hernia, and postnatal growth restriction. Visceral, vascular, and hemorrhagic complications occur but are incompletely quantified. The best quantified human dataset remains only 15 molecularly confirmed individuals; consequently, percentages below are descriptive, not robust population estimates. A 2024 expert review still classified prevalence as below 1 per 1,000,000 and noted only 15 reported children, with very limited adult follow-up. (dijk2024clinicaldiagnosisof pages 3-4)

Evidence types are labeled where important: human clinical/genetic, human fibroblast/in-vitro, mouse knockout, natural veterinary disease, or expert review. Recent dEDS-specific research in 2023–2024 was sparse; the principal 2024 advances were updated clinical and molecular diagnostic guidance rather than therapeutic trials. (dijk2024clinicaldiagnosisof pages 3-4, zschocke2024geneticdiagnosisof pages 8-9)

1. Disease information

Definition and nomenclature

dEDS is one of the monogenic Ehlers–Danlos syndromes, characterized by connective-tissue fragility arising from defective collagen processing. Historical names include Ehlers–Danlos syndrome type VIIC, EDS VIIC, human dermatosparaxis, dermatosparactic EDS, and EDS dermatosparaxis type. (kapfererseebacher2020dentalmanifestationsof pages 1-2, malek2021theroleof pages 2-3, colige1999humanehlersdanlossyndrome pages 1-2)

Identifiers

MONDO: MONDO:0009161, as supplied in the target specification.
OMIM/MIM: 225410. (neto2024unravelingthegenetic pages 5-6, malek2021theroleof pages 2-3, colige1999humanehlersdanlossyndrome pages 1-2)
Causal-gene disease label: ADAMTS2-related dermatosparaxis EDS.
Orphanet: an Orphanet disease entry exists, but its numeric ORPHA identifier was not established by the retrieved primary texts and should be verified directly before database loading.
ICD-10: no dEDS-specific code was established in the retrieved literature; it is generally subsumed under Ehlers–Danlos syndrome/congenital connective-tissue-malformation coding rather than represented as a subtype-specific diagnosis.
ICD-11 and MeSH: no dEDS-specific identifiers were verified in the retrieved full texts; use the broader Ehlers–Danlos syndrome concept with an ADAMTS2/dEDS qualifier after direct terminology-service validation.

The evidence summarized here is predominantly aggregated disease-level literature—case series, reviews, and experimental studies—not longitudinal EHR-derived data. Individual-patient observations from published case reports/series underpin many phenotype claims.

2. Etiology, risk, protection, and environment

Primary cause

The necessary initiating lesion is usually biallelic germline loss of ADAMTS2 function. ADAMTS2 encodes an extracellular zinc metalloprotease, historically called procollagen-I N-proteinase, that removes amino-terminal propeptides from major fibrillar procollagens. The landmark study found homozygous p.Gln225Ter in five of six then-known patients and homozygous p.Trp795Ter in the sixth, directly linking absent enzyme activity to human EDS VIIC. (colige1999humanehlersdanlossyndrome pages 1-2)

Genetic risk factors

Risk is determined primarily by inheriting two pathogenic alleles. Reported mechanisms include nonsense, frameshift, canonical splice-site, start-loss, and likely hypomorphic missense variants. Homozygosity is common in consanguineous families, although compound heterozygosity and affected individuals from nonconsanguineous families occur. In the 15-person summary, three individuals had known consanguineous parents; this is ascertainment evidence, not a population risk estimate. (damme2016expandingtheclinical pages 2-3, damme2016expandingtheclinical pages 7-8)

The 2016 human study reported:

c.2927_2928delCT, p.(Pro976Argfs*42), homozygous;
c.669_670dupG, p.(Pro224Argfs*24), homozygous;
c.2751-2A>T, causing out-of-frame exon-19 skipping, homozygous;
compound heterozygous c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs*26). (damme2016expandingtheclinical pages 1-2, damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)

These variants were absent from the population databases queried at the time—1000 Genomes, ESP6500, and ExAC—and several truncated transcripts underwent nonsense-mediated decay, demonstrated by markedly reduced fibroblast ADAMTS2 RNA. Modern gnomAD frequencies and current ClinVar classifications must be checked variant-by-variant; historical absence is not a substitute for current frequency data. (damme2016expandingtheclinical pages 2-3, damme2016expandingtheclinical pages 7-8)

Modifiers and protective factors

No validated human modifier gene or protective allele is known. ADAMTS3 and ADAMTS14 are biologically plausible tissue-specific compensators, not established clinical protective factors: ADAMTS3 processed procollagen I in dermatosparactic fibroblasts, while Adamts14 overlapped with Adamts2 in mature mouse dermis. Their differential expression may explain why skin is more severely affected than cartilage, tendon, bone, cornea, or aorta. (goff2006regulationofprocollagen pages 1-2, goff2006regulationofprocollagen pages 7-8)

There are no demonstrated dietary, lifestyle, pharmacological, or environmental factors that prevent the genotype from causing disease. Trauma and invasive procedures do not cause dEDS, but mechanically challenge fragile tissue and can precipitate tears, hematomas, hemorrhage, prolapse, or rupture. Avoidance of trauma is therefore complication prevention, not etiologic prevention.

Environmental and infectious factors

No toxin, radiation, pollution, occupational exposure, lifestyle behavior, or infectious organism is known to initiate dEDS. Smoking, alcohol, diet, and exercise have not been evaluated as disease-susceptibility factors. Gene–environment interaction is principally mechanical: genetically abnormal collagen reduces tissue tensile strength, while trauma, vomiting, defecation, surgery, and other physical stresses can reveal or exacerbate manifestations. Diaphragmatic rupture after vomiting and severe rectal prolapse/bleeding exemplify this interaction. (dijk2024clinicaldiagnosisof pages 3-4, damme2016expandingtheclinical pages 2-3, damme2016expandingtheclinical pages 3-5)

3. Phenotypes

The most useful quantified summary comes from 15 molecularly confirmed individuals from 14 families. Missing entries meant “not reported,” so the following fractions are not unbiased penetrance estimates. (damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)

Domain	Feature	Reported count / denominator	Approx. percentage	Onset/course	Suggested HPO term
Skin	Severe skin fragility/skin tears	14/15	93%	Congenital in 2; predominantly postnatal and may become more apparent with activity/age	Skin fragility (HP:0001030); Skin ulcer (HP:0200042)
Eye	Blue sclerae	13/15	87%	Usually congenital or evident in early childhood	Blue sclerae (HP:0000592)
Growth	Postnatal growth restriction	13/15	87%	Develops after birth; persistent short stature common	Postnatal growth retardation (HP:0008897)
Skin	Soft, doughy skin	12/15	80%	Congenital or early childhood; persistent	Soft skin (HP:0000977)
Craniofacial	Epicanthic folds	12/15	80%	Congenital/early childhood	Epicanthus (HP:0000286)
Craniofacial	Micrognathia	12/15	80%	Congenital or progressively recognizable in childhood	Micrognathia (HP:0000347)
Craniofacial	Large fontanel/delayed closure	11/15	73%	Congenital; closure delayed into childhood	Large fontanelle (HP:0000239); Delayed closure of the anterior fontanelle (HP:0001476)
Skin	Sagging or redundant skin	11/15	73%	Often congenital in severe disease; may become more apparent postnatally	Redundant skin (HP:0001582)
Musculoskeletal	Joint hypermobility	11/15	73%	Congenital or recognized in early childhood; persistent	Generalized joint hypermobility (HP:0002761)
Musculoskeletal/growth	Short limbs, hands, and feet	11/15	73%	Postnatal growth pattern; generally persistent	Short limb (HP:0009826); Short hand (HP:0200055); Short foot (HP:0001773)
Hematologic/skin	Easy bruising	11/15	73%	Usually begins in infancy or childhood; recurrent	Easy bruisability (HP:0000978)
Development	Delayed motor development	8/15	53%	Infancy/early childhood; variable severity	Motor delay (HP:0001270)
Hemorrhagic	Bleeding complications	7/15	47%	Congenital through later childhood; episodic and potentially severe	Abnormal bleeding (HP:0001892)
Visceral	Visceral fragility	5/15	33%	Congenital or postnatal; episodic rupture/prolapse complications	Visceral tissue fragility (closest available: HP:0003549)
Abdominal wall	Umbilical hernia	14/15	93%	Usually congenital	Umbilical hernia (HP:0001537)
Pregnancy/birth	Preterm birth	9/15	60%	Prenatal/perinatal; mean gestational age across 14 individuals was 34 weeks 4 days	Premature birth (HP:0001622)
Pregnancy/birth	Preterm premature rupture of membranes (PPROM)	6/15	40%	Prenatal; precedes some preterm deliveries	Premature rupture of membranes (HP:0001788)
Demographic	Sex ratio	11 male:4 female	73% male; 27% female	Cohort composition, not a phenotype or established sex predisposition	Biological sex (metadata; no disease-phenotype HPO term)
Evidence note	Missingness/ascertainment limitation	15 molecularly confirmed individuals	Not applicable	Blank entries were “not reported”; counts therefore are not strict prevalence estimates	Evidence qualifier: incomplete phenotype ascertainment
Source	Van Damme et al., Genetics in Medicine (2016), DOI: 10.1038/gim.2015.188	15 individuals from 14 families	Not applicable	Published September 2016	(damme2016expandingtheclinical pages 3-5, damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)

Table: Key clinical findings in the 15 molecularly confirmed individuals summarized by Van Damme et al. Counts reflect reported observations with incomplete ascertainment, so percentages should not be interpreted as unbiased prevalence estimates.

Additional reported manifestations include facial or mucosal lacerations, delayed healing, papyraceous or widened atrophic scars, translucent skin with visible veins, subcutaneous hematomas, hypertrichosis, hypotonia, pes planus, kyphoscoliosis, osteopenia, fractures including congenital skull fractures, myopia, microcornea, glaucoma, gingival hyperplasia or bleeding, microdontia/oligodontia, rectal prolapse, hiatal hernia, bladder diverticula/rupture, diaphragmatic rupture, mitral-valve prolapse, fatigue, and chronic joint pain. Dental evidence remains sparse and cannot support reliable frequencies. (dijk2024clinicaldiagnosisof pages 3-4, damme2016expandingtheclinical pages 3-5, damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)

Phenotype type and course. Skin tears, bruising, hemorrhage, hernia, prolapse, and rupture are clinical signs or complications; joint pain and fatigue are symptoms; hypermobility, craniofacial gestalt, short extremities, and redundant skin are examination findings. Routine coagulation testing can be normal despite severe bleeding, as illustrated by a later adolescent case with normal CBC, coagulation factors, and rotational thromboelastometry. (balagopal2026exploringthehemorrhagic pages 1-4)

Onset. Severe disease can be evident prenatally or at birth through premature membrane rupture, prematurity, friable umbilical cord, congenital tears, skull fractures, or hemorrhage. Milder disease may initially be facial/oral fragility and become more generalized as childhood activity increases. Mean diagnosis age in the 2016 dataset was 62 months, ranging from birth to 13 years, illustrating diagnostic delay and variable expressivity. (damme2016expandingtheclinical pages 7-8)

Quality of life. No dEDS-specific EQ-5D, SF-36, PROMIS, or validated disease-specific quality-of-life study was found. Published patients nevertheless experienced recurrent suturing, surgery, activity-limiting tissue injury, progressive widespread joint pain, fatigue, gastrointestinal symptoms, bleeding, and intensive medical follow-up. These observations indicate potentially substantial functional and psychosocial burden but cannot be converted into population-level utility scores. (damme2016expandingtheclinical pages 2-3, damme2016expandingtheclinical pages 3-5)

4. Genetic and molecular information

Causal gene and protein

Gene: ADAMTS2; biallelic pathogenic variants.
Protein: ADAMTS-2/procollagen-I N-proteinase, a secreted disintegrin-like metalloprotease with thrombospondin motifs, a zinc-binding catalytic site, cysteine-rich/disintegrin-like regions, and C-terminal ancillary domains. (goff2006regulationofprocollagen pages 1-2, colige1999humanehlersdanlossyndrome pages 1-2)
Disease mechanism: predominantly loss of function through premature termination, aberrant splicing, or nonsense-mediated RNA decay.
Origin: constitutional/germline. Somatic ADAMTS2 variants are not the cause of inherited dEDS.

The evidence for causality is strong: recessive segregation, recurrent truncating variants, absent/reduced enzymatic activity, abnormal procollagen processing, fibroblast transcript loss, collagen-fibril abnormalities, concordant animal disease, and knockout phenocopy. (colige1999humanehlersdanlossyndrome pages 1-2, damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)

Variant interpretation

Established biallelic null alleles are generally pathogenic under ACMG/AMP concepts because loss of function is the known mechanism. Missense variants require caution: rarity and computational prediction alone are insufficient, and enzymatic, RNA, biochemical, segregation, or collagen-ultrastructure evidence is desirable. A VUS should not by itself confirm dEDS; a 2024 expert review warned that indiscriminate testing can create misleading VUS-based diagnoses. (zschocke2024geneticdiagnosisof pages 2-3)

No validated dominant-negative or gain-of-function dEDS mechanism is known. Large deletions are biologically possible and should be detectable through copy-number analysis, but no recurrent chromosomal rearrangement or aneuploidy defines dEDS. No disease-specific DNA-methylation signature, histone alteration, or other epigenetic biomarker has been established.

Genotype–phenotype relationship

The 2016 cohort expanded the phenotype to include markedly milder patients despite molecularly demonstrated deficient ADAMTS-2 activity and abnormal procollagen processing. In natural canine disease, early truncating c.10delC/p.(Pro4ArgfsTer175) produced catastrophic juvenile skin fragility with euthanasia before 13 weeks in six dogs, whereas a homozygous p.(Arg966His) dog survived at least nine years, consistent with residual activity as a plausible—but unproven—explanation. This supports quantitative residual function as a candidate severity determinant but does not establish a human prognostic rule. (jaffey2022novelhomozygousadamts2 pages 1-2)

5. Environmental information

Environmental causation is not applicable. Practical exposure modifiers include trauma, friction, contact sports, falls, poorly fitted equipment, surgery, endoscopy, arterial puncture, forceful vomiting, and constipation/straining. These can precipitate complications in genetically fragile tissue. No infectious trigger, transmissible agent, or zoonotic risk exists.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic pathogenic ADAMTS2 variants lead to absent or markedly reduced functional extracellular ADAMTS-2.
Reduced ADAMTS-2 activity leads to deficient cleavage of N-terminal propeptides from procollagens I and III; effects on type II collagen are often limited by tissue-specific ADAMTS3 compensation. (goff2006regulationofprocollagen pages 1-2, goff2006regulationofprocollagen pages 7-8)
Failed cleavage leads to accumulation of pN-collagen/procollagen species retaining amino-terminal propeptides, directly demonstrated in patient fibroblasts and Adamts2-null tissues. (colige1999humanehlersdanlossyndrome pages 1-2, damme2016expandingtheclinical pages 5-7)
Retained propeptides lead to abnormal lateral packing and assembly of collagen monomers into thin, branched, ribbon-like or “hieroglyphic” fibrils rather than regular cylindrical fibrils. (goff2006regulationofprocollagen pages 1-2, colige1999humanehlersdanlossyndrome pages 1-2)
Abnormal fibrillogenesis leads to reduced extracellular-matrix tensile strength, most prominently in dermis and other mechanically stressed connective tissues.
Reduced tensile strength leads to skin tearing, poor wound healing, bruising/hematoma, hernias, joint laxity, mucosal and visceral fragility, and—in some patients—major hemorrhage or organ rupture.
Branch A: tissue-specific ADAMTS3/ADAMTS14 expression leads to partial rescue of procollagen processing in cartilage, bone, muscle/tendon, mature dermis, cornea, and possibly aorta; this branch is experimentally supported in mice/in-vitro but remains inferred as a human severity modifier. (goff2006regulationofprocollagen pages 1-2, goff2006regulationofprocollagen pages 7-8, jaffey2022novelhomozygousadamts2 pages 14-15)
Branch B: severe deficiency of type III procollagen processing in lung leads to distal-airspace enlargement in Adamts2-null mice; pulmonary surveillance relevance in humans is plausible but not established. (goff2006regulationofprocollagen pages 7-8)

Detailed biology and ontology suggestions

This is primarily an extracellular-matrix biosynthesis/assembly disorder, not a canonical Wnt, MAPK, mTOR, or PI3K–AKT signaling disease. Relevant biological processes include collagen biosynthesis and modification, extracellular-matrix organization, collagen-fibril organization, proteolysis, wound healing, and connective-tissue development. Suggested GO annotations include extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), proteolysis (GO:0006508), wound healing (GO:0042060), and metalloendopeptidase activity (GO:0004222).

The main cell type is the collagen-producing fibroblast (suggested CL:0000057), with relevant mesenchymal cells including dermal fibroblasts, tendon/ligament fibroblasts, chondrocytes (CL:0000138), osteoblast-lineage cells (CL:0000062), vascular smooth-muscle cells (CL:0000359), and lung mesenchymal cells. Expression in mouse lung occurred in mesenchyme rather than bronchial epithelium. (goff2006regulationofprocollagen pages 7-8)

Subcellular/localization annotations include the extracellular region (GO:0005576), extracellular matrix (GO:0031012), collagen-containing extracellular matrix (GO:0062023), and secretory pathway/ER for procollagen synthesis. The pathogenic cleavage and fibril-assembly defect is mainly extracellular; no primary mitochondrial, lysosomal, nuclear, autophagic, apoptotic, metabolic, or immune defect is established.

Molecular profiling. Patient fibroblast qPCR showed severely reduced ADAMTS2 expression for truncating alleles; radiolabeled-procollagen electrophoresis showed accumulation of pNα1(I)/pNα2(I) and near absence of pCα1(I)/pCα2(I); TEM showed irregular, branched fibrils, sometimes milder than the classic hieroglyphic pattern. These are targeted transcript, protein-processing, and ultrastructural findings—not unbiased transcriptomics, proteomics, metabolomics, lipidomics, single-cell, spatial, or multi-omics profiles. (damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)

No dEDS-specific single-cell atlas, spatial transcriptomic map, metabolomic/lipidomic signature, patient organoid, iPSC model, or published therapeutic CRISPR screen was identified.

Exact primary-literature statement: Colige et al. reported that retained-propeptide molecules “self-assemble into abnormal ribbonlike fibrils that fail to provide normal tensile strength to tissues.” (colige1999humanehlersdanlossyndrome pages 1-2)

7. Anatomical structures affected

Primary organs/tissues: skin—especially dermis—and subcutaneous connective tissue; suggested UBERON:0002097 (skin of body) and UBERON:0002067 (dermis). The extracellular collagen-fibril network is the primary tissue target.

Additional structures: joints, ligaments, tendons, skeletal connective tissue, craniofacial soft tissues, oral/gingival tissues, abdominal wall and umbilicus, gastrointestinal and pelvic-support tissues, diaphragm, bladder, eyes/sclera, and potentially vessels and lungs. Suggested terms include sclera (UBERON:0001775), lung (UBERON:0002048), urinary bladder (UBERON:0001255), diaphragm (UBERON:0001103), and umbilical region/umbilical cord where appropriate.

No consistent lateralization is expected. Findings are generally generalized or bilateral; individual tears, hematomas, fractures, or prolapses may be anatomically focal.

At the cellular level, dermal fibroblasts synthesize abnormal procollagen substrates, while the defect is manifested in collagen-containing ECM. At the subcellular level, procollagen synthesis begins in rough ER/Golgi, but pathogenic N-propeptide retention and fibril malassembly occur after secretion in the extracellular compartment. (goff2006regulationofprocollagen pages 1-2)

8. Temporal development and natural history

The molecular defect is present from conception, and the disease is congenital and lifelong. Prenatal/perinatal vulnerability includes membrane rupture, prematurity, friable or ruptured umbilical cord, congenital skin injury, skull fracture, and hemorrhage. In the 15-person series, nine were preterm, six had premature membrane rupture, mean gestational age among 14 was 34 weeks 4 days (range 28–41 weeks), and one newborn died from hemorrhage and shock. (damme2016expandingtheclinical pages 7-8)

During infancy and childhood, activity exposes skin and mucosal fragility; joint hypermobility, delayed motor development, postnatal growth restriction, and characteristic facial appearance become more apparent. Milder patients may lack striking neonatal redundant skin and develop generalized fragility later. Chronic later manifestations may include pain, fatigue, scarring, prolapse, varicose veins, ocular disease, and recurrent hemorrhage. (damme2016expandingtheclinical pages 2-3, damme2016expandingtheclinical pages 3-5, damme2016expandingtheclinical pages 7-8)

There is no validated staging system, remission pattern, or quantified progression rate. The disorder does not remit because the collagen-processing defect persists, although injury frequency may change with age, activity, protection, and residual enzyme function. Critical periods are pregnancy/delivery, early mobility, surgery or invasive procedures, and episodes of vomiting or straining.

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy carries a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of a child inheriting neither familial variant. Unaffected siblings have a 2/3 carrier probability after excluding disease.

Clinical penetrance for two true null alleles appears high, but precise penetrance is unknown and hypomorphic alleles may produce subtle disease. Expressivity is clearly variable. Anticipation is not expected. Germline mosaicism has not been established as a characteristic mechanism but cannot be excluded for an apparently de novo parental allele. Consanguinity increases the probability that both partners carry the same rare allele. No validated human founder mutation, carrier frequency, ethnic enrichment, geographic endemicity, or incidence rate is available.

Prevalence is estimated at <1:1,000,000. The 2016 synthesis contained 15 molecularly proven patients from 14 families; the 2024 review continued to emphasize only 15 reported childhood cases and extremely limited adult observation. This is a literature count rather than incidence surveillance. (dijk2024clinicaldiagnosisof pages 3-4, damme2016expandingtheclinical pages 7-8)

The 2016 cohort sex ratio was 11 male:4 female, but autosomal inheritance and extreme sample size provide no evidence of biological male predominance. Reported families span multiple ancestries and regions; dEDS should not be considered ethnicity-specific. (damme2016expandingtheclinical pages 7-8)

10. Diagnostics

Clinical recognition and criteria

The 2017 framework uses nine major criteria; a 2024 expert review considered the most discriminating combination to be: (1) extreme skin fragility with congenital or postnatal tears, (2) characteristic craniofacial appearance, (3) redundant/lax skin with wrist and ankle folds, and (4) severe bruising with subcutaneous hematoma/hemorrhage risk. Molecular confirmation is essential because milder dEDS can resemble classical EDS. (dijk2024clinicaldiagnosisof pages 3-4)

The 2016 proposed clinical criteria comprised severe skin fragility; sagging/redundant skin; easy bruising; characteristic congenital or progressive facial gestalt with periorbital swelling, blue sclerae, downslanting palpebral fissures, epicanthi, micrognathia, delayed fontanel closure, and dental anomalies; postnatal growth restriction; short extremities; joint hypermobility; umbilical hernia; and congenital/postnatal visceral or vascular fragility. (damme2016expandingtheclinical pages 7-8)

Recommended genetic testing

Obtain detailed personal, pregnancy/birth, wound, bleeding, surgical, and three-generation family histories plus examination documenting skin fragility, scars, bruising, redundant skin, craniofacial findings, hernia, hypermobility, growth, eyes, teeth, and prolapse.
Use a massively parallel inherited-connective-tissue/monogenic-EDS panel including ADAMTS2. A 2024 review calls panel testing the current gold standard for monogenic EDS confirmation. Extreme skin fragility specifically prioritizes ADAMTS2. (zschocke2024geneticdiagnosisof pages 8-9)
Include full coding/splice-region sequencing and deletion/duplication analysis; phase two variants and perform parental segregation.
If panel/exome sequencing is negative despite strong suspicion, consider genome sequencing, analysis of deep intronic/promoter/regulatory regions, RNA sequencing/transcript studies, and reanalysis. Standard exome calling can miss copy-number, intronic, or structurally complex variants. (zschocke2024geneticdiagnosisof pages 8-9)
WES or WGS is useful where phenotype overlaps classical EDS, cutis laxa, osteogenesis imperfecta, brittle-cornea syndrome, or skeletal dysplasia. WGS offers better noncoding and structural-variant coverage but does not automatically resolve VUS.
CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion assays are not first-line for isolated typical dEDS because it is a sequence-level single-gene disorder.

Functional and pathology tests

Skin-biopsy TEM: irregular, branched, ribbon-like or hieroglyphic collagen fibrils support the diagnosis, but mild cases may lack the classic severe pattern; a normal/nonspecific biopsy therefore does not exclude dEDS. (damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)
Cultured fibroblast procollagen analysis: accumulation of pN-collagen chains and deficient mature processing can demonstrate ADAMTS-2 dysfunction. (damme2016expandingtheclinical pages 5-7)
RNA studies/qPCR: useful for splice variants and suspected nonsense-mediated decay. (damme2016expandingtheclinical pages 7-8)
Routine hemostasis: CBC, PT/aPTT, coagulation factors, and thromboelastometry may be normal despite bruising or bleeding; no validated circulating biomarker exists. (balagopal2026exploringthehemorrhagic pages 1-4)
Imaging: targeted echocardiography, ophthalmic assessment, skeletal imaging, ultrasound/CT/MRI, or organ imaging is driven by manifestations; no diagnostic imaging signature exists.

Differential diagnosis

Important alternatives include classical EDS (COL5A1/COL5A2), classical-like EDS (TNXB/AEBP1), arthrochalasia EDS (COL1A1/COL1A2 exon-6-related), vascular EDS (COL3A1), kyphoscoliotic EDS (PLOD1/FKBP14), brittle-cornea syndrome (ZNF469/PRDM5), musculocontractural EDS (CHST14/DSE), periodontal EDS (C1R/C1S), osteogenesis imperfecta/COL1 overlap disorders, cutis laxa syndromes, and nonaccidental injury when unexplained bruises or tears occur. dEDS is favored by extreme congenital/postnatal skin fragility, redundant wrist/ankle skin, characteristic face, blue sclerae, short plump extremities, umbilical hernia, and biallelic ADAMTS2 variants.

Screening

There is no population or newborn screening program. Appropriate strategies are cascade testing for adult relatives, targeted familial-variant prenatal testing, and preimplantation genetic testing after molecular confirmation. Carrier screening is reasonable in known families or partners from a high-consanguinity pedigree but is not part of universal screening.

11. Outcome and prognosis

No reliable 5-year/10-year survival, life expectancy, mortality rate, disability-adjusted burden, prognostic score, or biomarker has been published. Outcomes range from fatal neonatal hemorrhage to survival into adulthood. In the historic 15-person dataset, one infant died shortly after birth from severe hemorrhage/shock, while only two had follow-up into puberty/adulthood; the 2024 review cited one individual followed to age 19. (dijk2024clinicaldiagnosisof pages 3-4, damme2016expandingtheclinical pages 7-8)

Major morbidity arises from recurrent skin/mucosal wounds, scars, bruising and hematomas, bleeding, hernias, prolapse, pain, fatigue, growth and motor delay, ocular/dental complications, and visceral rupture. Recovery from individual injuries is possible, but healing may be slow and structurally fragile tissue persists. Prognosis is plausibly worse with complete enzyme loss, congenital hemorrhage, major organ fragility, or recurrent traumatic exposure; this remains unvalidated in humans.

The absence of large adult cohorts is a major knowledge gap. Normal coagulation results do not imply low hemorrhagic risk, and mild childhood skin ultrastructure does not guarantee benign long-term disease. (balagopal2026exploringthehemorrhagic pages 1-4, damme2016expandingtheclinical pages 7-8)

12. Treatment and current applications

Disease-modifying therapy

There is no approved dEDS-specific drug, enzyme replacement, gene therapy, cell therapy, RNA therapy, CRISPR treatment, or validated targeted therapy. The ClinicalTrials.gov search returned no relevant dEDS interventional trial. No treatment-response rates or pharmacogenomic recommendations exist.

Supportive management

Management is individualized and multidisciplinary, ideally involving clinical genetics, dermatology/wound care, pediatrics/internal medicine, physiotherapy/occupational therapy, pain medicine, ophthalmology, dentistry, gastroenterology/colorectal or urologic specialists, surgery/anesthesia, hematology for severe bleeding, and high-risk obstetrics where relevant.

Recommended practical measures, based on pathophysiology and rare-disease expert practice rather than trials, include:

minimize friction, falls, contact sports, heavy collision activity, and unnecessary invasive procedures;
use protective clothing/padding and adapt home/school/work environments;
gentle wound handling, low-tension closure strategies, prolonged support, and specialist wound review;
treat constipation, vomiting, and cough promptly to reduce mechanical stress;
individualized low-impact strengthening/proprioceptive therapy while avoiding forceful manipulation and end-range loading;
standard analgesia tailored to comorbidity and bleeding risk;
regular dental and ophthalmic care;
establish an emergency plan describing tissue and bleeding fragility;
undertake surgery or endoscopy only when clinically justified, with experienced teams and anticipation of difficult hemostasis and poor wound healing. General EDS guidance advises reserving surgery for necessary complications because of wound risk. (balagopal2026exploringthehemorrhagic pages 6-7, islam2021ehlersdanlossyndromeimmunologic pages 1-8)

Ascorbic acid, zinc, desmopressin, or celiprolol have occasionally been discussed across EDS care, but dEDS-specific efficacy is unproven. Celiprolol evidence from vascular EDS must not be transferred to dEDS, and supplementation should not be presented as correction of ADAMTS-2 deficiency. A 2026 case used celiprolol and vitamin C, but one uncontrolled case cannot establish benefit. (balagopal2026exploringthehemorrhagic pages 1-4, balagopal2026exploringthehemorrhagic pages 6-7)

Suggested NCIT intervention concepts include Genetic Counseling, Physical Therapy, Occupational Therapy, Wound Care, Pain Management, Surgical Procedure, Genetic Testing, and Supportive Care; exact NCIT codes should be resolved against the current NCI Thesaurus release.

13. Prevention

Primary prevention: the phenotype cannot be prevented by vaccination, diet, or environmental modification after an affected genotype is present. Reproductive options include carrier testing, partner testing, preimplantation genetic testing, chorionic-villus/amniotic-fluid testing for known familial variants, donor gametes, and informed family planning.

Secondary prevention: early clinical recognition and molecular confirmation permit anticipatory guidance, cascade testing, protection from trauma, and targeted surveillance. There is no newborn biochemical screen.

Tertiary prevention: prevent tears, hematomas, hemorrhage, poor surgical outcomes, prolapse, and organ rupture through environmental adaptation, prompt wound care, constipation/vomiting control, cautious procedures, rehabilitation, and emergency planning. Standard immunizations remain appropriate but do not specifically alter dEDS; injection technique and post-injection pressure may need adaptation for bruising.

Genetic counseling should explain recessive recurrence risks, variable expressivity, limitations of prenatal phenotype prediction, and the possibility that a hypomorphic genotype may be milder but not harmless.

14. Other species and natural disease

Naturally occurring dermatosparaxis has been reported in cattle, sheep, cats, dogs, and other domestic species. The disease is homologous rather than infectious and has no zoonotic transmission. In the original bovine strain, a homozygous 17-bp ADAMTS2 deletion shifted the reading frame, while affected calf tissues accumulated incompletely processed procollagen and abnormal ribbon-like fibrils. (damme2016expandingtheclinical pages 1-2, colige1999humanehlersdanlossyndrome pages 1-2)

Dog—Canis lupus familiaris, NCBI Taxon 9615. A 2022 study identified homozygous ADAMTS2 variants in Pit Bull Terrier, Alapaha Blue Blood Bulldog, Catahoula Leopard Dog, and previously a Doberman Pinscher. Six dogs homozygous for c.10delC/p.(Pro4ArgfsTer175) had wounds, scars, hyperextensible skin, joint hypermobility and swelling; all were euthanized before 13 weeks. Dermal fibrils in two had hieroglyphic cross-sections. By contrast, a p.(Arg966His) Catahoula survived at least nine years. (jaffey2022novelhomozygousadamts2 pages 10-11, jaffey2022novelhomozygousadamts2 pages 1-2)

Among 167 sampled Alapaha Blue Blood Bulldogs selected for carrying at least one likely causal allele, the c.10delC allele frequency was 0.27; because sampling was enriched, this is not a breed-population carrier estimate. In a collection of 26 canine EDS whole genomes, only four had likely causal homozygous ADAMTS2 variants, emphasizing genetic heterogeneity in canine EDS. (jaffey2022novelhomozygousadamts2 pages 10-11, jaffey2022novelhomozygousadamts2 pages 14-15)

Veterinary relevance includes early recognition, avoidance of repeated injury, molecular subclassification, responsible breeding, and carrier testing within affected lineages. Suggested breed concepts require current VBO lookup; the source literature names the breeds but does not provide VBO identifiers.

Comparative pathology is highly conserved: recessive ADAMTS2 deficiency, retained procollagen propeptides, abnormal dermal fibrils, skin hyperextensibility/fragility, wounds, and joint laxity parallel the human condition. Species and genotype differences in survival and extracutaneous disease limit direct prognosis extrapolation.

15. Model organisms and experimental systems

Adamts2-null mouse

The principal engineered mammalian model is the Adamts2 knockout mouse. It reproduces deficient fibrillar-procollagen processing and abnormal dermal fibrils/skin fragility, while enabling tissue-specific mechanistic study. Mouse work demonstrated that Adamts2 is a major procollagen-III N-proteinase; mutant tissues showed markedly reduced type III processing. Mutant lungs had enlarged distal airspaces and reduced parenchymal density without inflammation or overt fibrosis, whereas two-month-old aortic histology and fibril ultrastructure appeared normal despite impaired collagen I/III processing. (goff2006regulationofprocollagen pages 1-2, goff2006regulationofprocollagen pages 7-8)

The model’s major application is resolving protease redundancy: Adamts3 co-expression with Col2a1 in cartilage and Col1a1 in bone/musculotendinous tissue, plus in-vitro rescue of procollagen-I processing, supports compensation outside skin; Adamts14 co-expression in mature dermis may account for residual processing. (goff2006regulationofprocollagen pages 1-2, goff2006regulationofprocollagen pages 7-8)

Limitations: mouse tissue compensation differs from humans; severe human craniofacial, hemorrhagic, hernia, growth, and visceral manifestations are not comprehensively reproduced; normal young-mouse aortic structure does not exclude later or stress-dependent vascular disease.

Natural and cellular models

Dermatosparactic cattle and dogs provide large-animal natural models with striking collagen ultrastructure and mechanical fragility. Dogs offer genotype-severity contrasts and clinically realistic wound burden, but euthanasia and breed structure complicate natural-history inference. Patient-derived dermal fibroblasts are useful for transcript analysis, procollagen-processing assays, TEM correlation, splice validation, and candidate rescue studies. ADAMTS3-mediated rescue of procollagen-I processing is a proof-of-mechanism in-vitro result, not a therapy. (goff2006regulationofprocollagen pages 1-2, damme2016expandingtheclinical pages 5-7)

No validated zebrafish, Drosophila, C. elegans, yeast, human organoid, or iPSC disease model was identified in the retrieved evidence. Relevant resources for model registration include MGI/IMSR for mice and OMIA for natural veterinary disease.

Recent developments, expert interpretation, and research priorities

The important 2024 development was refinement of clinical and molecular diagnosis. Experts emphasized that monogenic EDS should be confirmed by phenotype-directed massively parallel panel testing, that extreme skin fragility prioritizes ADAMTS2, and that negative exome testing may warrant copy-number, noncoding, genome, or transcript analysis. They also warned against overinterpreting VUS. (zschocke2024geneticdiagnosisof pages 2-3, zschocke2024geneticdiagnosisof pages 8-9)

The central expert interpretation is that dEDS severity cannot be inferred solely from the presence of biallelic variants. Residual function, variant position, nonsense-mediated decay, and tissue-specific ADAMTS3/14 compensation probably shape phenotype; however, this model is supported much more strongly by fibroblast, mouse, and canine evidence than by adequately powered human genotype–phenotype studies. (jaffey2022novelhomozygousadamts2 pages 1-2, goff2006regulationofprocollagen pages 1-2, goff2006regulationofprocollagen pages 7-8, damme2016expandingtheclinical pages 7-8)

Highest-priority research needs are: an international longitudinal registry; systematic adult natural history; prospective hemorrhage, vascular, pulmonary, pregnancy, surgical, and quality-of-life outcomes; current ClinVar/gnomAD curation and functional classification of missense/splice variants; standardized procollagen biomarkers; patient-derived iPSC/3D-skin models; and preclinical testing of ADAMTS2 replacement or gene restoration.

Key sources, publication dates, URLs, and quotations

van Dijk et al., “Clinical diagnosis of the monogenic Ehlers-Danlos syndromes,” November 2024. DOI/URL: https://doi.org/10.1515/medgen-2024-2060. It reports dEDS prevalence below 1:1,000,000 and stresses extreme skin fragility, characteristic craniofacial findings, redundant wrist/ankle skin, and severe bruising. (dijk2024clinicaldiagnosisof pages 3-4)
Zschocke et al., “Genetic diagnosis of the Ehlers-Danlos syndromes,” November 2024. DOI/URL: https://doi.org/10.1515/medgen-2024-2061. Abstract quotation: “Gene panel testing with massively parallel sequencing is currently gold standard to confirm diagnoses of the monogenic EDS types.” (zschocke2024geneticdiagnosisof pages 2-3, zschocke2024geneticdiagnosisof pages 8-9)
Van Damme et al., “Expanding the clinical and mutational spectrum…,” online January 14, 2016; print September 2016. DOI/URL: https://doi.org/10.1038/gim.2015.188. This primary human study added five patients, bringing the molecularly confirmed total to 15, and directly demonstrated reduced transcript, abnormal procollagen processing, and collagen-fibril defects. (damme2016expandingtheclinical pages 1-2, damme2016expandingtheclinical pages 2-3, damme2016expandingtheclinical pages 5-7, damme2016expandingtheclinical pages 7-8)
Colige et al., “Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis…,” electronically published June 23, 1999. DOI/URL: https://doi.org/10.1086/302504. Abstract quotation: “These data provide direct evidence that EDS type VIIC and dermatosparaxis result from mutations in the pNPI gene.” PMID was not present in the retrieved full text. (colige1999humanehlersdanlossyndrome pages 1-2)
Le Goff et al., “Regulation of procollagen amino-propeptide processing…,” April 2006. DOI/URL: https://doi.org/10.1242/dev.02308. Abstract quotation: “Not all collagen-rich tissues are affected to the same degree, which suggests compensation by the ADAMTS2 homologs ADAMTS3 and ADAMTS14.” (goff2006regulationofprocollagen pages 1-2)
Jaffey et al., “Novel Homozygous ADAMTS2 Variants…in Dogs,” published November 19, 2022. DOI/URL: https://doi.org/10.3390/genes13112158. Abstract quotation: “Due to severe skin fragility, the owners of all 6 dogs elected euthanasia before the dogs reached 13 weeks of age.” (jaffey2022novelhomozygousadamts2 pages 1-2)

PMIDs were not exposed in the retrieved full-text records and are therefore not guessed. DOI URLs above provide stable primary-source links.

References

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(zschocke2024geneticdiagnosisof pages 8-9): Johannes Zschocke, Serwet Demirdas, and Fleur S. van Dijk. Genetic diagnosis of the ehlers-danlos syndromes. Medizinische Genetik, 36:235-245, Nov 2024. URL: https://doi.org/10.1515/medgen-2024-2061, doi:10.1515/medgen-2024-2061. This article has 7 citations.
(kapfererseebacher2020dentalmanifestationsof pages 1-2): I. Kapferer-Seebacher, D. Schnabl, J. Zschocke, and F. Pope. Dental manifestations of ehlers-danlos syndromes: a systematic review. Acta Dermato-Venereologica, 100:adv00092-160, Mar 2020. URL: https://doi.org/10.2340/00015555-3428, doi:10.2340/00015555-3428. This article has 48 citations and is from a domain leading peer-reviewed journal.
(malek2021theroleof pages 2-3): Sabeeha Malek and Darius V. Köster. The role of cell adhesion and cytoskeleton dynamics in the pathogenesis of the ehlers-danlos syndromes and hypermobility spectrum disorders. Frontiers in Cell and Developmental Biology, Apr 2021. URL: https://doi.org/10.3389/fcell.2021.649082, doi:10.3389/fcell.2021.649082. This article has 27 citations.
(colige1999humanehlersdanlossyndrome pages 1-2): Alain Colige, Aleksander L. Sieron, Shi-Wu Li, Ulrike Schwarze, Elizabeth Petty, Wladimir Wertelecki, William Wilcox, Deborah Krakow, Daniel H. Cohn, W. Reardon, Peter H. Byers, Charles M. Lapière, Darwin J. Prockop, and Betty V. Nusgens. Human ehlers-danlos syndrome type vii c and bovine dermatosparaxis are caused by mutations in the procollagen i n-proteinase gene. American journal of human genetics, 65 2:308-17, Aug 1999. URL: https://doi.org/10.1086/302504, doi:10.1086/302504. This article has 482 citations and is from a highest quality peer-reviewed journal.
(neto2024unravelingthegenetic pages 5-6): Nilton Salles Rosa Neto, Ivânio Alves Pereira, Flávio Roberto Sztajnbok, and Valderílio Feijó Azevedo. Unraveling the genetic collagen connection: clinical and therapeutic insights on genetic connective tissue disorders. Advances in Rheumatology, Apr 2024. URL: https://doi.org/10.1186/s42358-024-00373-z, doi:10.1186/s42358-024-00373-z. This article has 11 citations.
(damme2016expandingtheclinical pages 2-3): Tim Van Damme, Alain Colige, Delfien Syx, Cecilia Giunta, Uschi Lindert, Marianne Rohrbach, Omid Aryani, Yasemin Alanay, Pelin Özlem Simsek-Kiper, Hester Y. Kroes, Koen Devriendt, Marc Thiry, Sofie Symoens, Anne De Paepe, and Fransiska Malfait. Expanding the clinical and mutational spectrum of the ehlers–danlos syndrome, dermatosparaxis type. Sep 2016. URL: https://doi.org/10.1038/gim.2015.188, doi:10.1038/gim.2015.188. This article has 68 citations and is from a highest quality peer-reviewed journal.
(damme2016expandingtheclinical pages 7-8): Tim Van Damme, Alain Colige, Delfien Syx, Cecilia Giunta, Uschi Lindert, Marianne Rohrbach, Omid Aryani, Yasemin Alanay, Pelin Özlem Simsek-Kiper, Hester Y. Kroes, Koen Devriendt, Marc Thiry, Sofie Symoens, Anne De Paepe, and Fransiska Malfait. Expanding the clinical and mutational spectrum of the ehlers–danlos syndrome, dermatosparaxis type. Sep 2016. URL: https://doi.org/10.1038/gim.2015.188, doi:10.1038/gim.2015.188. This article has 68 citations and is from a highest quality peer-reviewed journal.
(damme2016expandingtheclinical pages 1-2): Tim Van Damme, Alain Colige, Delfien Syx, Cecilia Giunta, Uschi Lindert, Marianne Rohrbach, Omid Aryani, Yasemin Alanay, Pelin Özlem Simsek-Kiper, Hester Y. Kroes, Koen Devriendt, Marc Thiry, Sofie Symoens, Anne De Paepe, and Fransiska Malfait. Expanding the clinical and mutational spectrum of the ehlers–danlos syndrome, dermatosparaxis type. Sep 2016. URL: https://doi.org/10.1038/gim.2015.188, doi:10.1038/gim.2015.188. This article has 68 citations and is from a highest quality peer-reviewed journal.
(damme2016expandingtheclinical pages 5-7): Tim Van Damme, Alain Colige, Delfien Syx, Cecilia Giunta, Uschi Lindert, Marianne Rohrbach, Omid Aryani, Yasemin Alanay, Pelin Özlem Simsek-Kiper, Hester Y. Kroes, Koen Devriendt, Marc Thiry, Sofie Symoens, Anne De Paepe, and Fransiska Malfait. Expanding the clinical and mutational spectrum of the ehlers–danlos syndrome, dermatosparaxis type. Sep 2016. URL: https://doi.org/10.1038/gim.2015.188, doi:10.1038/gim.2015.188. This article has 68 citations and is from a highest quality peer-reviewed journal.
(goff2006regulationofprocollagen pages 1-2): Carine Le Goff, Robert P. T. Somerville, Frederic Kesteloot, Kimerly Powell, David E. Birk, Alain C. Colige, and Suneel S. Apte. Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous adamts proteases: insights on collagen biosynthesis and dermatosparaxis. Development, 133(8):1587-1596, Apr 2006. URL: https://doi.org/10.1242/dev.02308, doi:10.1242/dev.02308. This article has 142 citations and is from a domain leading peer-reviewed journal.
(goff2006regulationofprocollagen pages 7-8): Carine Le Goff, Robert P. T. Somerville, Frederic Kesteloot, Kimerly Powell, David E. Birk, Alain C. Colige, and Suneel S. Apte. Regulation of procollagen amino-propeptide processing during mouse embryogenesis by specialization of homologous adamts proteases: insights on collagen biosynthesis and dermatosparaxis. Development, 133(8):1587-1596, Apr 2006. URL: https://doi.org/10.1242/dev.02308, doi:10.1242/dev.02308. This article has 142 citations and is from a domain leading peer-reviewed journal.
(damme2016expandingtheclinical pages 3-5): Tim Van Damme, Alain Colige, Delfien Syx, Cecilia Giunta, Uschi Lindert, Marianne Rohrbach, Omid Aryani, Yasemin Alanay, Pelin Özlem Simsek-Kiper, Hester Y. Kroes, Koen Devriendt, Marc Thiry, Sofie Symoens, Anne De Paepe, and Fransiska Malfait. Expanding the clinical and mutational spectrum of the ehlers–danlos syndrome, dermatosparaxis type. Sep 2016. URL: https://doi.org/10.1038/gim.2015.188, doi:10.1038/gim.2015.188. This article has 68 citations and is from a highest quality peer-reviewed journal.
(balagopal2026exploringthehemorrhagic pages 1-4): Akshaya Kumar Balagopal, Santhi T S, Ashokraj Selvam, and Vimalraj Vijayakumar. Exploring the hemorrhagic manifestations of an adolescent with dermatosparaxis-type ehlers-danlos syndrome: a case report. Cureus, May 2026. URL: https://doi.org/10.7759/cureus.108459, doi:10.7759/cureus.108459. This article has 0 citations.
(zschocke2024geneticdiagnosisof pages 2-3): Johannes Zschocke, Serwet Demirdas, and Fleur S. van Dijk. Genetic diagnosis of the ehlers-danlos syndromes. Medizinische Genetik, 36:235-245, Nov 2024. URL: https://doi.org/10.1515/medgen-2024-2061, doi:10.1515/medgen-2024-2061. This article has 7 citations.
(jaffey2022novelhomozygousadamts2 pages 1-2): Jared A. Jaffey, Garrett Bullock, Juyuan Guo, Tendai Mhlanga-Mutangadura, Dennis P. O’Brien, Joan R. Coates, Rochelle Morrissey, Robert Hutchison, Kevin S. Donnelly, Leah A. Cohn, Martin L. Katz, and Gary S. Johnson. Novel homozygous adamts2 variants and associated disease phenotypes in dogs with dermatosparactic ehlers–danlos syndrome. Nov 2022. URL: https://doi.org/10.3390/genes13112158, doi:10.3390/genes13112158. This article has 16 citations.
(jaffey2022novelhomozygousadamts2 pages 14-15): Jared A. Jaffey, Garrett Bullock, Juyuan Guo, Tendai Mhlanga-Mutangadura, Dennis P. O’Brien, Joan R. Coates, Rochelle Morrissey, Robert Hutchison, Kevin S. Donnelly, Leah A. Cohn, Martin L. Katz, and Gary S. Johnson. Novel homozygous adamts2 variants and associated disease phenotypes in dogs with dermatosparactic ehlers–danlos syndrome. Nov 2022. URL: https://doi.org/10.3390/genes13112158, doi:10.3390/genes13112158. This article has 16 citations.
(balagopal2026exploringthehemorrhagic pages 6-7): Akshaya Kumar Balagopal, Santhi T S, Ashokraj Selvam, and Vimalraj Vijayakumar. Exploring the hemorrhagic manifestations of an adolescent with dermatosparaxis-type ehlers-danlos syndrome: a case report. Cureus, May 2026. URL: https://doi.org/10.7759/cureus.108459, doi:10.7759/cureus.108459. This article has 0 citations.
(islam2021ehlersdanlossyndromeimmunologic pages 1-8): Mareesa Islam, Christopher Chang, and M. Eric Gershwin. Ehlers-danlos syndrome: immunologic contrasts and connective tissue comparisons. Jan 2021. URL: https://doi.org/10.1016/j.jtauto.2020.100077, doi:10.1016/j.jtauto.2020.100077. This article has 40 citations and is from a peer-reviewed journal.
(jaffey2022novelhomozygousadamts2 pages 10-11): Jared A. Jaffey, Garrett Bullock, Juyuan Guo, Tendai Mhlanga-Mutangadura, Dennis P. O’Brien, Joan R. Coates, Rochelle Morrissey, Robert Hutchison, Kevin S. Donnelly, Leah A. Cohn, Martin L. Katz, and Gary S. Johnson. Novel homozygous adamts2 variants and associated disease phenotypes in dogs with dermatosparactic ehlers–danlos syndrome. Nov 2022. URL: https://doi.org/10.3390/genes13112158, doi:10.3390/genes13112158. This article has 16 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	5
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	40
Resolved	39
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	0
Terms whose name was checked	16
Terms named correctly	15
Terms named as a different term	1

Terms the report names something else

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

MONDO:0009161 (2 mentions) - the report calls it "if available"; MONDO calls it Ehlers-Danlos syndrome, dermatosparaxis type

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:0062023 (obsolete collagen-containing extracellular matrix) (1 mention) - replaced by GO:0031012

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

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.
No quality-of-life or PRO data specific to dEDS (no EQ-5D/SF-36/PROMIS studies).
No omics resources (transcriptomic/proteomic/metabolomic/single-cell) dedicated to human dEDS; mechanism rests on biochemistry, EM, and genetics.
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.
Genotype–phenotype correlation is incomplete — the basis for the "typical severe" vs. "milder" variant distinction, and modifiers of expressivity, are not resolved in humans.
Therapeutics gap: no disease-modifying therapy; no dEDS-specific clinical trials identified.
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

Establish a dEDS patient registry (multicenter, international) to capture prevalence, natural history, complication rates, and standardized quality-of-life outcomes.
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.
Deep phenotyping of visceral/vascular fragility (imaging surveillance protocols) to define screening recommendations and prevent life-threatening events such as gastric volvulus.
Bone-health natural history — systematic assessment of BMD and fracture risk across the lifespan to guide surveillance and intervention.
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).
Molecular/EM diagnostic standardization — validate the pN-collagen biochemical assay and fibril-morphometry as adjuncts to molecular testing.
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.
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.

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Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

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Output Format

Dermatosparaxis Ehlers–Danlos syndrome: disease-characteristics report

Executive summary and evidence scope

1. Disease information

Definition and nomenclature

2. Etiology, risk, protection, and environment

Primary cause

Genetic risk factors

Modifiers and protective factors

Environmental and infectious factors

3. Phenotypes

4. Genetic and molecular information

Causal gene and protein

Variant interpretation

Genotype–phenotype relationship

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Detailed biology and ontology suggestions

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance and population

10. Diagnostics

Clinical recognition and criteria

Recommended genetic testing

Functional and pathology tests

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment and current applications

Disease-modifying therapy

Supportive management

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Adamts2-null mouse

Natural and cellular models

Recent developments, expert interpretation, and research priorities

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