Arthrochalasia Ehlers-Danlos Syndrome

Mendelian MONDO:0007525 Pathograph 59 Show in embeddings browser Ehlers-Danlos Syndrome Connective Tissue Disorder

Arthrochalasia Ehlers–Danlos syndrome is a rare type I collagen disorder usually presenting at birth with congenital hip dislocation, severe generalized joint hypermobility and recurrent dislocations. Classic disease is caused by heterozygous COL1A1 or COL1A2 variants that remove all or part of exon 6 from the collagen transcript, disrupting N-propeptide cleavage. Skin abnormalities, hypotonia, motor delay and skeletal complications vary. The clinical diagnosis requires molecular interpretation; other COL1-related overlap phenotypes, including an emerging recessive arthrochalasia-like presentation, should not be assumed to share this exon-6 mechanism.

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Inheritance

Autosomal dominant HP:0000006

Classic exon-6-related disease may be inherited or arise de novo. An affected heterozygous parent has a one-in-two transmission probability per pregnancy. A negative parental blood result does not exclude gonadal mosaicism, but the reviewed aEDS reports do not establish a numeric mosaic recurrence risk. Familial transmission and affected adults with children contradict a presumed universal reproductive limitation.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:32091183 SUPPORT BACKGROUND Human Clinical

"Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder"

Disease inheritance context.

PMID:1990839 SUPPORT PRIMARY RESULT Human Clinical

"Allele-specific oligonucleotide hybridizations demonstrated that the proband's mother, father, and brother did not have the mutation. Therefore, the mutation was a sporadic one."

Family testing in one case, not an estimate of the de novo proportion.

PMID:1556139 SUPPORT PRIMARY RESULT Human Clinical

"The proband and her son were heterozygous for the mutation."

Direct familial transmission.

+ 1 more reference

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Subtypes

Arthrochalasia Type 1 (EDS VIIA, COL1A1-related) MONDO:0020521

COL1A1 hgnc:2197

The COL1A1-related form, historically EDS VIIA, affects proalpha1(I). A more severe musculoskeletal phenotype has been suggested, but small selected cohorts and related participants limit comparison with COL1A2 disease.

Show evidence (2 references)

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features."

A 12-patient cohort reports COL1A1 exon 6 loss variants associate with more severe musculoskeletal disease.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"However, according to our series of patients, the phenotype seems to be similar in patients with COL1A1 (patients 5-7) and COL1A2 mutations (patients 1-4), at least in the neonatal and postnatal periods."

The three COL1A1 participants belong to one family; this is not a powered comparison.

Arthrochalasia Type 2 (EDS VIIB, COL1A2-related) MONDO:0040501

COL1A2 hgnc:2198

The COL1A2-related form, historically EDS VIIB, affects proalpha2(I). Variants remove all or part of exon 6, including the N-proteinase cleavage site; both splice donor and cryptic splice acceptor mechanisms are documented.

Show evidence (1 reference)

PMID:10073586 SUPPORT PRIMARY RESULT Human Clinical

"both of our patients had type-VIIB Ehlers-Danlos syndrome, which is caused by heterozygous new mutations of the COL1A2 gene that encodes the proalpha2(I) chain of type-I procollagen. The obligatory GT dinucleotide at the splice donor site of intron 6 was altered in both of our patients"

Documents heterozygous COL1A2 splice-donor mutations at the intron 6 boundary as the molecular cause of type VIIB arthrochalasia.

Discussions and Knowledge Gaps

How should biallelic non-exon-6 COL1A1 arthrochalasia-like disease be classified?

KNOWLEDGE GAP OPEN aeds_recessive_overlap_boundary

Attached to

genetic#COL1A1

A 2026 report describes one ten-month-old child homozygous for exon 31 p.Glu684Lys with healthy heterozygous parents. The authors call the variant likely pathogenic using PM1/PM2/PP3/PP5, including a prior assertion whose underlying evidence was unavailable. They explicitly distinguish an arthrochalasia-like or COL1-related overlap phenotype from the currently recognized dominant form. No RNA, N-propeptide processing, helix stability, integrin binding or rescue assay was performed. Proposed charge and GFOGER-binding effects remain hypotheses; long-term cognition, course and founder origin are unresolved. These observations should not change classic aEDS inheritance or its exon 6 mechanism by assumption.

Show evidence (3 references)

PMID:42353838 SUPPORT PRIMARY RESULT Other

"The molecular mechanism of the missense variant c.2050G>A (p.Glu684Lys) has not been definitively established."

Explicit absence of an established variant mechanism.

PMID:42353838 SUPPORT PRIMARY RESULT Other

"Although the p.Glu684Lys substitution is predicted to disrupt integrin–collagen interaction, in vivo impairment of this interaction has not been experimentally confirmed for this particular variant. Consequently, the functional consequences remain hypothetical."

No direct binding or organismal validation.

PMID:42353838 SUPPORT PRIMARY RESULT Human Clinical

"Haplotype analysis was not performed in the current study; therefore, it remains unknown whether this variant represents a shared founder haplotype or arose as an independent mutational event."

Founder origin is untested.

What is the age-specific fracture burden in molecularly confirmed aEDS?

KNOWLEDGE GAP OPEN aeds_fracture_risk_and_source_conflicts

Attached to

phenotypes#Bone Fractures phenotypes#Osteopenia

The 2020 selected cohort reports 9/12 with fractures; the 2019 mixed-EDS study contains only one probable, non-molecularly confirmed aEDS case without fractures. Its pooled odds ratio and infant findings should not become aEDS-specific risk estimates. The 2012 article contains incompatible fracture statements: patient 4 had slowly healing fractures and a positive table cell, but the table total is 0/7 and discussion says none. The 2022 review also misrepresents the 2020 bone review, whose abstract explicitly includes aEDS among rare types with frequent fractures/low BMD. A deduplicated, genetically defined longitudinal cohort is needed; source contradictions should not be resolved by inventing a numerator.

Show evidence (3 references)

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment."

Selected cohort observation.

PMID:30856599 SUPPORT PRIMARY RESULT Human Clinical

"The subject with arthrochalasia EDS had no fractures."

One negative observation.

PMID:32162201 SUPPORT REVIEW SYNTHESIS Human Clinical

"Low bone mineral density and fractures seem to be frequent in some of the rare EDS types (kyphoscoliotic, arthrochalasia, spondylodysplastic, and classic-like EDS)."

Actual bone-review statement contradicts its later secondary characterization.

Does COL1A1 exon6 disruption consistently cause more severe disease than COL1A2 disruption?

KNOWLEDGE GAP OPEN aeds_genotype_severity

Attached to

genetic#COL1A1 genetic#COL1A2

Type I collagen contains two alpha1 chains and one alpha2 chain, motivating a mutant-molecule stoichiometry hypothesis. Clinical comparisons remain small and overlapping. The 2020 series suggested more severe COL1A1 musculoskeletal involvement; the 2012 series reported similar early phenotypes, but its three COL1A1 participants came from one family. Neither establishes a deterministic prognosis or a universally measured fraction of defective molecules.

Show evidence (2 references)

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

Selected cohort inference.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Part of this similarity can be attributed to the fact that patients 5-7 all come from the same family"

Non-independence limits genotype comparison.

What cardiovascular surveillance is justified in molecularly confirmed aEDS?

KNOWLEDGE GAP OPEN aeds_cardiovascular_scope

Attached to

phenotypes#Mitral Regurgitation treatments#Cardiovascular assessment and individualized follow-up

One confirmed COL1A2 exon-6 case developed valve regurgitation while systolic function and aortic-root dimensions remained normal. This differs genetically from recessive cardiac-valvular EDS due to biallelic COL1A2 null variants. A systematic review of nonvascular EDS included 17 selected aEDS patients and identified one perioperative hemorrhage, plus a separate report of postpartum bleeding; its surgical paragraph inconsistently gives a denominator of 18. These case-based data do not establish population risks or a vascular-EDS-like arterial phenotype. The review did not report arterial aneurysm or dissection in its aEDS subset. This is absence from selected literature, not proof that such an event is impossible. Routine preventive vascular drugs or intensive arterial screening cannot be inferred from the reviewed reports.

Show evidence (3 references)

PMID:23158907 SUPPORT PRIMARY RESULT Human Clinical

"Left ventricular ejection fraction was within normal reference (65%)."

Normal systolic function in the valve case.

PMID:28981071 SUPPORT REVIEW SYNTHESIS Human Clinical

"in one patient with aEDS (1/18, 6%) who bled excessively at surgery (unspecified)"

Positive surgical-bleeding report; denominator conflicts with Table3 and is not used as a risk estimate.

PMID:28981071 SUPPORT REVIEW SYNTHESIS Human Clinical

"the data summarized here are derived mostly from either case reports (n = 51) or case series (n = 59), which are prone to publication and selection bias"

Explicit source ascertainment limit.

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Pathophysiology

COL1A1 Exon 6-Affecting Variants

Heterozygous splice-region variants or genomic deletions affect exon 6 of COL1A1. This is a structural collagen-processing disorder, not a general loss of enzyme production.

COL1A1 hgnc:2197

Downstream

Loss of Exon 6 Sequence from Collagen Transcripts Splice-region or genomic changes remove the corresponding coding sequence from the transcript.

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Genetic investigations in individuals with suspected aEDS should focus on pathogenic COL1A2 or COL1A1 variants affecting exon 6 splicing and should include exon (5 and) 6 deletion analysis."

Variant classes in a contemporary diagnostic review.

COL1A2 Exon 6-Affecting Variants

Heterozygous splice-region variants or genomic deletions affect exon 6 of COL1A2. This is a structural collagen-processing disorder, not a general loss of enzyme production.

COL1A2 hgnc:2198

Downstream

Loss of Exon 6 Sequence from Collagen Transcripts Splice-region or genomic changes remove the corresponding coding sequence from the transcript.

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Genetic investigations in individuals with suspected aEDS should focus on pathogenic COL1A2 or COL1A1 variants affecting exon 6 splicing and should include exon (5 and) 6 deletion analysis."

Variant classes in a contemporary diagnostic review.

Loss of Exon 6 Sequence from Collagen Transcripts

Complete exon skipping or cryptic splice-site use removes different lengths of coding sequence. Whole-exon losses affect 24 residues in proalpha1(I) or 18 in proalpha2(I); a COL1A2 partial deletion can remove only five residues.

Experimental models

COL1A2 whole-exon-skipping patient fibroblasts PRIMARY CELL CULTURE Patient transcript sequencing identified the skipped exon.

COL1A2 partial-exon deletion biochemical studies PRIMARY CELL CULTURE Cryptic splicing removes fifteen coding nucleotides from the collagen transcript.

Downstream

Loss of Procollagen N-Proteinase Cleavage Site Loss of exon-encoded residues removes the substrate cleavage site.

Mitral Regurgitation This molecularly confirmed child had valve regurgitation; the proposed collagen-mediated valve-tissue mechanism was not directly tested and the intervening pathway remains uncertain.

Aortic Regurgitation This molecularly confirmed child had valve regurgitation; the proposed collagen-mediated valve-tissue mechanism was not directly tested and the intervening pathway remains uncertain.

Tricuspid Regurgitation This molecularly confirmed child had valve regurgitation; the proposed collagen-mediated valve-tissue mechanism was not directly tested and the intervening pathway remains uncertain.

Motor Developmental Delay The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Congenital or Early-Onset Hypotonia The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Short Stature The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Hypertelorism The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Epicanthal Folds The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Micrognathia The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Sparse Hair The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Frontal Bossing The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Depressed Nasal Bridge The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Midfacial Hypoplasia The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Large Fontanelles The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Feeding Difficulties The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.

Show evidence (3 references)

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2."

Direct patient-cell RNA result.

PMID:8081389 SUPPORT PRIMARY RESULT In Vitro

"Exon 6 encodes 18 amino acids of the N-telopeptide which contains the procollagen N-proteinase cleavage site and a cross-link precursor lysine."

COL1A2 exon-encoded segment; this length is not generalized to COL1A1.

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

"These 15 nucleotides were deleted in the splicing of alpha 2(I) pre-mRNA to mRNA as a result of inactivation of the 3' splice site of intron 5 by an AG to AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6."

Allele-specific cryptic splicing; not whole-exon loss.

Loss of Procollagen N-Proteinase Cleavage Site

The shortened collagen substrate lacks its normal N-proteinase cleavage site. Some complete deletions also remove a crosslinking lysine, but the five-residue COL1A2 deletion preserves that lysine; lysine loss is not required in every case.

Downstream

Retained Procollagen N-Propeptide The structurally altered substrate is poorly cleaved despite normal protease production.

Show evidence (2 references)

PMID:3082886 SUPPORT PRIMARY RESULT In Vitro

"Loss of the procollagen N-proteinase cleavage site from the mutant pro-alpha 1(I) chain accounted for the persistence of its NH2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts."

Structural substrate defect despite normal enzyme production.

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

"In contrast to previously reported cases of EDS-VIIB, Lys5 of the N-telopeptide was not deleted and appeared to take part in the formation of intramolecular cross-linkages."

Counterexample to universal crosslink-lysine deletion.

Retained Procollagen N-Propeptide

Impaired cleavage leaves pN collagen chains with the amino-terminal propeptide attached. Patient fibroblast assays demonstrate delayed processing; they do not establish a systemic deficiency of procollagen N-proteinase.

Experimental models

COL1A2 whole-exon-skipping patient fibroblasts PRIMARY CELL CULTURE Amino-propeptide processing was substantially delayed relative to controls.

COL1A2 partial-exon deletion biochemical studies PRIMARY CELL CULTURE Mutant pN chains persisted in patient collagen preparations.

COL1A1 patient collagen-processing studies PRIMARY CELL CULTURE Patient-cell collagen retained amino-terminal propeptide.

Downstream

Disordered Collagen Fibril Architecture Persisting propeptides alter collagen assembly and packing; patient ultrastructure supports the downstream matrix abnormality without isolating every assembly step.

Show evidence (2 references)

PMID:3082886 SUPPORT PRIMARY RESULT In Vitro

Normal enzyme output distinguishes this from ADAMTS2-related dermatosparaxis.

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband."

Pulse-labeling comparison with control cultures over five days.

Disordered Collagen Fibril Architecture

Patient skin shows altered collagen fibril size, packing and contour. The abnormal collagen-processing state is linked to disturbed fibrillogenesis, but a skin biopsy is not a direct tensile-strength measurement of every affected tissue.

Downstream

Reduced Periarticular Tissue Stability Disordered matrix is inferred to reduce tissue mechanical integrity; direct tissue-specific biomechanical measurements are lacking.

Reduced Dermal Mechanical Integrity Disordered matrix is inferred to reduce tissue mechanical integrity; direct tissue-specific biomechanical measurements are lacking.

Bone Fractures This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.

Blue Sclerae This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.

Osteopenia This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.

Wormian Bones This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.

Ectopia Lentis This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.

Dentinogenesis Imperfecta This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.

Umbilical Hernia Abnormal collagen-containing abdominal support tissues are inferred to contribute to herniation; no direct fascial biomechanical measurement was reported.

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Fibril density was lower in the dermis than in control, and occasional cauliflower deformations of the fibrils were seen. Collagen fibrils were irregular in contour and had distinctly smaller diameters than in control samples (43.82 +/- 6.09 nm)."

Dermal ultrastructure in one investigated participant; no whole-body biomechanical assay.

Reduced Periarticular Tissue Stability

Mechanism confidence: Provisional

Abnormal collagen-containing joint-support tissues are inferred to underlie marked instability and dislocations. The clinical and collagen findings support this bridge, while the cited studies do not directly measure fetal capsule or ligament tensile strength.

Downstream

Congenital Hip Dislocation Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Generalized Joint Hypermobility Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Recurrent Joint Dislocation Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Kyphoscoliosis Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Clubfoot Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Pes Planus Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Genu Valgum Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Lumbar Hyperlordosis Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Joint Pain Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Premature Osteoarthritis Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.

Show evidence (1 reference)

PMID:21801164 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation."

Human clinical instability; biomechanical mediation is inferred.

Reduced Dermal Mechanical Integrity

Mechanism confidence: Provisional

Disordered collagen matrix contributes to skin fragility and altered mechanical behavior. Relative contributions of fibril packing and crosslinking vary by allele; the human clinical findings do not isolate a single mechanical mediator.

Downstream

Hyperextensible Skin Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.

Bruising Susceptibility Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.

Fragile Skin Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.

Poor Wound Healing Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.

Atrophic Scars Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.

Soft Skin Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.

Piezogenic Pedal Papules Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.

Show evidence (1 reference)

PMID:21801164 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child."

Clinical skin findings in patient 4; tissue-mechanical bridge is inferred.

⬡

Pathograph

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

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Phenotypes

Blood 1

Bruising Susceptibility HP:0000978

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child."

One adult with bruising and skin fragility; table totals are inconsistent and not used.

Cardiovascular 3

Mitral Regurgitation HP:0001653

Show evidence (1 reference)

PMID:23158907 SUPPORT PRIMARY RESULT Human Clinical

"Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild."

One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.

Aortic Regurgitation HP:0001659

Show evidence (1 reference)

PMID:23158907 SUPPORT PRIMARY RESULT Human Clinical

"Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild."

One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.

Tricuspid Regurgitation HP:0005180

Show evidence (1 reference)

PMID:23158907 SUPPORT PRIMARY RESULT Human Clinical

"Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild."

One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.

Digestive 2

Umbilical Hernia HP:0001537

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"He developed an umbilical hernia in the first year of life."

Case report documents umbilical hernia developing in infancy in an arthrochalasia EDS patient.

Feeding Difficulties HP:0011968

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"He was hospitalized 10 days after birth because of poor feeding and growth."

Patient3 neonatal history.

Eye 3

Blue Sclerae HP:0000592

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Several of our patients (patients 1 and 5-7) have blue sclerae and some have abnormal dentition, features known to be present in OI."

Case report documents blue sclerae in a majority of the described arthrochalasia EDS patients, noting the clinical overlap with osteogenesis imperfecta.

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia."

Clinical spectrum review.

Ectopia Lentis HP:0001083

Show evidence (1 reference)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Blue sclerae (n ¼ 3) and ectopia lentis (n ¼ 1) were recorded."

Selected published-case review; not a population denominator.

Head and Neck 8

Epicanthal Folds Epicanthus HP:0000286

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia."

Clinical spectrum review.

Micrognathia HP:0000347

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Patient 1 (Figure 1 and 2) was born at 35 weeks gestation by vaginal breech delivery with hypotonia and dysmorphic features that included micrognathia and sparse hair."

Affected infant; not the separate mutation-negative mother who underwent mandibular surgery.

Frontal Bossing HP:0002007

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia."

Human clinical review; no uniform frequency inferred.

Depressed Nasal Bridge HP:0005280

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia."

Human clinical review; no uniform frequency inferred.

Midfacial Hypoplasia Midface retrusion HP:0011800

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia."

Human clinical review; no uniform frequency inferred.

Large Fontanelles HP:0000239

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"At birth she presented with bilateral congenital dislocation of the hips, severe joint hypermobility and large fontanels."

History of patient 4.

Wormian Bones HP:0002645

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Radiographic evaluation of the skeleton revealed presence of Wormian bones, thoracic scoliosis and generalized osteopenia. Bone densitometry however yielded normal values for DEXA Z-scores at the level of the femur and the lumbar spine."

Radiographic observation in patient 4.

Dentinogenesis Imperfecta HP:0000703

Show evidence (1 reference)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Dentinogenesis imperfecta was re- corded in a few patients (n ¼ 3)."

Published-case synthesis; related-family overlap limits frequency.

Integument 7

Hyperextensible Skin HP:0000974

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Most individuals also display the typical EDS features of soft, doughy, hyperextensible or redundant skin, often with easy bruising and atrophic scarring."

Clinical spectrum review.

Sparse Hair HP:0008070

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Patient 1 (Figure 1 and 2) was born at 35 weeks gestation by vaginal breech delivery with hypotonia and dysmorphic features that included micrognathia and sparse hair."

Affected infant; not the separate mutation-negative mother who underwent mandibular surgery.

Fragile Skin HP:0001030

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child."

Adult clinical finding.

Poor Wound Healing HP:0001058

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child."

Adult clinical finding.

Atrophic Scars HP:0001075

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Her skin was very soft with some hyperextensibility and several cigarette-paper-like scars."

Direct adult examination.

Soft Skin HP:0000977

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Hypermobility and dislocations of all joints persisted, and soft and velvety skin with criss-cross patterning of the palms and soles was noted."

Direct infant examination.

Piezogenic Pedal Papules HP:0025509

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"He still has very loose, soft skin with piezogenic papules (herniation of fat through the dermis) along the lateral aspects of his heels."

Direct patient 3 examination.

Limbs 4

Congenital Hip Dislocation HP:0001374

Show evidence (2 references)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"After birth extreme hyperlaxity of both small and large joints was noted, with bilateral hip dislocation, bilateral subluxation of the radius and a stable subluxation of vertebrae C1-C2 without spinal cord compression, in combination with neonatal hypotonia"

One molecularly confirmed neonatal presentation.

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"One unreported molecularly proven aEDS patient is known to have had congenital unilateral hip dislocation"

Consensus footnote describes an exceptional case from personal communication.

Clubfoot Talipes equinovarus HP:0001762

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"bilateral clubfeet (correctable after plaster casts and night splints), bilateral congenital dislocation of the hips and soft, velvety skin were noted"

Case report documents bilateral clubfeet, correctable with casting/splinting, in an arthrochalasia EDS patient.

Pes Planus HP:0001763

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine"

Direct adult examination.

Genu Valgum HP:0002857

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine"

Direct adult examination.

Musculoskeletal 8

Generalized Joint Hypermobility HP:0002761

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation."

Direct examination of patient 1.

Recurrent Joint Dislocation HP:0001373

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation."

Direct examination of patient 1.

Congenital or Early-Onset Hypotonia HP:0001252

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"It is not clear whether the hypotonia is solely caused by the laxity of the connective tissue or whether there is a muscular component. Remarkably, the hypotonia seems to diminish with increasing age, regardless of the level of joint hypermobility at that time."

Clinical observation and explicit mechanistic uncertainty.

Bone Fractures HP:0020110

Show evidence (4 references)

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment."

Selected twelve-person cohort, including six previously reported adults.

PMID:30856599 SUPPORT PRIMARY RESULT Human Clinical

"the one subject with arthochalasia EDS was felt to be a probable case with multiple consistent clinical findings and a positive skin biopsy but no molecular testing."

Limits the single comparison case.

PMID:30856599 SUPPORT PRIMARY RESULT Human Clinical

"The subject with arthrochalasia EDS had no fractures."

One negative clinical observation, not a refutation of fractures in other aEDS cohorts.

+ 1 more reference

Kyphoscoliosis HP:0002751

Show evidence (1 reference)

PMID:35162892 SUPPORT REVIEW SYNTHESIS Human Clinical

"such as muscular hypotonia, kyphoscoliosis, radiologically mild osteopenia, tissue fragility, including atrophic scarring, and hematomas."

Diagnostic clinical spectrum synthesized by the review.

Osteopenia HP:0000938

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

Paired radiograph and densitometry findings in patient 4.

Lumbar Hyperlordosis HP:0002938

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine"

Direct adult examination.

Premature Osteoarthritis HP:0003088

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"The right knee demonstrated moderate tricompartmental osteoarthritic changes. The left knee was normal."

Imaging at age 8 in patient 6.

Nervous System 1

Motor Developmental Delay Motor delay HP:0001270

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Motor development is significantly delayed in the neonatal and postnatal period due to muscular hypotonia and recurrent joint luxations, but cognitive development is usually normal."

Seven-person series; normal cognition does not imply intact mobility.

Constitutional 1

Joint Pain Arthralgia HP:0002829

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"She tends to walk with an antalgic gait and complains of subluxations of her right knee and chronic knee and hip pain."

Patient7 follow-up.

Growth 1

Short Stature HP:0004322

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Short stature | - | - | - | + | + | + | + | 4 / 7 | 2 / 6 | 21"

Table row supports presence in named participants; selected related cases do not provide a population frequency.

🧬

Genetic Associations

COL1A1 (Causative)

Gene: COL1A1 hgnc:2197 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"aEDS is caused by complete or partial loss of exon 6 of either COL1A2 or COL1A1 that precludes trimming by procollagen N-proteinase and leads to retention of the N-propeptide in the collagen type I triple helix."

Contemporary molecular diagnostic synthesis.

COL1A2 (Causative)

Gene: COL1A2 hgnc:2198 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

Contemporary molecular diagnostic synthesis.

💊

Medical Actions

Physical and occupational therapy

Action: Physical Therapy NCIT:C15302

Early individualized rehabilitation supports motor development, safe mobility and daily activities. Recommendations come mainly from expert review and case experience, not controlled aEDS trials.

Mechanism Target:

MODULATES Motor Developmental Delay — Therapy supports functional skill acquisition despite persistent collagen-related instability.

Show evidence (1 reference)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"Orthotic management and early intervention, including physical and occupational therapy are recom- mended to assist standing, walking, and activities of daily living"

Disease-specific expert management synthesis.

Show evidence (1 reference)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"Orthotic management and early intervention, including physical and occupational therapy are recom- mended to assist standing, walking, and activities of daily living"

Disease-specific expert management synthesis.

Joint orthoses and activity adaptation

Select orthoses and footwear for joint stability and tolerance. Skin abrasions or hematomas may require modification or discontinuation. Avoid activities with high dislocation risk; prescribed rehabilitation should remain individualized.

Mechanism Target:

BYPASSES Reduced Periarticular Tissue Stability — External support partly compensates for unstable joints without correcting collagen processing.

Show evidence (3 references)

PMID:21801164 SUPPORT REVIEW SYNTHESIS Other

"If skin problems are mild, the use of orthoses to stabilize knee, ankle and of foot joints can improve motor development."

Clinical series recommendation, not a randomized effect.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"The use of these orthoses had to be discontinued because of skin abrasions and hematomas."

Observed intolerance in one child.

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"Contact sports should be avoided to prevent dislocations"

Expert precaution.

Show evidence (3 references)

PMID:21801164 SUPPORT REVIEW SYNTHESIS Other

"If skin problems are mild, the use of orthoses to stabilize knee, ankle and of foot joints can improve motor development."

Clinical series recommendation, not a randomized effect.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"The use of these orthoses had to be discontinued because of skin abrasions and hematomas."

Observed intolerance in one child.

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"Contact sports should be avoided to prevent dislocations"

Expert precaution.

Hip surgical management

Action: Orthopedic Surgical Procedure NCIT:C16186

Closed reduction often fails in published selected cases. A specialist team weighs mobility goals, recurrence and wound risk when considering open reduction with pelvic or femoral osteotomy. Case-series experience does not establish a universal operation or inevitable failure of every conservative attempt.

Mechanism Target:

MODULATES Congenital Hip Dislocation — Reduction and osteotomy aim to improve femoral-head containment; collagen-related laxity can persist.

Show evidence (3 references)

PMID:10073586 SUPPORT PRIMARY RESULT Human Clinical

"The results of open reduction were improved when capsulorrhaphy was combined with iliac or femoral osteotomy, or both."

Historical selected-case comparison.

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery."

Treatment exposure, not comparative efficacy.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"She underwent a bilateral open hip reduction surgery at age 18 months but the right hip immediately redislocated."

Observed recurrence despite surgery.

Show evidence (3 references)

PMID:10073586 SUPPORT PRIMARY RESULT Human Clinical

"The results of open reduction were improved when capsulorrhaphy was combined with iliac or femoral osteotomy, or both."

Historical selected-case comparison.

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery."

Treatment exposure, not comparative efficacy.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"She underwent a bilateral open hip reduction surgery at age 18 months but the right hip immediately redislocated."

Observed recurrence despite surgery.

Individualized scoliosis bracing

A genetically diagnosed COL1A2 case improved from a 43.6-degree lumbar curve to 8 degrees after 3.5 years of a Wood-Rigo-Cheneau brace plus weekly physical therapy; at age 6 the curve measured 14 degrees after six months out of brace. Ongoing growth surveillance was required. This uncontrolled combination cannot prove brace superiority or permanent avoidance of surgery.

Mechanism Target:

MODULATES Kyphoscoliosis — External corrective forces can modify spinal alignment in selected patients while growth and skin tolerance are monitored.

Show evidence (2 references)

PMID:39343458 SUPPORT PRIMARY RESULT Human Clinical

"Through shared decision making with their EDS specialist, the family elected to proceed with conservative management using the WRC brace, in conjunction with weekly physical therapy."

Combined exposure in one child.

PMID:39343458 SUPPORT PRIMARY RESULT Human Clinical

"After 3.5 years, the patient’s Cobb angle decreased to 8°. His Cobb angle was stable under 15° on brace for 12 months. At the age of 6, after being out of brace for 6 months, his curve measured 14°"

Actual follow-up; not a controlled treatment comparison.

Show evidence (2 references)

PMID:39343458 SUPPORT PRIMARY RESULT Human Clinical

"Through shared decision making with their EDS specialist, the family elected to proceed with conservative management using the WRC brace, in conjunction with weekly physical therapy."

Combined exposure in one child.

PMID:39343458 SUPPORT PRIMARY RESULT Human Clinical

Actual follow-up; not a controlled treatment comparison.

Specialist surgery for severe spinal deformity

Action: Orthopedic Surgical Procedure NCIT:C16186

A 2025 report followed one clinically diagnosed patient for 17 years: traditional rods at age 5 were later replaced by magnetically lengthened rods at age 10. Kyphosis improved and sitting balance was good, but the scoliosis Cobb angle remained 100 degrees and wheelchair use persisted because of hip dislocation. The exchange procedure involved 1000 cc blood loss. No genotype, control group or general efficacy advantage was established.

Mechanism Target:

MODULATES Kyphoscoliosis — Instrumentation stabilizes or corrects selected components of spinal deformity; it does not restore normal collagen or guarantee ambulatory improvement.

Show evidence (2 references)

PMID:40227332 SUPPORT PRIMARY RESULT Human Clinical

"The procedure was complicated by 1000 cc of blood loss, attributed to the vascular fragility of this patient due to their aEDS."

Major blood loss during rod exchange qualifies the favorable abstract.

PMID:40227332 SUPPORT PRIMARY RESULT Human Clinical

"His Cobb angle has remained stable 100 degrees with good correction of kyphosis. He still ambulates in a wheelchair (due to a chronic hip dislocation since aged 9) with good sitting balance."

Long-term outcome distinguishes stability, kyphosis and mobility.

Show evidence (2 references)

PMID:40227332 SUPPORT PRIMARY RESULT Human Clinical

"The procedure was complicated by 1000 cc of blood loss, attributed to the vascular fragility of this patient due to their aEDS."

Major blood loss during rod exchange qualifies the favorable abstract.

PMID:40227332 SUPPORT PRIMARY RESULT Human Clinical

"His Cobb angle has remained stable 100 degrees with good correction of kyphosis. He still ambulates in a wheelchair (due to a chronic hip dislocation since aged 9) with good sitting balance."

Long-term outcome distinguishes stability, kyphosis and mobility.

Bone-health assessment and selected bisphosphonate use

Action: Bisphosphonate Therapy NCIT:C198585

Agent: Biphosphonate NCIT:C443

Assess fractures and radiographic findings in context; DXA may be normal despite radiographic osteopenia. One of twelve participants received a bisphosphonate, but the available cohort abstract gives no agent, dose, response or comparative benefit. This is documented use, not an aEDS-specific routine-treatment recommendation.

Show evidence (2 references)

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment."

Exposure only; no BMD or fracture response reported.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

Radiographic and DXA discordance supports careful assessment.

Skin protection and wound planning

Action: Wound Care Management NCIT:C116681

Minimize skin trauma from devices and procedures. Plan tension-free closure and follow-up with awareness of delayed healing; the review recommends longer suture retention, but timing should reflect the wound and specialist assessment. This guidance does not imply that every patient has extreme skin fragility.

Mechanism Target:

MODULATES Poor Wound Healing — Careful closure and reduced tension compensate for fragile healing tissues; the underlying matrix defect persists.

Show evidence (1 reference)

PMID:35162892 SUPPORT REVIEW SYNTHESIS Other

"Certain guidelines should be taken into account to avoid complications such as leaving sutures twice as long as normal before suture removal and that wounds should be closed without tension"

Expert guidance summarized by a review, not comparative outcome evidence.

Show evidence (1 reference)

PMID:35162892 SUPPORT REVIEW SYNTHESIS Other

"Certain guidelines should be taken into account to avoid complications such as leaving sutures twice as long as normal before suture removal and that wounds should be closed without tension"

Expert guidance summarized by a review, not comparative outcome evidence.

Pain and psychological support

Action: Pain Therapy NCIT:C15180

Individualize pain management and support coping with chronic instability and disability. The literature recommends anti-inflammatory medication and psychological or behavioral support, but does not establish a preferred regimen or aEDS-specific trial benefit.

Mechanism Target:

INHIBITS Joint Pain — Symptom-directed treatment aims to reduce pain without claiming correction of collagen assembly.

Show evidence (1 reference)

PMID:35162892 SUPPORT REVIEW SYNTHESIS Other

"Anti-inflammatory drugs can help patients with joint pain. In patients with muscle hypotonia and joint instability with chronic pain, emotional support and behavioral and psychological therapy to aid in accepting and offering coping strategies to manage disability is advised."

Review recommendations, with no disease-specific comparative effect estimate.

Show evidence (1 reference)

PMID:35162892 SUPPORT REVIEW SYNTHESIS Other

Review recommendations, with no disease-specific comparative effect estimate.

Pregnancy and delivery planning

Offer specialist follow-up through pregnancy and plan delivery where maternal and neonatal complications can be managed. Published affected mothers had live births, including affected children; possible perineal or pelvic-floor risks extrapolated from classical EDS should not be represented as measured aEDS event rates. Postpartum hemorrhage has been reported in one published affected mother; the selected literature denominator is not a prospective risk estimate.

Show evidence (2 references)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"Delivery should be performed in a medical center where intensive treat- ment could be given to an affected pregnant woman and an affected neonate"

Expert aEDS delivery recommendation.

PMID:28981071 SUPPORT REVIEW SYNTHESIS Human Clinical

"postpartum hemorrhaging was reported in one patient with aEDS (1/12 females, 8%) after the birth of each of her children"

One selected literature case, not an estimated pregnancy risk.

Multidisciplinary clinical surveillance

Monitor mobility, spinal alignment, skin/device tolerance, bone health and relevant dental or ocular findings. The 2017 review refers skin, cardiovascular and ophthalmic management to classical-EDS guidance; this does not establish a vascular-EDS-like rupture risk or universal intensive cardiac surveillance schedule.

Show evidence (1 reference)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"The advice to management of the skin, cardiovascular, and ophthalmological features is similar to that for patients with classical EDS"

Broader-EDS extrapolation is explicit.

Genetic counseling and family evaluation

Action: Genetic Counseling NCIT:C15240

Counsel on dominant transmission in classic disease, testing of a known family variant, variable functional severity and reproductive options. Both inherited and sporadic cases occur. Do not assign the lethal-OI parental-mosaicism percentage to aEDS or infer a confirmed carrier from mild features alone.

Show evidence (3 references)

PMID:1990839 SUPPORT PRIMARY RESULT Human Clinical

"Allele-specific oligonucleotide hybridizations demonstrated that the proband's mother, father, and brother did not have the mutation. Therefore, the mutation was a sporadic one."

One family with an apparent de novo variant.

PMID:1556139 SUPPORT PRIMARY RESULT Human Clinical

"The proband and her son were heterozygous for the mutation."

Direct inherited variant.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Somatic mosaicism for this IVS6+1G>T mutation was not demonstrated."

Negative testing is not proof of an aEDS mosaic parent.

Cardiovascular assessment and individualized follow-up

Consider cardiology assessment and echocardiographic follow-up according to examination and detected abnormalities. One molecularly confirmed child developed mitral, aortic and tricuspid regurgitation during annual follow-up. The case report supports vigilance but cannot establish universal annual imaging or preventive cardiovascular medication for all aEDS patients.

Show evidence (2 references)

PMID:23158907 SUPPORT PRIMARY RESULT Human Clinical

"Transthoracic echocardiograms using semiquantitative grading of valve regurgitation, were performed once a year. After two-year follow-up, combined valvulopathy, resulting in mitral, tricuspidal and aortic regurgitation, were detected."

Observed follow-up and progression in one child.

PMID:23158907 SUPPORT REVIEW SYNTHESIS Other

"Since we demonstrated a progressive valvular involvement a careful cardiac follow-up is warranted for EDS type VII patients"

Case-report recommendation, not a consensus surveillance interval.

🔬

Diagnosis

Clinical suspicion and molecular confirmation

Congenital hip dislocation, severe generalized hypermobility and skin hyperextensibility prompt testing. The 2017 minimum clinical criteria are suggestive, not independently confirmatory. Sequence and copy-number evaluation should include COL1A1/COL1A2 exon 6 and neighboring exon 5 deletions where appropriate; variant interpretation must distinguish classic aEDS from other COL1-related disorders.

Genetic Testing NCIT:C15709

Show evidence (2 references)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"Confirmatory molecular testing is obligatory to reach a final diagnosis."

International classification recommendation.

PMID:39629471 SUPPORT REVIEW SYNTHESIS Human Clinical

"Genetic investigations in individuals with suspected aEDS should focus on pathogenic COL1A2 or COL1A1 variants affecting exon 6 splicing and should include exon (5 and) 6 deletion analysis."

Updated diagnostic review.

RNA and collagen-processing studies

Transcript analysis can establish complete exon skipping or cryptic splice-site use. Fibroblast collagen electrophoresis may show retained pN chains and delayed processing. These assays characterize uncertain molecular effects and were diagnostic in historical cases; current diagnosis is not established by an arbitrary collagen-gene VUS alone.

Show evidence (2 references)

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2."

Patient-cell transcript assay.

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband."

Patient-cell processing assay.

Dermal ultrastructure as an adjunct

Transmission electron microscopy may show disorganized small irregular fibrils, but it cannot independently confirm aEDS or reliably replace molecular testing.

Show evidence (2 references)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Other

"These findings may support the diagnosis, but cannot confirm it."

Classification qualification immediately after its aEDS TEM description.

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

Positive biopsy finding in one molecularly investigated adult.

📈

Progression

Congenital and infantile presentation

Hip dislocation and generalized hypermobility can be evident at birth; hypotonia and recurrent instability delay motor milestones. Cognitive and motor development must be assessed separately.

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Motor development is significantly delayed in the neonatal and postnatal period due to muscular hypotonia and recurrent joint luxations, but cognitive development is usually normal."

Case-series trajectory; not a population prognosis.

Childhood and adulthood

Hypotonia may improve while instability, pain, scoliosis, fractures or mobility restrictions persist. The 2020 selected series included 4/12 participants unable to walk unaided or using wheelchairs, while most of eight adults entered a career. These are neither independent population estimates nor an inevitable course.

Show evidence (2 references)

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"As much as 4/12 patients were wheelchair-bound or unable to walk unaided."

Selected cohort including six previously reported adults.

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"Of the eight adults in our cohort, the majority entered a career."

Adult participation outcome in a selected cohort.

📊

Prevalence

Published arthrochalasia EDS literature

Cases In Literature

True population prevalence is unknown. Published totals differ with date and case inclusion: the 2017 rare-types review counted 49 individuals from 36 families, whereas the 2020 cohort cited42 earlier reports and comprised six new participants plus six follow-ups. These overlapping totals should not be added or converted to a numeric prevalence band.

Show evidence (2 references)

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf SUPPORT REVIEW SYNTHESIS Human Clinical

"Prevalence of this condition is unknown."

Explicit absence of a population estimate.

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients."

Distinguishes new participants from repeat follow-up.

⚖️

Clinical Burden

High

Severe congenital instability, repeated orthopedic care, fractures and impaired mobility can produce substantial disability. Four of twelve selected participants used wheelchairs or could not walk unaided, while other affected individuals remained ambulatory; the cohort does not establish the population distribution.

Show evidence (1 reference)

PMID:32091183 SUPPORT PRIMARY RESULT Human Clinical

"As much as 4/12 patients were wheelchair-bound or unable to walk unaided."

Quantifies the loss of independent ambulation in a dedicated arthrochalasia EDS cohort, the clearest single figure for the disease's functional burden.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Arthrochalasia Ehlers-Danlos Syndrome:

Larsen syndrome and congenital neuromuscular disorders

Overlapping Features Congenital joint dislocations and hypotonia can mimic skeletal or neuromuscular disease. Skin findings and properly interpreted molecular studies guide the differential rather than hypotonia alone.

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT Human Clinical

"Many children with arthrochalasia type EDS are suspected of having another connective tissue disorder (particularly Larsen syndrome), a neurological disorder or some type of skeletal dysplasia."

Clinical diagnostic overlap.

🧫

Experimental Models

COL1A2 whole-exon-skipping patient fibroblasts PRIMARY_CELL_CULTURE

Patient 4 fibroblasts showed heterozygous exon 6 skipping from an intron 6 donor variant and delayed amino-propeptide processing. Dermal electron microscopy was a separate patient-tissue investigation, not an outcome of a fibroblast rescue.

Cell source

Patient-derived cultured dermal fibroblasts

Pathograph links

Loss of Exon 6 Sequence from Collagen Transcripts partially recapitulates fidelity: moderate observes: molecular Patient transcript sequencing identified the skipped exon.

Limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested.

Readouts

Exon 6-skipped RNA

Direction: ALTERED

Interpretation: Patient transcript sequencing identified the skipped exon.

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2."

RNA sequencing establishes whole-exon skipping in patient 4.

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2."

RNA sequencing establishes whole-exon skipping in patient 4.

Retained Procollagen N-Propeptide partially recapitulates fidelity: moderate observes: molecular Amino-propeptide processing was substantially delayed relative to controls.

Limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested.

Readouts

Delayed propeptide processing

Direction: INCREASED

Interpretation: Amino-propeptide processing was substantially delayed relative to controls.

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband."

Processing compared with control cultures during a five-day pulse-chase experiment.

Show evidence (1 reference)

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband."

Processing compared with control cultures during a five-day pulse-chase experiment.

Show evidence (2 references)

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2."

RNA sequencing establishes whole-exon skipping in patient 4.

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband."

Processing compared with control cultures during a five-day pulse-chase experiment.

COL1A2 partial-exon deletion biochemical studies PRIMARY_CELL_CULTURE

Cultured fibroblasts and collagen peptide/cDNA analysis from a heterozygous family showed loss of fifteen nucleotides and five residues, with persistent pNalpha2 chains. The crosslink lysine remained; dermal solubility/extraction suggested altered crosslinking but did not map every crosslink. The available cache is abstract-only.

Cell source

Patient-derived cultured dermal fibroblasts

Pathograph links

Loss of Exon 6 Sequence from Collagen Transcripts partially recapitulates fidelity: moderate observes: molecular Cryptic splicing removes fifteen coding nucleotides from the collagen transcript.

Limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested. Methods beyond the available abstract were inaccessible.

Readouts

Partial exon 6 deletion

Direction: ALTERED

Interpretation: Cryptic splicing removes fifteen coding nucleotides from the collagen transcript.

Show evidence (1 reference)

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

Five-residue deletion arises through cryptic splice-site use.

Show evidence (1 reference)

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

Five-residue deletion arises through cryptic splice-site use.

Retained Procollagen N-Propeptide partially recapitulates fidelity: moderate observes: molecular Mutant pN chains persisted in patient collagen preparations.

Limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested.

Readouts

Persistent pNalpha2 chains

Direction: ALTERED

Interpretation: Mutant pN chains persisted in patient collagen preparations.

Show evidence (1 reference)

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

"Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures."

Substrate cleavage defect and retained propeptide.

Show evidence (1 reference)

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

"Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures."

Substrate cleavage defect and retained propeptide.

Show evidence (2 references)

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

Five-residue deletion arises through cryptic splice-site use.

PMID:1556139 SUPPORT PRIMARY RESULT In Vitro

"Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures."

Substrate cleavage defect and retained propeptide.

COL1A1 patient collagen-processing studies PRIMARY_CELL_CULTURE

Independent patient-derived studies characterize N-propeptide retention: the 1986 report identified a 24-residue alpha1 deletion despite normal N-proteinase production, while the 2012 family showed retained pNalpha1 by electrophoresis. The family biochemical observation does not supply a newly sequenced variant or a controlled clinical rescue.

Cell source

Patient-derived cultured dermal fibroblasts

Pathograph links

Retained Procollagen N-Propeptide partially recapitulates fidelity: moderate observes: molecular Patient-cell collagen retained amino-terminal propeptide.

Limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested. The 1986 source is available only as an abstract; the 2012 full study and family relationship were inspected.

Readouts

Persistent pNalpha1 chains

Direction: ALTERED

Interpretation: Patient-cell collagen retained amino-terminal propeptide.

Show evidence (1 reference)

PMID:3082886 SUPPORT PRIMARY RESULT In Vitro

Peptide biochemistry separates altered substrate from normal enzyme production.

Show evidence (1 reference)

PMID:3082886 SUPPORT PRIMARY RESULT In Vitro

Peptide biochemistry separates altered substrate from normal enzyme production.

Show evidence (2 references)

PMID:3082886 SUPPORT PRIMARY RESULT In Vitro

Peptide biochemistry separates altered substrate from normal enzyme production.

PMID:21801164 SUPPORT PRIMARY RESULT In Vitro

"The assay revealed retention of the aminoterminal propeptide of the pro alpha 1(I) chains of type I collagen, suggesting abnormal conversion of products of one COL1A1 allele"

Biochemical study in patient 6, with similar findings in relatives.

{ }

Source YAML

click to show

name: Arthrochalasia Ehlers-Danlos Syndrome
category: Mendelian
creation_date: '2026-09-15T22:22:27Z'
disease_term:
  preferred_term: Arthrochalasia Ehlers-Danlos Syndrome
  term:
    id: MONDO:0007525
    label: Ehlers-Danlos syndrome, arthrochalasia type
synonyms:
- aEDS
- EDS VII
- EDS type VII
- Ehlers-Danlos syndrome type 7
- Ehlers-Danlos syndrome, type VII
- arthrochalasis multiplex congenita
- arthrochalasia EDS
parents:
- Ehlers-Danlos Syndrome
- Connective Tissue Disorder
description: Arthrochalasia Ehlers–Danlos syndrome is a rare type I collagen disorder usually presenting at birth with congenital hip dislocation, severe generalized joint hypermobility and recurrent dislocations. Classic disease is caused by heterozygous COL1A1 or COL1A2 variants that remove all or part of exon 6 from the collagen transcript, disrupting N-propeptide cleavage. Skin abnormalities, hypotonia, motor delay and skeletal complications vary. The clinical diagnosis requires molecular interpretation; other COL1-related overlap phenotypes, including an emerging recessive arthrochalasia-like presentation, should not be assumed to share this exon-6 mechanism.
has_subtypes:
- name: Arthrochalasia Type 1
  display_name: Arthrochalasia Type 1 (EDS VIIA, COL1A1-related)
  subtype_term:
    preferred_term: COL1A1-related arthrochalasia Ehlers-Danlos syndrome
    term:
      id: MONDO:0020521
      label: Ehlers-Danlos syndrome type 7A
  genes:
  - preferred_term: COL1A1
    term:
      id: hgnc:2197
      label: COL1A1
  description: The COL1A1-related form, historically EDS VIIA, affects proalpha1(I). A more severe musculoskeletal phenotype has been suggested, but small selected cohorts and related participants limit comparison with COL1A2 disease.
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features.
    explanation: A 12-patient cohort reports COL1A1 exon 6 loss variants associate with more severe musculoskeletal disease.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: However, according to our series of patients, the phenotype seems to be similar in patients with COL1A1 (patients 5-7) and COL1A2 mutations (patients 1-4), at least in the neonatal and postnatal periods.
    explanation: The three COL1A1 participants belong to one family; this is not a powered comparison.
- name: Arthrochalasia Type 2
  display_name: Arthrochalasia Type 2 (EDS VIIB, COL1A2-related)
  subtype_term:
    preferred_term: COL1A2-related arthrochalasia Ehlers-Danlos syndrome
    term:
      id: MONDO:0040501
      label: Ehlers-Danlos syndrome, arthrochalasia type, 2
  genes:
  - preferred_term: COL1A2
    term:
      id: hgnc:2198
      label: COL1A2
  description: The COL1A2-related form, historically EDS VIIB, affects proalpha2(I). Variants remove all or part of exon 6, including the N-proteinase cleavage site; both splice donor and cryptic splice acceptor mechanisms are documented.
  evidence:
  - reference: PMID:10073586
    reference_title: 'Ehlers-Danlos syndrome type VII: clinical features and molecular defects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: both of our patients had type-VIIB Ehlers-Danlos syndrome, which is caused by heterozygous new mutations of the COL1A2 gene that encodes the proalpha2(I) chain of type-I procollagen. The obligatory GT dinucleotide at the splice donor site of intron 6 was altered in both of our patients
    explanation: Documents heterozygous COL1A2 splice-donor mutations at the intron 6 boundary as the molecular cause of type VIIB arthrochalasia.
    quote_role: PRIMARY_RESULT
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: Classic exon-6-related disease may be inherited or arise de novo. An affected heterozygous parent has a one-in-two transmission probability per pregnancy. A negative parental blood result does not exclude gonadal mosaicism, but the reviewed aEDS reports do not establish a numeric mosaic recurrence risk. Familial transmission and affected adults with children contradict a presumed universal reproductive limitation.
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder
    explanation: Disease inheritance context.
  - reference: PMID:1990839
    reference_title: 'A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Allele-specific oligonucleotide hybridizations demonstrated that the proband's mother, father, and brother did not have the mutation. Therefore, the mutation was a sporadic one.
    explanation: Family testing in one case, not an estimate of the de novo proportion.
  - reference: PMID:1556139
    reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The proband and her son were heterozygous for the mutation.
    explanation: Direct familial transmission.
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: One patient gave birth to two affected children and went through preterm labor requiring medication but had no additional complications.
    explanation: One observed pregnancy history; not universal pregnancy safety.
pathophysiology:
- name: COL1A1 Exon 6-Affecting Variants
  description: Heterozygous splice-region variants or genomic deletions affect exon 6 of COL1A1. This is a structural collagen-processing disorder, not a general loss of enzyme production.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Genetic investigations in individuals with suspected aEDS should focus on pathogenic COL1A2 or COL1A1 variants affecting exon 6 splicing and should include exon (5 and) 6 deletion analysis.
    explanation: Variant classes in a contemporary diagnostic review.
  role: trigger
  gene:
    preferred_term: COL1A1
    term:
      id: hgnc:2197
      label: COL1A1
  downstream:
  - target: Loss of Exon 6 Sequence from Collagen Transcripts
    description: Splice-region or genomic changes remove the corresponding coding sequence from the transcript.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: aEDS is caused by complete or partial loss of exon 6 of either COL1A2 or COL1A1 that precludes trimming by procollagen N-proteinase and leads to retention of the N-propeptide in the collagen type I triple helix.
      explanation: Molecular diagnostic synthesis.
- name: COL1A2 Exon 6-Affecting Variants
  description: Heterozygous splice-region variants or genomic deletions affect exon 6 of COL1A2. This is a structural collagen-processing disorder, not a general loss of enzyme production.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Genetic investigations in individuals with suspected aEDS should focus on pathogenic COL1A2 or COL1A1 variants affecting exon 6 splicing and should include exon (5 and) 6 deletion analysis.
    explanation: Variant classes in a contemporary diagnostic review.
  role: trigger
  gene:
    preferred_term: COL1A2
    term:
      id: hgnc:2198
      label: COL1A2
  downstream:
  - target: Loss of Exon 6 Sequence from Collagen Transcripts
    description: Splice-region or genomic changes remove the corresponding coding sequence from the transcript.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: aEDS is caused by complete or partial loss of exon 6 of either COL1A2 or COL1A1 that precludes trimming by procollagen N-proteinase and leads to retention of the N-propeptide in the collagen type I triple helix.
      explanation: Molecular diagnostic synthesis.
- name: Loss of Exon 6 Sequence from Collagen Transcripts
  description: Complete exon skipping or cryptic splice-site use removes different lengths of coding sequence. Whole-exon losses affect 24 residues in proalpha1(I) or 18 in proalpha2(I); a COL1A2 partial deletion can remove only five residues.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2.
    explanation: Direct patient-cell RNA result.
  - reference: PMID:8081389
    reference_title: Further evidence that the failure to cleave the aminopropeptide of type I procollagen is the cause of Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Exon 6 encodes 18 amino acids of the N-telopeptide which contains the procollagen N-proteinase cleavage site and a cross-link precursor lysine.
    explanation: COL1A2 exon-encoded segment; this length is not generalized to COL1A1.
  - reference: PMID:1556139
    reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: These 15 nucleotides were deleted in the splicing of alpha 2(I) pre-mRNA to mRNA as a result of inactivation of the 3' splice site of intron 5 by an AG to AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6.
    explanation: Allele-specific cryptic splicing; not whole-exon loss.
  downstream:
  - target: Loss of Procollagen N-Proteinase Cleavage Site
    description: Loss of exon-encoded residues removes the substrate cleavage site.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3082886
      reference_title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: The segment deleted from the mutant pro-alpha 1(I) chain contains the small globular region of the NH2-propeptide, the procollagen N-proteinase cleavage site, the NH2-telopeptide, and first triplet of the helix of the alpha I(I) collagen chain
      explanation: Direct peptide characterization of the COL1A1 deletion.
  - target: Mitral Regurgitation
    description: This molecularly confirmed child had valve regurgitation; the proposed collagen-mediated valve-tissue mechanism was not directly tested and the intervening pathway remains uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23158907
      reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild.
      explanation: One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.
  - target: Aortic Regurgitation
    description: This molecularly confirmed child had valve regurgitation; the proposed collagen-mediated valve-tissue mechanism was not directly tested and the intervening pathway remains uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23158907
      reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild.
      explanation: One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.
  - target: Tricuspid Regurgitation
    description: This molecularly confirmed child had valve regurgitation; the proposed collagen-mediated valve-tissue mechanism was not directly tested and the intervening pathway remains uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23158907
      reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild.
      explanation: One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.
  - target: Motor Developmental Delay
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Motor development is significantly delayed in the neonatal and postnatal period due to muscular hypotonia and recurrent joint luxations, but cognitive development is usually normal.
      explanation: Seven-person series; normal cognition does not imply intact mobility.
      directness: INDIRECT
  - target: Congenital or Early-Onset Hypotonia
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: It is not clear whether the hypotonia is solely caused by the laxity of the connective tissue or whether there is a muscular component. Remarkably, the hypotonia seems to diminish with increasing age, regardless of the level of joint hypermobility at that time.
      explanation: Clinical observation and explicit mechanistic uncertainty.
      directness: INDIRECT
  - target: Short Stature
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Short stature | - | - | - | + | + | + | + | 4 / 7 | 2 / 6 | 21
      explanation: Table row supports presence in named participants; selected related cases do not provide a population frequency.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Hypertelorism
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
      explanation: Clinical spectrum review.
      directness: INDIRECT
  - target: Epicanthal Folds
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
      explanation: Clinical spectrum review.
      directness: INDIRECT
  - target: Micrognathia
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Patient 1 (Figure 1 and 2) was born at 35 weeks gestation by vaginal breech delivery with hypotonia and dysmorphic features that included micrognathia and sparse hair.
      explanation: Affected infant; not the separate mutation-negative mother who underwent mandibular surgery.
      directness: INDIRECT
  - target: Sparse Hair
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Patient 1 (Figure 1 and 2) was born at 35 weeks gestation by vaginal breech delivery with hypotonia and dysmorphic features that included micrognathia and sparse hair.
      explanation: Affected infant; not the separate mutation-negative mother who underwent mandibular surgery.
      directness: INDIRECT
  - target: Frontal Bossing
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
      explanation: Human clinical review; no uniform frequency inferred.
      directness: INDIRECT
  - target: Depressed Nasal Bridge
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
      explanation: Human clinical review; no uniform frequency inferred.
      directness: INDIRECT
  - target: Midfacial Hypoplasia
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
      explanation: Human clinical review; no uniform frequency inferred.
      directness: INDIRECT
  - target: Large Fontanelles
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: At birth she presented with bilateral congenital dislocation of the hips, severe joint hypermobility and large fontanels.
      explanation: History of patient 4.
      directness: INDIRECT
  - target: Feeding Difficulties
    description: The clinical finding is associated with the collagen-related phenotype; a specific causal developmental pathway has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: He was hospitalized 10 days after birth because of poor feeding and growth.
      explanation: Patient3 neonatal history.
      directness: INDIRECT
- name: Loss of Procollagen N-Proteinase Cleavage Site
  description: The shortened collagen substrate lacks its normal N-proteinase cleavage site. Some complete deletions also remove a crosslinking lysine, but the five-residue COL1A2 deletion preserves that lysine; lysine loss is not required in every case.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:3082886
    reference_title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Loss of the procollagen N-proteinase cleavage site from the mutant pro-alpha 1(I) chain accounted for the persistence of its NH2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts.
    explanation: Structural substrate defect despite normal enzyme production.
  - reference: PMID:1556139
    reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In contrast to previously reported cases of EDS-VIIB, Lys5 of the N-telopeptide was not deleted and appeared to take part in the formation of intramolecular cross-linkages.
    explanation: Counterexample to universal crosslink-lysine deletion.
  downstream:
  - target: Retained Procollagen N-Propeptide
    description: The structurally altered substrate is poorly cleaved despite normal protease production.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:3082886
      reference_title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Loss of the procollagen N-proteinase cleavage site from the mutant pro-alpha 1(I) chain accounted for the persistence of its NH2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts.
      explanation: Direct patient-derived fibroblast biochemical evidence.
- name: Retained Procollagen N-Propeptide
  description: Impaired cleavage leaves pN collagen chains with the amino-terminal propeptide attached. Patient fibroblast assays demonstrate delayed processing; they do not establish a systemic deficiency of procollagen N-proteinase.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:3082886
    reference_title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Loss of the procollagen N-proteinase cleavage site from the mutant pro-alpha 1(I) chain accounted for the persistence of its NH2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts.
    explanation: Normal enzyme output distinguishes this from ADAMTS2-related dermatosparaxis.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband.
    explanation: Pulse-labeling comparison with control cultures over five days.
  downstream:
  - target: Disordered Collagen Fibril Architecture
    description: Persisting propeptides alter collagen assembly and packing; patient ultrastructure supports the downstream matrix abnormality without isolating every assembly step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Fibril density was lower in the dermis than in control, and occasional cauliflower deformations of the fibrils were seen. Collagen fibrils were irregular in contour and had distinctly smaller diameters than in control samples (43.82 +/- 6.09 nm).
      explanation: Same disease context; no separate controlled propeptide-removal rescue.
      directness: INDIRECT
- name: Disordered Collagen Fibril Architecture
  description: Patient skin shows altered collagen fibril size, packing and contour. The abnormal collagen-processing state is linked to disturbed fibrillogenesis, but a skin biopsy is not a direct tensile-strength measurement of every affected tissue.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Fibril density was lower in the dermis than in control, and occasional cauliflower deformations of the fibrils were seen. Collagen fibrils were irregular in contour and had distinctly smaller diameters than in control samples (43.82 +/- 6.09 nm).
    explanation: Dermal ultrastructure in one investigated participant; no whole-body biomechanical assay.
  downstream:
  - target: Reduced Periarticular Tissue Stability
    description: Disordered matrix is inferred to reduce tissue mechanical integrity; direct tissue-specific biomechanical measurements are lacking.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation.
      explanation: Human clinical instability; biomechanical mediation is inferred.
      directness: INDIRECT
  - target: Reduced Dermal Mechanical Integrity
    description: Disordered matrix is inferred to reduce tissue mechanical integrity; direct tissue-specific biomechanical measurements are lacking.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
      explanation: Clinical skin findings in patient 4; tissue-mechanical bridge is inferred.
      directness: INDIRECT
  - target: Bone Fractures
    description: This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32091183
      reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment.
      explanation: Selected twelve-person cohort, including six previously reported adults.
      directness: INDIRECT
  - target: Blue Sclerae
    description: This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Several of our patients (patients 1 and 5-7) have blue sclerae and some have abnormal dentition, features known to be present in OI.
      explanation: Case report documents blue sclerae in a majority of the described arthrochalasia EDS patients, noting the clinical overlap with osteogenesis imperfecta.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Osteopenia
    description: This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Radiographic evaluation of the skeleton revealed presence of Wormian bones, thoracic scoliosis and generalized osteopenia. Bone densitometry however yielded normal values for DEXA Z-scores at the level of the femur and the lumbar spine.
      explanation: Paired radiograph and densitometry findings in patient 4.
      directness: INDIRECT
  - target: Wormian Bones
    description: This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Radiographic evaluation of the skeleton revealed presence of Wormian bones, thoracic scoliosis and generalized osteopenia. Bone densitometry however yielded normal values for DEXA Z-scores at the level of the femur and the lumbar spine.
      explanation: Radiographic observation in patient 4.
      directness: INDIRECT
  - target: Ectopia Lentis
    description: This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Blue sclerae (n ¼ 3) and ectopia lentis (n ¼ 1) were recorded.
      explanation: Selected published-case review; not a population denominator.
      directness: INDIRECT
  - target: Dentinogenesis Imperfecta
    description: This clinical feature accompanies the collagen disorder; its specific developmental or tissue-level mediator remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Dentinogenesis imperfecta was re- corded in a few patients (n ¼ 3).
      explanation: Published-case synthesis; related-family overlap limits frequency.
      directness: INDIRECT
  - target: Umbilical Hernia
    description: Abnormal collagen-containing abdominal support tissues are inferred to contribute to herniation; no direct fascial biomechanical measurement was reported.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He developed an umbilical hernia in the first year of life.
      explanation: Case report documents umbilical hernia developing in infancy in an arthrochalasia EDS patient.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Reduced Periarticular Tissue Stability
  description: Abnormal collagen-containing joint-support tissues are inferred to underlie marked instability and dislocations. The clinical and collagen findings support this bridge, while the cited studies do not directly measure fetal capsule or ligament tensile strength.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation.
    explanation: Human clinical instability; biomechanical mediation is inferred.
    directness: INDIRECT
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Congenital Hip Dislocation
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: After birth extreme hyperlaxity of both small and large joints was noted, with bilateral hip dislocation, bilateral subluxation of the radius and a stable subluxation of vertebrae C1-C2 without spinal cord compression, in combination with neonatal hypotonia
      explanation: One molecularly confirmed neonatal presentation.
      directness: INDIRECT
  - target: Generalized Joint Hypermobility
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation.
      explanation: Direct examination of patient 1.
      directness: INDIRECT
  - target: Recurrent Joint Dislocation
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation.
      explanation: Direct examination of patient 1.
      directness: INDIRECT
  - target: Kyphoscoliosis
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35162892
      reference_title: 'Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: such as muscular hypotonia, kyphoscoliosis, radiologically mild osteopenia, tissue fragility, including atrophic scarring, and hematomas.
      explanation: Diagnostic clinical spectrum synthesized by the review.
      directness: INDIRECT
  - target: Clubfoot
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: bilateral clubfeet (correctable after plaster casts and night splints), bilateral congenital dislocation of the hips and soft, velvety skin were noted
      explanation: Case report documents bilateral clubfeet, correctable with casting/splinting, in an arthrochalasia EDS patient.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Pes Planus
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine
      explanation: Direct adult examination.
      directness: INDIRECT
  - target: Genu Valgum
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine
      explanation: Direct adult examination.
      directness: INDIRECT
  - target: Lumbar Hyperlordosis
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine
      explanation: Direct adult examination.
      directness: INDIRECT
  - target: Joint Pain
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: She tends to walk with an antalgic gait and complains of subluxations of her right knee and chronic knee and hip pain.
      explanation: Patient7 follow-up.
      directness: INDIRECT
  - target: Premature Osteoarthritis
    description: Impaired joint support contributes to this musculoskeletal finding; exact tissue and developmental intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The right knee demonstrated moderate tricompartmental osteoarthritic changes. The left knee was normal.
      explanation: Imaging at age 8 in patient 6.
      directness: INDIRECT
- name: Reduced Dermal Mechanical Integrity
  description: Disordered collagen matrix contributes to skin fragility and altered mechanical behavior. Relative contributions of fibril packing and crosslinking vary by allele; the human clinical findings do not isolate a single mechanical mediator.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
    explanation: Clinical skin findings in patient 4; tissue-mechanical bridge is inferred.
    directness: INDIRECT
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Hyperextensible Skin
    description: Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39629471
      reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: Most individuals also display the typical EDS features of soft, doughy, hyperextensible or redundant skin, often with easy bruising and atrophic scarring.
      explanation: Clinical spectrum review.
      directness: INDIRECT
  - target: Bruising Susceptibility
    description: Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
      explanation: One adult with bruising and skin fragility; table totals are inconsistent and not used.
      directness: INDIRECT
  - target: Fragile Skin
    description: Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
      explanation: Adult clinical finding.
      directness: INDIRECT
  - target: Poor Wound Healing
    description: Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
      explanation: Adult clinical finding.
      directness: INDIRECT
  - target: Atrophic Scars
    description: Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Her skin was very soft with some hyperextensibility and several cigarette-paper-like scars.
      explanation: Direct adult examination.
      directness: INDIRECT
  - target: Soft Skin
    description: Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hypermobility and dislocations of all joints persisted, and soft and velvety skin with criss-cross patterning of the palms and soles was noted.
      explanation: Direct infant examination.
      directness: INDIRECT
  - target: Piezogenic Pedal Papules
    description: Abnormal connective-tissue mechanics contribute to this clinical finding without isolating its specific matrix mediator.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: He still has very loose, soft skin with piezogenic papules (herniation of fat through the dermis) along the lateral aspects of his heels.
      explanation: Direct patient 3 examination.
      directness: INDIRECT
phenotypes:
- name: Congenital Hip Dislocation
  category: Musculoskeletal
  description: Congenital dislocation is usually bilateral and is a major diagnostic clue. The classification notes an exceptional molecularly confirmed unilateral case; this is not an obligatory bilateral finding in every individual.
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: After birth extreme hyperlaxity of both small and large joints was noted, with bilateral hip dislocation, bilateral subluxation of the radius and a stable subluxation of vertebrae C1-C2 without spinal cord compression, in combination with neonatal hypotonia
    explanation: One molecularly confirmed neonatal presentation.
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: One unreported molecularly proven aEDS patient is known to have had congenital unilateral hip dislocation
    explanation: Consensus footnote describes an exceptional case from personal communication.
- name: Generalized Joint Hypermobility
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Generalized joint hypermobility
    term:
      id: HP:0002761
      label: Generalized joint hypermobility
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation.
    explanation: Direct examination of patient 1.
  description: Marked instability affects large and small joints. Recurrent dislocation severity varies; one four-year-old could walk and run without luxations despite striking hypermobility.
- name: Recurrent Joint Dislocation
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Examination of the limbs of patient 1 showed severe hypermobility of large and small joints with dislocations, even after gentle manipulation.
    explanation: Direct examination of patient 1.
  description: Marked instability affects large and small joints. Recurrent dislocation severity varies; one four-year-old could walk and run without luxations despite striking hypermobility.
- name: Congenital or Early-Onset Hypotonia
  category: Neurologic
  description: Hypotonia can be severe neonatally and diminish with age. Its cause is not resolved as purely connective-tissue laxity or primary muscle dysfunction; improvement does not prove complete resolution.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: It is not clear whether the hypotonia is solely caused by the laxity of the connective tissue or whether there is a muscular component. Remarkably, the hypotonia seems to diminish with increasing age, regardless of the level of joint hypermobility at that time.
    explanation: Clinical observation and explicit mechanistic uncertainty.
- name: Hyperextensible Skin
  category: Dermatologic
  phenotype_term:
    preferred_term: Hyperextensible skin
    term:
      id: HP:0000974
      label: Hyperextensible skin
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Most individuals also display the typical EDS features of soft, doughy, hyperextensible or redundant skin, often with easy bruising and atrophic scarring.
    explanation: Clinical spectrum review.
- name: Bruising Susceptibility
  category: Dermatologic
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
    explanation: One adult with bruising and skin fragility; table totals are inconsistent and not used.
- name: Bone Fractures
  category: Musculoskeletal
  description: Fractures occurred in 9/12 selected participants in the 2020 series; that count does not establish recurrence in all nine or a population rate. One probable, molecularly unconfirmed aEDS participant in a mixed-EDS study had no childhood fracture; this does not refute disease-level skeletal fragility. A separate molecularly diagnosed girl born at 35 weeks had a pathologic skull fracture after vaginal delivery; the abstract does not establish a spontaneous mechanism or neonatal death.
  phenotype_term:
    preferred_term: Bone fracture
    term:
      id: HP:0020110
      label: Bone fracture
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment.
    explanation: Selected twelve-person cohort, including six previously reported adults.
  - reference: PMID:30856599
    reference_title: Fracture incidence in Ehlers-Danlos syndrome - A population-based case-control study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: the one subject with arthochalasia EDS was felt to be a probable case with multiple consistent clinical findings and a positive skin biopsy but no molecular testing.
    explanation: Limits the single comparison case.
  - reference: PMID:30856599
    reference_title: Fracture incidence in Ehlers-Danlos syndrome - A population-based case-control study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The subject with arthrochalasia EDS had no fractures.
    explanation: One negative clinical observation, not a refutation of fractures in other aEDS cohorts.
  - reference: PMID:32338564
    reference_title: 'Pathologic Skull Fracture in a Near-Term Neonate with Arthrochalasia Type Ehlers-Danlos Syndrome: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We report a female infant born at 35 weeks of gestation presenting with pathologic skull fracture following vaginal delivery.
    explanation: Primary case abstract; perinatal trauma context is retained.
- name: Kyphoscoliosis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:35162892
    reference_title: 'Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: such as muscular hypotonia, kyphoscoliosis, radiologically mild osteopenia, tissue fragility, including atrophic scarring, and hematomas.
    explanation: Diagnostic clinical spectrum synthesized by the review.
  description: Spinal deformity can arise early and progress, with variable severity and treatment response.
- name: Short Stature
  category: Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Short stature | - | - | - | + | + | + | + | 4 / 7 | 2 / 6 | 21
    explanation: Table row supports presence in named participants; selected related cases do not provide a population frequency.
    quote_role: PRIMARY_RESULT
  description: Short stature was recorded in some participants in the seven-person series, including related family members; no population frequency is estimated.
- name: Clubfoot
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bilateral clubfeet (correctable after plaster casts and night splints), bilateral congenital dislocation of the hips and soft, velvety skin were noted
    explanation: Case report documents bilateral clubfeet, correctable with casting/splinting, in an arthrochalasia EDS patient.
    quote_role: PRIMARY_RESULT
- name: Umbilical Hernia
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He developed an umbilical hernia in the first year of life.
    explanation: Case report documents umbilical hernia developing in infancy in an arthrochalasia EDS patient.
    quote_role: PRIMARY_RESULT
- name: Blue Sclerae
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Several of our patients (patients 1 and 5-7) have blue sclerae and some have abnormal dentition, features known to be present in OI.
    explanation: Case report documents blue sclerae in a majority of the described arthrochalasia EDS patients, noting the clinical overlap with osteogenesis imperfecta.
    quote_role: PRIMARY_RESULT
- name: Osteopenia
  category: Skeletal
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Radiographic evaluation of the skeleton revealed presence of Wormian bones, thoracic scoliosis and generalized osteopenia. Bone densitometry however yielded normal values for DEXA Z-scores at the level of the femur and the lumbar spine.
    explanation: Paired radiograph and densitometry findings in patient 4.
  description: Radiographic osteopenia and measured low mineral density are not interchangeable. One adult had generalized radiographic osteopenia but normal femoral and lumbar DXA Z scores.
- name: Hypertelorism
  category: Craniofacial
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
    explanation: Clinical spectrum review.
- name: Epicanthal Folds
  category: Craniofacial
  phenotype_term:
    preferred_term: Epicanthal folds
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
    explanation: Clinical spectrum review.
- name: Micrognathia
  category: Craniofacial
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patient 1 (Figure 1 and 2) was born at 35 weeks gestation by vaginal breech delivery with hypotonia and dysmorphic features that included micrognathia and sparse hair.
    explanation: Affected infant; not the separate mutation-negative mother who underwent mandibular surgery.
  description: Documented in an affected infant; presence in this selected case does not establish a universal finding.
- name: Sparse Hair
  category: Dermatologic
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Patient 1 (Figure 1 and 2) was born at 35 weeks gestation by vaginal breech delivery with hypotonia and dysmorphic features that included micrognathia and sparse hair.
    explanation: Affected infant; not the separate mutation-negative mother who underwent mandibular surgery.
  description: Documented in an affected infant; presence in this selected case does not establish a universal finding.
- name: Frontal Bossing
  category: Craniofacial
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  description: Part of the reported variable craniofacial spectrum.
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
    explanation: Human clinical review; no uniform frequency inferred.
- name: Depressed Nasal Bridge
  category: Craniofacial
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  description: Part of the reported variable craniofacial spectrum.
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
    explanation: Human clinical review; no uniform frequency inferred.
- name: Midfacial Hypoplasia
  category: Craniofacial
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  description: Part of the reported variable craniofacial spectrum.
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Dysmorphic facial features include frontal bossing, hypertelorism, epicanthal folds, midfacial hypoplasia, depressed nasal bridge, and micrognathia.
    explanation: Human clinical review; no uniform frequency inferred.
- name: Motor Developmental Delay
  category: Neurologic
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  description: Motor milestones may be limited by hypotonia and recurrent dislocations; this should not be relabeled global cognitive delay.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Motor development is significantly delayed in the neonatal and postnatal period due to muscular hypotonia and recurrent joint luxations, but cognitive development is usually normal.
    explanation: Seven-person series; normal cognition does not imply intact mobility.
- name: Fragile Skin
  category: Dermatologic
  phenotype_term:
    preferred_term: Fragile skin
    term:
      id: HP:0001030
      label: Fragile skin
  description: Minor trauma and orthoses can damage the skin; severity is variable.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
    explanation: Adult clinical finding.
- name: Poor Wound Healing
  category: Dermatologic
  phenotype_term:
    preferred_term: Poor wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  description: Slow wound healing is reported in individual patients and informs procedural planning.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her skin findings include very fragile skin with slow wound healing, easy bruising and a history of slowly healing fractures, ever since she was a child.
    explanation: Adult clinical finding.
- name: Atrophic Scars
  category: Dermatologic
  phenotype_term:
    preferred_term: Atrophic scars
    term:
      id: HP:0001075
      label: Atrophic scars
  description: Atrophic or cigarette-paper scars occur, without uniform severity.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Her skin was very soft with some hyperextensibility and several cigarette-paper-like scars.
    explanation: Direct adult examination.
- name: Soft Skin
  category: Dermatologic
  phenotype_term:
    preferred_term: Soft skin
    term:
      id: HP:0000977
      label: Soft skin
  description: Soft or velvety skin is part of the phenotype.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hypermobility and dislocations of all joints persisted, and soft and velvety skin with criss-cross patterning of the palms and soles was noted.
    explanation: Direct infant examination.
- name: Large Fontanelles
  category: Craniofacial
  phenotype_term:
    preferred_term: Large fontanelles
    term:
      id: HP:0000239
      label: Large fontanelles
  description: Large fontanelles are reported; inconsistent table denominators prevent reliable frequency estimation.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At birth she presented with bilateral congenital dislocation of the hips, severe joint hypermobility and large fontanels.
    explanation: History of patient 4.
- name: Wormian Bones
  category: Skeletal
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  description: Accessory skull bones overlap with other type I collagen disorders.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Radiographic evaluation of the skeleton revealed presence of Wormian bones, thoracic scoliosis and generalized osteopenia. Bone densitometry however yielded normal values for DEXA Z-scores at the level of the femur and the lumbar spine.
    explanation: Radiographic observation in patient 4.
- name: Ectopia Lentis
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Ectopia lentis
    term:
      id: HP:0001083
      label: Ectopia lentis
  description: Lens dislocation was reported in one individual in the reviewed clinical literature.
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Blue sclerae (n ¼ 3) and ectopia lentis (n ¼ 1) were recorded.
    explanation: Selected published-case review; not a population denominator.
- name: Dentinogenesis Imperfecta
  category: Dental
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  description: Dentinogenesis-imperfecta-like dental changes were described in a few reported patients, including related individuals.
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Dentinogenesis imperfecta was re- corded in a few patients (n ¼ 3).
    explanation: Published-case synthesis; related-family overlap limits frequency.
- name: Pes Planus
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  description: Reported musculoskeletal finding with variable functional consequences.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine
    explanation: Direct adult examination.
- name: Genu Valgum
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Genu valgum
    term:
      id: HP:0002857
      label: Genu valgum
  description: Reported musculoskeletal finding with variable functional consequences.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine
    explanation: Direct adult examination.
- name: Lumbar Hyperlordosis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Lumbar hyperlordosis
    term:
      id: HP:0002938
      label: Lumbar hyperlordosis
  description: Reported musculoskeletal finding with variable functional consequences.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Upon physical examination at age 28, she manifested joint hypermobility (Beighton score of 8/9), genua valga, flexible pes planus and hyperlordosis of the lower spine
    explanation: Direct adult examination.
- name: Piezogenic Pedal Papules
  category: Dermatologic
  phenotype_term:
    preferred_term: Piezogenic pedal papules
    term:
      id: HP:0025509
      label: Piezogenic pedal papules
  description: Fat herniation through dermis was observed around the heels of one child.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He still has very loose, soft skin with piezogenic papules (herniation of fat through the dermis) along the lateral aspects of his heels.
    explanation: Direct patient 3 examination.
- name: Joint Pain
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  description: Recurrent instability can coexist with chronic joint pain; this is not inevitable in all patients.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She tends to walk with an antalgic gait and complains of subluxations of her right knee and chronic knee and hip pain.
    explanation: Patient7 follow-up.
- name: Premature Osteoarthritis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Premature osteoarthritis
    term:
      id: HP:0003088
      label: Premature osteoarthritis
  description: Osteoarthritic changes were documented in a severely affected child, rather than inferred from pain alone.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The right knee demonstrated moderate tricompartmental osteoarthritic changes. The left knee was normal.
    explanation: Imaging at age 8 in patient 6.
- name: Feeding Difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  description: Early feeding difficulty occurred in one reported infant; no gastrointestinal mechanism was demonstrated.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He was hospitalized 10 days after birth because of poor feeding and growth.
    explanation: Patient3 neonatal history.
- name: Mitral Regurgitation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  description: One child developed moderate mitral regurgitation by age seven during serial echocardiographic follow-up. Left ventricular ejection fraction and aortic-root dimensions remained normal. This single observation does not establish a uniform progressive valvulopathy.
  evidence:
  - reference: PMID:23158907
    reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild.
    explanation: One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.
- name: Aortic Regurgitation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Aortic regurgitation
    term:
      id: HP:0001659
      label: Aortic regurgitation
  description: One child developed mild aortic regurgitation by age seven during serial echocardiographic follow-up. Left ventricular ejection fraction and aortic-root dimensions remained normal. This single observation does not establish a uniform progressive valvulopathy.
  evidence:
  - reference: PMID:23158907
    reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild.
    explanation: One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.
- name: Tricuspid Regurgitation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  description: One child developed mild tricuspid regurgitation by age seven during serial echocardiographic follow-up. Left ventricular ejection fraction and aortic-root dimensions remained normal. This single observation does not establish a uniform progressive valvulopathy.
  evidence:
  - reference: PMID:23158907
    reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Mitral regurgitation was graded as moderate (Jet area/Left atrium area % correspond to 25%), while aortic and tricuspidal regurgitation were defined mild.
    explanation: One biochemically and molecularly confirmed COL1A2 exon-6 case; not a population rate.
genetic:
- name: COL1A1
  gene_term:
    preferred_term: COL1A1
    term:
      id: hgnc:2197
      label: COL1A1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: Classic disease involves heterozygous variants affecting all or part of exon 6. Other variants in the same gene can cause osteogenesis imperfecta or COL1-related overlap phenotypes; gene identity alone is insufficient. Genotype–severity comparisons remain limited by selected cohorts and family overlap.
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: aEDS is caused by complete or partial loss of exon 6 of either COL1A2 or COL1A1 that precludes trimming by procollagen N-proteinase and leads to retention of the N-propeptide in the collagen type I triple helix.
    explanation: Contemporary molecular diagnostic synthesis.
- name: COL1A2
  gene_term:
    preferred_term: COL1A2
    term:
      id: hgnc:2198
      label: COL1A2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: Classic disease involves heterozygous variants affecting all or part of exon 6. Other variants in the same gene can cause osteogenesis imperfecta or COL1-related overlap phenotypes; gene identity alone is insufficient. Genotype–severity comparisons remain limited by selected cohorts and family overlap.
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: aEDS is caused by complete or partial loss of exon 6 of either COL1A2 or COL1A1 that precludes trimming by procollagen N-proteinase and leads to retention of the N-propeptide in the collagen type I triple helix.
    explanation: Contemporary molecular diagnostic synthesis.
progression:
- phase: Congenital and infantile presentation
  notes: Hip dislocation and generalized hypermobility can be evident at birth; hypotonia and recurrent instability delay motor milestones. Cognitive and motor development must be assessed separately.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Motor development is significantly delayed in the neonatal and postnatal period due to muscular hypotonia and recurrent joint luxations, but cognitive development is usually normal.
    explanation: Case-series trajectory; not a population prognosis.
- phase: Childhood and adulthood
  notes: Hypotonia may improve while instability, pain, scoliosis, fractures or mobility restrictions persist. The 2020 selected series included 4/12 participants unable to walk unaided or using wheelchairs, while most of eight adults entered a career. These are neither independent population estimates nor an inevitable course.
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: As much as 4/12 patients were wheelchair-bound or unable to walk unaided.
    explanation: Selected cohort including six previously reported adults.
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Of the eight adults in our cohort, the majority entered a career.
    explanation: Adult participation outcome in a selected cohort.
clinical_burden:
  burden_level: HIGH
  rationale: Severe congenital instability, repeated orthopedic care, fractures and impaired mobility can produce substantial disability. Four of twelve selected participants used wheelchairs or could not walk unaided, while other affected individuals remained ambulatory; the cohort does not establish the population distribution.
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As much as 4/12 patients were wheelchair-bound or unable to walk unaided.
    explanation: Quantifies the loss of independent ambulation in a dedicated arthrochalasia EDS cohort, the clearest single figure for the disease's functional burden.
    quote_role: PRIMARY_RESULT
prevalence:
- population: Published arthrochalasia EDS literature
  measure_type: CASES_IN_LITERATURE
  notes: 'True population prevalence is unknown. Published totals differ with date and case inclusion: the 2017 rare-types review counted 49 individuals from 36 families, whereas the 2020 cohort cited42 earlier reports and comprised six new participants plus six follow-ups. These overlapping totals should not be added or converted to a numeric prevalence band.'
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Prevalence of this condition is unknown.
    explanation: Explicit absence of a population estimate.
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients.
    explanation: Distinguishes new participants from repeat follow-up.
diagnosis:
- name: Clinical suspicion and molecular confirmation
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: Congenital hip dislocation, severe generalized hypermobility and skin hyperextensibility prompt testing. The 2017 minimum clinical criteria are suggestive, not independently confirmatory. Sequence and copy-number evaluation should include COL1A1/COL1A2 exon 6 and neighboring exon 5 deletions where appropriate; variant interpretation must distinguish classic aEDS from other COL1-related disorders.
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Confirmatory molecular testing is obligatory to reach a final diagnosis.
    explanation: International classification recommendation.
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Genetic investigations in individuals with suspected aEDS should focus on pathogenic COL1A2 or COL1A1 variants affecting exon 6 splicing and should include exon (5 and) 6 deletion analysis.
    explanation: Updated diagnostic review.
- name: RNA and collagen-processing studies
  description: Transcript analysis can establish complete exon skipping or cryptic splice-site use. Fibroblast collagen electrophoresis may show retained pN chains and delayed processing. These assays characterize uncertain molecular effects and were diagnostic in historical cases; current diagnosis is not established by an arbitrary collagen-gene VUS alone.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2.
    explanation: Patient-cell transcript assay.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband.
    explanation: Patient-cell processing assay.
- name: Dermal ultrastructure as an adjunct
  description: Transmission electron microscopy may show disorganized small irregular fibrils, but it cannot independently confirm aEDS or reliably replace molecular testing.
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: These findings may support the diagnosis, but cannot confirm it.
    explanation: Classification qualification immediately after its aEDS TEM description.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Fibril density was lower in the dermis than in control, and occasional cauliflower deformations of the fibrils were seen. Collagen fibrils were irregular in contour and had distinctly smaller diameters than in control samples (43.82 +/- 6.09 nm).
    explanation: Positive biopsy finding in one molecularly investigated adult.
differential_diagnoses:
- name: Other COL1-related disorders including osteogenesis imperfecta
  description: COL1A1/COL1A2 variants can cause bone-fragility phenotypes and EDS/OI overlap. Blue sclerae, dental changes or fractures alone do not distinguish these conditions. Classic aEDS is associated specifically with the exon 6 processing defect.
  evidence:
  - reference: PMID:39629471
    reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Some individuals carry pathogenic variants previously reported as causative for osteogenesis imperfecta
    explanation: Overlap and variable expressivity in the COL1-related-disorder section.
- name: ADAMTS2-related dermatosparaxis EDS
  description: Both conditions can retain procollagen N-propeptides, but dermatosparaxis results from enzyme deficiency whereas aEDS alters its collagen substrate; severe skin fragility can overlap.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: dermatosparaxis type (VIIC), caused by mutations in the procollagen I N-proteinase, ADAMTS2, that prevent proper processing of the type I procollagen and in which extreme skin fragility and easy bruising are the predominant clinical features.
    explanation: Allelic and mechanistic differential.
- name: Larsen syndrome and congenital neuromuscular disorders
  description: Congenital joint dislocations and hypotonia can mimic skeletal or neuromuscular disease. Skin findings and properly interpreted molecular studies guide the differential rather than hypotonia alone.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Many children with arthrochalasia type EDS are suspected of having another connective tissue disorder (particularly Larsen syndrome), a neurological disorder or some type of skeletal dysplasia.
    explanation: Clinical diagnostic overlap.
treatments:
- name: Physical and occupational therapy
  description: Early individualized rehabilitation supports motor development, safe mobility and daily activities. Recommendations come mainly from expert review and case experience, not controlled aEDS trials.
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Orthotic management and early intervention, including physical and occupational therapy are recom- mended to assist standing, walking, and activities of daily living
    explanation: Disease-specific expert management synthesis.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Motor Developmental Delay
    treatment_effect: MODULATES
    description: Therapy supports functional skill acquisition despite persistent collagen-related instability.
    evidence:
    - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Orthotic management and early intervention, including physical and occupational therapy are recom- mended to assist standing, walking, and activities of daily living
      explanation: Disease-specific expert management synthesis.
- name: Joint orthoses and activity adaptation
  description: Select orthoses and footwear for joint stability and tolerance. Skin abrasions or hematomas may require modification or discontinuation. Avoid activities with high dislocation risk; prescribed rehabilitation should remain individualized.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: If skin problems are mild, the use of orthoses to stabilize knee, ankle and of foot joints can improve motor development.
    explanation: Clinical series recommendation, not a randomized effect.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The use of these orthoses had to be discontinued because of skin abrasions and hematomas.
    explanation: Observed intolerance in one child.
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Contact sports should be avoided to prevent dislocations
    explanation: Expert precaution.
  target_mechanisms:
  - target: Reduced Periarticular Tissue Stability
    treatment_effect: BYPASSES
    description: External support partly compensates for unstable joints without correcting collagen processing.
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: If skin problems are mild, the use of orthoses to stabilize knee, ankle and of foot joints can improve motor development.
      explanation: Clinical series recommendation, not a randomized effect.
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The use of these orthoses had to be discontinued because of skin abrasions and hematomas.
      explanation: Observed intolerance in one child.
    - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Contact sports should be avoided to prevent dislocations
      explanation: Expert precaution.
- name: Hip surgical management
  description: Closed reduction often fails in published selected cases. A specialist team weighs mobility goals, recurrence and wound risk when considering open reduction with pelvic or femoral osteotomy. Case-series experience does not establish a universal operation or inevitable failure of every conservative attempt.
  evidence:
  - reference: PMID:10073586
    reference_title: 'Ehlers-Danlos syndrome type VII: clinical features and molecular defects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The results of open reduction were improved when capsulorrhaphy was combined with iliac or femoral osteotomy, or both.
    explanation: Historical selected-case comparison.
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery.
    explanation: Treatment exposure, not comparative efficacy.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She underwent a bilateral open hip reduction surgery at age 18 months but the right hip immediately redislocated.
    explanation: Observed recurrence despite surgery.
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Congenital Hip Dislocation
    treatment_effect: MODULATES
    description: Reduction and osteotomy aim to improve femoral-head containment; collagen-related laxity can persist.
    evidence:
    - reference: PMID:10073586
      reference_title: 'Ehlers-Danlos syndrome type VII: clinical features and molecular defects.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The results of open reduction were improved when capsulorrhaphy was combined with iliac or femoral osteotomy, or both.
      explanation: Historical selected-case comparison.
    - reference: PMID:32091183
      reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery.
      explanation: Treatment exposure, not comparative efficacy.
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: She underwent a bilateral open hip reduction surgery at age 18 months but the right hip immediately redislocated.
      explanation: Observed recurrence despite surgery.
- name: Individualized scoliosis bracing
  description: A genetically diagnosed COL1A2 case improved from a 43.6-degree lumbar curve to 8 degrees after 3.5 years of a Wood-Rigo-Cheneau brace plus weekly physical therapy; at age 6 the curve measured 14 degrees after six months out of brace. Ongoing growth surveillance was required. This uncontrolled combination cannot prove brace superiority or permanent avoidance of surgery.
  evidence:
  - reference: PMID:39343458
    reference_title: Syndromic scoliosis in a patient with arthrochalasia Ehlers-Danlos syndrome corrected with a Wood-Rigo-Cheneau derotational brace.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Through shared decision making with their EDS specialist, the family elected to proceed with conservative management using the WRC brace, in conjunction with weekly physical therapy.
    explanation: Combined exposure in one child.
  - reference: PMID:39343458
    reference_title: Syndromic scoliosis in a patient with arthrochalasia Ehlers-Danlos syndrome corrected with a Wood-Rigo-Cheneau derotational brace.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: After 3.5 years, the patient’s Cobb angle decreased to 8°. His Cobb angle was stable under 15° on brace for 12 months. At the age of 6, after being out of brace for 6 months, his curve measured 14°
    explanation: Actual follow-up; not a controlled treatment comparison.
  target_mechanisms:
  - target: Kyphoscoliosis
    treatment_effect: MODULATES
    description: External corrective forces can modify spinal alignment in selected patients while growth and skin tolerance are monitored.
    evidence:
    - reference: PMID:39343458
      reference_title: Syndromic scoliosis in a patient with arthrochalasia Ehlers-Danlos syndrome corrected with a Wood-Rigo-Cheneau derotational brace.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: Through shared decision making with their EDS specialist, the family elected to proceed with conservative management using the WRC brace, in conjunction with weekly physical therapy.
      explanation: Combined exposure in one child.
    - reference: PMID:39343458
      reference_title: Syndromic scoliosis in a patient with arthrochalasia Ehlers-Danlos syndrome corrected with a Wood-Rigo-Cheneau derotational brace.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: After 3.5 years, the patient’s Cobb angle decreased to 8°. His Cobb angle was stable under 15° on brace for 12 months. At the age of 6, after being out of brace for 6 months, his curve measured 14°
      explanation: Actual follow-up; not a controlled treatment comparison.
- name: Specialist surgery for severe spinal deformity
  description: 'A 2025 report followed one clinically diagnosed patient for 17 years: traditional rods at age 5 were later replaced by magnetically lengthened rods at age 10. Kyphosis improved and sitting balance was good, but the scoliosis Cobb angle remained 100 degrees and wheelchair use persisted because of hip dislocation. The exchange procedure involved 1000 cc blood loss. No genotype, control group or general efficacy advantage was established.'
  evidence:
  - reference: PMID:40227332
    reference_title: Seventeen-year outcome of surgical management of severe early onset kyphoscoliosis in a patient with arthrochalasia-type Ehlers-Danlos.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The procedure was complicated by 1000 cc of blood loss, attributed to the vascular fragility of this patient due to their aEDS.
    explanation: Major blood loss during rod exchange qualifies the favorable abstract.
  - reference: PMID:40227332
    reference_title: Seventeen-year outcome of surgical management of severe early onset kyphoscoliosis in a patient with arthrochalasia-type Ehlers-Danlos.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: His Cobb angle has remained stable 100 degrees with good correction of kyphosis. He still ambulates in a wheelchair (due to a chronic hip dislocation since aged 9) with good sitting balance.
    explanation: Long-term outcome distinguishes stability, kyphosis and mobility.
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Kyphoscoliosis
    treatment_effect: MODULATES
    description: Instrumentation stabilizes or corrects selected components of spinal deformity; it does not restore normal collagen or guarantee ambulatory improvement.
    evidence:
    - reference: PMID:40227332
      reference_title: Seventeen-year outcome of surgical management of severe early onset kyphoscoliosis in a patient with arthrochalasia-type Ehlers-Danlos.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: The procedure was complicated by 1000 cc of blood loss, attributed to the vascular fragility of this patient due to their aEDS.
      explanation: Major blood loss during rod exchange qualifies the favorable abstract.
    - reference: PMID:40227332
      reference_title: Seventeen-year outcome of surgical management of severe early onset kyphoscoliosis in a patient with arthrochalasia-type Ehlers-Danlos.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: His Cobb angle has remained stable 100 degrees with good correction of kyphosis. He still ambulates in a wheelchair (due to a chronic hip dislocation since aged 9) with good sitting balance.
      explanation: Long-term outcome distinguishes stability, kyphosis and mobility.
- name: Bone-health assessment and selected bisphosphonate use
  description: Assess fractures and radiographic findings in context; DXA may be normal despite radiographic osteopenia. One of twelve participants received a bisphosphonate, but the available cohort abstract gives no agent, dose, response or comparative benefit. This is documented use, not an aEDS-specific routine-treatment recommendation.
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment.
    explanation: Exposure only; no BMD or fracture response reported.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Radiographic evaluation of the skeleton revealed presence of Wormian bones, thoracic scoliosis and generalized osteopenia. Bone densitometry however yielded normal values for DEXA Z-scores at the level of the femur and the lumbar spine.
    explanation: Radiographic and DXA discordance supports careful assessment.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
    therapeutic_agent:
    - preferred_term: Biphosphonate
      term:
        id: NCIT:C443
        label: Biphosphonate
- name: Skin protection and wound planning
  description: Minimize skin trauma from devices and procedures. Plan tension-free closure and follow-up with awareness of delayed healing; the review recommends longer suture retention, but timing should reflect the wound and specialist assessment. This guidance does not imply that every patient has extreme skin fragility.
  evidence:
  - reference: PMID:35162892
    reference_title: 'Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Certain guidelines should be taken into account to avoid complications such as leaving sutures twice as long as normal before suture removal and that wounds should be closed without tension
    explanation: Expert guidance summarized by a review, not comparative outcome evidence.
  treatment_term:
    preferred_term: Wound Care Management
    term:
      id: NCIT:C116681
      label: Wound Care Management
  target_mechanisms:
  - target: Poor Wound Healing
    treatment_effect: MODULATES
    description: Careful closure and reduced tension compensate for fragile healing tissues; the underlying matrix defect persists.
    evidence:
    - reference: PMID:35162892
      reference_title: 'Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Certain guidelines should be taken into account to avoid complications such as leaving sutures twice as long as normal before suture removal and that wounds should be closed without tension
      explanation: Expert guidance summarized by a review, not comparative outcome evidence.
- name: Pain and psychological support
  description: Individualize pain management and support coping with chronic instability and disability. The literature recommends anti-inflammatory medication and psychological or behavioral support, but does not establish a preferred regimen or aEDS-specific trial benefit.
  evidence:
  - reference: PMID:35162892
    reference_title: 'Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Anti-inflammatory drugs can help patients with joint pain. In patients with muscle hypotonia and joint instability with chronic pain, emotional support and behavioral and psychological therapy to aid in accepting and offering coping strategies to manage disability is advised.
    explanation: Review recommendations, with no disease-specific comparative effect estimate.
  treatment_term:
    preferred_term: Pain Therapy
    term:
      id: NCIT:C15180
      label: Pain Therapy
  target_mechanisms:
  - target: Joint Pain
    treatment_effect: INHIBITS
    description: Symptom-directed treatment aims to reduce pain without claiming correction of collagen assembly.
    evidence:
    - reference: PMID:35162892
      reference_title: 'Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Anti-inflammatory drugs can help patients with joint pain. In patients with muscle hypotonia and joint instability with chronic pain, emotional support and behavioral and psychological therapy to aid in accepting and offering coping strategies to manage disability is advised.
      explanation: Review recommendations, with no disease-specific comparative effect estimate.
- name: Pregnancy and delivery planning
  description: Offer specialist follow-up through pregnancy and plan delivery where maternal and neonatal complications can be managed. Published affected mothers had live births, including affected children; possible perineal or pelvic-floor risks extrapolated from classical EDS should not be represented as measured aEDS event rates. Postpartum hemorrhage has been reported in one published affected mother; the selected literature denominator is not a prospective risk estimate.
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Delivery should be performed in a medical center where intensive treat- ment could be given to an affected pregnant woman and an affected neonate  # codespell:ignore-line
    explanation: Expert aEDS delivery recommendation.
  - reference: PMID:28981071
    reference_title: 'Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: postpartum hemorrhaging was reported in one patient with aEDS (1/12 females, 8%) after the birth of each of her children
    explanation: One selected literature case, not an estimated pregnancy risk.
- name: Multidisciplinary clinical surveillance
  description: Monitor mobility, spinal alignment, skin/device tolerance, bone health and relevant dental or ocular findings. The 2017 review refers skin, cardiovascular and ophthalmic management to classical-EDS guidance; this does not establish a vascular-EDS-like rupture risk or universal intensive cardiac surveillance schedule.
  evidence:
  - reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    reference_title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The advice to management of the skin, cardiovascular, and ophthalmological features is similar to that for patients with classical EDS
    explanation: Broader-EDS extrapolation is explicit.
- name: Genetic counseling and family evaluation
  description: Counsel on dominant transmission in classic disease, testing of a known family variant, variable functional severity and reproductive options. Both inherited and sporadic cases occur. Do not assign the lethal-OI parental-mosaicism percentage to aEDS or infer a confirmed carrier from mild features alone.
  evidence:
  - reference: PMID:1990839
    reference_title: 'A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Allele-specific oligonucleotide hybridizations demonstrated that the proband's mother, father, and brother did not have the mutation. Therefore, the mutation was a sporadic one.
    explanation: One family with an apparent de novo variant.
  - reference: PMID:1556139
    reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The proband and her son were heterozygous for the mutation.
    explanation: Direct inherited variant.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Somatic mosaicism for this IVS6+1G>T mutation was not demonstrated.
    explanation: Negative testing is not proof of an aEDS mosaic parent.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Cardiovascular assessment and individualized follow-up
  description: Consider cardiology assessment and echocardiographic follow-up according to examination and detected abnormalities. One molecularly confirmed child developed mitral, aortic and tricuspid regurgitation during annual follow-up. The case report supports vigilance but cannot establish universal annual imaging or preventive cardiovascular medication for all aEDS patients.
  evidence:
  - reference: PMID:23158907
    reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Transthoracic echocardiograms using semiquantitative grading of valve regurgitation, were performed once a year. After two-year follow-up, combined valvulopathy, resulting in mitral, tricuspidal and aortic regurgitation, were detected.
    explanation: Observed follow-up and progression in one child.
  - reference: PMID:23158907
    reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Since we demonstrated a progressive valvular involvement a careful cardiac follow-up is warranted for EDS type VII patients
    explanation: Case-report recommendation, not a consensus surveillance interval.
experimental_models:
- name: COL1A2 whole-exon-skipping patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Patient-derived cultured dermal fibroblasts
  description: Patient 4 fibroblasts showed heterozygous exon 6 skipping from an intron 6 donor variant and delayed amino-propeptide processing. Dermal electron microscopy was a separate patient-tissue investigation, not an outcome of a fibroblast rescue.
  evidence:
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2.
    explanation: RNA sequencing establishes whole-exon skipping in patient 4.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband.
    explanation: Processing compared with control cultures during a five-day pulse-chase experiment.
  modeled_mechanisms:
  - target: Loss of Exon 6 Sequence from Collagen Transcripts
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Patient transcript sequencing identified the skipped exon.
    limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested.
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2.
      explanation: RNA sequencing establishes whole-exon skipping in patient 4.
    readouts:
    - name: Exon 6-skipped RNA
      target: Loss of Exon 6 Sequence from Collagen Transcripts
      direction: ALTERED
      interpretation: Patient transcript sequencing identified the skipped exon.
      evidence:
      - reference: PMID:21801164
        reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: In cells from the proband direct sequencing of the RT-PCR product revealed heterozygous skipping of the entire sequence of exon 6 of COL1A2.
        explanation: RNA sequencing establishes whole-exon skipping in patient 4.
  - target: Retained Procollagen N-Propeptide
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Amino-propeptide processing was substantially delayed relative to controls.
    limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested.
    evidence:
    - reference: PMID:21801164
      reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband.
      explanation: Processing compared with control cultures during a five-day pulse-chase experiment.
    readouts:
    - name: Delayed propeptide processing
      target: Retained Procollagen N-Propeptide
      direction: INCREASED
      interpretation: Amino-propeptide processing was substantially delayed relative to controls.
      evidence:
      - reference: PMID:21801164
        reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: In comparison with processing of procollagen from control cell cultures, amino propeptide processing was substantially delayed in this proband.
        explanation: Processing compared with control cultures during a five-day pulse-chase experiment.
- name: COL1A2 partial-exon deletion biochemical studies
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Patient-derived cultured dermal fibroblasts
  description: Cultured fibroblasts and collagen peptide/cDNA analysis from a heterozygous family showed loss of fifteen nucleotides and five residues, with persistent pNalpha2 chains. The crosslink lysine remained; dermal solubility/extraction suggested altered crosslinking but did not map every crosslink. The available cache is abstract-only.
  evidence:
  - reference: PMID:1556139
    reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: These 15 nucleotides were deleted in the splicing of alpha 2(I) pre-mRNA to mRNA as a result of inactivation of the 3' splice site of intron 5 by an AG to AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6.
    explanation: Five-residue deletion arises through cryptic splice-site use.
  - reference: PMID:1556139
    reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures.
    explanation: Substrate cleavage defect and retained propeptide.
  modeled_mechanisms:
  - target: Loss of Exon 6 Sequence from Collagen Transcripts
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Cryptic splicing removes fifteen coding nucleotides from the collagen transcript.
    limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested. Methods beyond the available abstract were inaccessible.
    evidence:
    - reference: PMID:1556139
      reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: These 15 nucleotides were deleted in the splicing of alpha 2(I) pre-mRNA to mRNA as a result of inactivation of the 3' splice site of intron 5 by an AG to AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6.
      explanation: Five-residue deletion arises through cryptic splice-site use.
    readouts:
    - name: Partial exon 6 deletion
      target: Loss of Exon 6 Sequence from Collagen Transcripts
      direction: ALTERED
      interpretation: Cryptic splicing removes fifteen coding nucleotides from the collagen transcript.
      evidence:
      - reference: PMID:1556139
        reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: These 15 nucleotides were deleted in the splicing of alpha 2(I) pre-mRNA to mRNA as a result of inactivation of the 3' splice site of intron 5 by an AG to AC mutation and the activation of a cryptic AG splice acceptor site corresponding to positions +14 and +15 of exon 6.
        explanation: Five-residue deletion arises through cryptic splice-site use.
  - target: Retained Procollagen N-Propeptide
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Mutant pN chains persisted in patient collagen preparations.
    limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested.
    evidence:
    - reference: PMID:1556139
      reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures.
      explanation: Substrate cleavage defect and retained propeptide.
    readouts:
    - name: Persistent pNalpha2 chains
      target: Retained Procollagen N-Propeptide
      direction: ALTERED
      interpretation: Mutant pN chains persisted in patient collagen preparations.
      evidence:
      - reference: PMID:1556139
        reference_title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Loss of the N-proteinase cleavage site explained the persistence of the pN-alpha 2(I)' chains in the dermis and in fibroblast cultures.
        explanation: Substrate cleavage defect and retained propeptide.
- name: COL1A1 patient collagen-processing studies
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Patient-derived cultured dermal fibroblasts
  description: 'Independent patient-derived studies characterize N-propeptide retention: the 1986 report identified a 24-residue alpha1 deletion despite normal N-proteinase production, while the 2012 family showed retained pNalpha1 by electrophoresis. The family biochemical observation does not supply a newly sequenced variant or a controlled clinical rescue.'
  evidence:
  - reference: PMID:3082886
    reference_title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Loss of the procollagen N-proteinase cleavage site from the mutant pro-alpha 1(I) chain accounted for the persistence of its NH2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts.
    explanation: Peptide biochemistry separates altered substrate from normal enzyme production.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The assay revealed retention of the aminoterminal propeptide of the pro alpha 1(I) chains of type I collagen, suggesting abnormal conversion of products of one COL1A1 allele
    explanation: Biochemical study in patient 6, with similar findings in relatives.
  modeled_mechanisms:
  - target: Retained Procollagen N-Propeptide
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Patient-cell collagen retained amino-terminal propeptide.
    limitations: Patient-cell observations with limited sampling; no gene correction, tissue-mechanical rescue, orthopedic outcome or treatment efficacy was tested. The 1986 source is available only as an abstract; the 2012 full study and family relationship were inspected.
    evidence:
    - reference: PMID:3082886
      reference_title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Loss of the procollagen N-proteinase cleavage site from the mutant pro-alpha 1(I) chain accounted for the persistence of its NH2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts.
      explanation: Peptide biochemistry separates altered substrate from normal enzyme production.
    readouts:
    - name: Persistent pNalpha1 chains
      target: Retained Procollagen N-Propeptide
      direction: ALTERED
      interpretation: Patient-cell collagen retained amino-terminal propeptide.
      evidence:
      - reference: PMID:3082886
        reference_title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: Loss of the procollagen N-proteinase cleavage site from the mutant pro-alpha 1(I) chain accounted for the persistence of its NH2-propeptide despite normal production of the N-proteinase by cultured mutant fibroblasts.
        explanation: Peptide biochemistry separates altered substrate from normal enzyme production.
discussions:
- discussion_id: aeds_recessive_overlap_boundary
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How should biallelic non-exon-6 COL1A1 arthrochalasia-like disease be classified?
  attaches_to:
  - genetic#COL1A1
  rationale: A 2026 report describes one ten-month-old child homozygous for exon 31 p.Glu684Lys with healthy heterozygous parents. The authors call the variant likely pathogenic using PM1/PM2/PP3/PP5, including a prior assertion whose underlying evidence was unavailable. They explicitly distinguish an arthrochalasia-like or COL1-related overlap phenotype from the currently recognized dominant form. No RNA, N-propeptide processing, helix stability, integrin binding or rescue assay was performed. Proposed charge and GFOGER-binding effects remain hypotheses; long-term cognition, course and founder origin are unresolved. These observations should not change classic aEDS inheritance or its exon 6 mechanism by assumption.
  evidence:
  - reference: PMID:42353838
    reference_title: 'A Homozygous Missense COL1A1 Variant (p.Glu684Lys) Associated with an Arthrochalasia-like Ehlers-Danlos Syndrome Phenotype: A Case Report.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: The molecular mechanism of the missense variant c.2050G>A (p.Glu684Lys) has not been definitively established.
    explanation: Explicit absence of an established variant mechanism.
  - reference: PMID:42353838
    reference_title: 'A Homozygous Missense COL1A1 Variant (p.Glu684Lys) Associated with an Arthrochalasia-like Ehlers-Danlos Syndrome Phenotype: A Case Report.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: Although the p.Glu684Lys substitution is predicted to disrupt integrin–collagen interaction, in vivo impairment of this interaction has not been experimentally confirmed for this particular variant. Consequently, the functional consequences remain hypothetical.
    explanation: No direct binding or organismal validation.
  - reference: PMID:42353838
    reference_title: 'A Homozygous Missense COL1A1 Variant (p.Glu684Lys) Associated with an Arthrochalasia-like Ehlers-Danlos Syndrome Phenotype: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Haplotype analysis was not performed in the current study; therefore, it remains unknown whether this variant represents a shared founder haplotype or arose as an independent mutational event.
    explanation: Founder origin is untested.
- discussion_id: aeds_fracture_risk_and_source_conflicts
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What is the age-specific fracture burden in molecularly confirmed aEDS?
  attaches_to:
  - phenotypes#Bone Fractures
  - phenotypes#Osteopenia
  rationale: 'The 2020 selected cohort reports 9/12 with fractures; the 2019 mixed-EDS study contains only one probable, non-molecularly confirmed aEDS case without fractures. Its pooled odds ratio and infant findings should not become aEDS-specific risk estimates. The 2012 article contains incompatible fracture statements: patient 4 had slowly healing fractures and a positive table cell, but the table total is 0/7 and discussion says none. The 2022 review also misrepresents the 2020 bone review, whose abstract explicitly includes aEDS among rare types with frequent fractures/low BMD. A deduplicated, genetically defined longitudinal cohort is needed; source contradictions should not be resolved by inventing a numerator.'
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment.
    explanation: Selected cohort observation.
  - reference: PMID:30856599
    reference_title: Fracture incidence in Ehlers-Danlos syndrome - A population-based case-control study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The subject with arthrochalasia EDS had no fractures.
    explanation: One negative observation.
  - reference: PMID:32162201
    reference_title: Bone Disease in Patients with Ehlers-Danlos Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Low bone mineral density and fractures seem to be frequent in some of the rare EDS types (kyphoscoliotic, arthrochalasia, spondylodysplastic, and classic-like EDS).
    explanation: Actual bone-review statement contradicts its later secondary characterization.
- discussion_id: aeds_genotype_severity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does COL1A1 exon6 disruption consistently cause more severe disease than COL1A2 disruption?
  attaches_to:
  - genetic#COL1A1
  - genetic#COL1A2
  rationale: Type I collagen contains two alpha1 chains and one alpha2 chain, motivating a mutant-molecule stoichiometry hypothesis. Clinical comparisons remain small and overlapping. The 2020 series suggested more severe COL1A1 musculoskeletal involvement; the 2012 series reported similar early phenotypes, but its three COL1A1 participants came from one family. Neither establishes a deterministic prognosis or a universally measured fraction of defective molecules.
  evidence:
  - reference: PMID:32091183
    reference_title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features.
    explanation: Selected cohort inference.
  - reference: PMID:21801164
    reference_title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Part of this similarity can be attributed to the fact that patients 5-7 all come from the same family
    explanation: Non-independence limits genotype comparison.
- discussion_id: aeds_cardiovascular_scope
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What cardiovascular surveillance is justified in molecularly confirmed aEDS?
  attaches_to:
  - phenotypes#Mitral Regurgitation
  - treatments#Cardiovascular assessment and individualized follow-up
  rationale: One confirmed COL1A2 exon-6 case developed valve regurgitation while systolic function and aortic-root dimensions remained normal. This differs genetically from recessive cardiac-valvular EDS due to biallelic COL1A2 null variants. A systematic review of nonvascular EDS included 17 selected aEDS patients and identified one perioperative hemorrhage, plus a separate report of postpartum bleeding; its surgical paragraph inconsistently gives a denominator of 18. These case-based data do not establish population risks or a vascular-EDS-like arterial phenotype. The review did not report arterial aneurysm or dissection in its aEDS subset. This is absence from selected literature, not proof that such an event is impossible. Routine preventive vascular drugs or intensive arterial screening cannot be inferred from the reviewed reports.
  evidence:
  - reference: PMID:23158907
    reference_title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Left ventricular ejection fraction was within normal reference (65%).
    explanation: Normal systolic function in the valve case.
  - reference: PMID:28981071
    reference_title: 'Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: in one patient with aEDS (1/18, 6%) who bled excessively at surgery (unspecified)
    explanation: Positive surgical-bleeding report; denominator conflicts with Table3 and is not used as a risk estimate.
  - reference: PMID:28981071
    reference_title: 'Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: the data summarized here are derived mostly from either case reports (n = 51) or case series (n = 59), which are prone to publication and selection bias
    explanation: Explicit source ascertainment limit.
notes: No disease-specific GeneReviews or StatPearls chapter was identified by the repository baseline checks. The 2017 international classification and rare-types review, updated2024 diagnostic review and primary case reports provide the clinical baseline. Care is supportive and individualized; no controlled disease-modifying intervention or faithful aEDS whole-animal efficacy model was established in the reviewed evidence.
review_notes: Reviewed the entire original entry, its matching deep-research narrative/citation inventory, all nine cited available abstracts and actual full scientific bodies. Read the complete 2012 case-series and 2022 review bodies/tables; recovered 2017 classification and rare-types PDFs and read their general framework and complete aEDS sections rather than treating unrelated EDS chapters as aEDS evidence. New full 2019 fracture study and 2024/2025 spine cases were read completely, including the parent narrative and long-term limitations. The 2024 genetic diagnostic review was read for relevant collagen/neuromuscular differential and testing scope. The2026 recessive arthrochalasia-like report was read completely and independently audited; it is kept as an unresolved boundary rather than merged into the classic mechanism. The 2020 cohort remains abstract-only after unsuccessful publisher/repository recovery; unavailable 2008 correspondence and an image-heavy 2021 teaching deck are not used as positive evidence. Published-case totals overlap and differ by inclusion rules; no population frequency or prevalence band is inferred. The 2012 table has inconsistent totals for hips, fractures,
  criss-cross skin, fontanelles and some other signs; narrative findings and identified patient scope are preferred without reconstructing unsupported denominators. A micrognathia surgery quotation from the mutation-negative mother was removed from the affected-infant phenotype. The 2012 imported lethal-OI mosaic risk is not an aEDS recurrence estimate. The 2025 surgical abstract understates its 1000 cc bleeding and does not state that scoliosis remained 100 degrees. The entire 2012 valve case and 2018 nonvascular-EDS vascular review bodies/tables were also read; individual valvulopathy and bleeding were kept separate from arterial risk in vascular EDS. The neonatal skull-fracture abstract supports a perinatal fracture, not the neonatal death asserted by the 2022 review. Historical exon 46 nomenclature in the 1986 source was not reproduced as modern exon numbering. Generated caches were not hand-edited.
references:
- reference: PMID:10073586
  title: 'Ehlers-Danlos syndrome type VII: clinical features and molecular defects.'
  findings: []
- reference: PMID:1556139
  title: A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.
  findings: []
- reference: PMID:1990839
  title: 'A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype.'
  findings: []
- reference: PMID:21801164
  title: 'Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.'
  findings: []
- reference: PMID:23158907
  title: 'Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?'
  findings: []
- reference: PMID:28306225
  title: The Ehlers-Danlos syndromes, rare types.
  findings: []
- reference: PMID:28306229
  title: The 2017 international classification of the Ehlers-Danlos syndromes.
  findings: []
- reference: PMID:28981071
  title: 'Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review.'
  findings: []
- reference: PMID:3082886
  title: Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.
  findings: []
- reference: PMID:30856599
  title: Fracture incidence in Ehlers-Danlos syndrome - A population-based case-control study.
  findings: []
- reference: PMID:32091183
  title: Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.
  findings: []
- reference: PMID:32162201
  title: Bone Disease in Patients with Ehlers-Danlos Syndromes.
  findings: []
- reference: PMID:32338564
  title: 'Pathologic Skull Fracture in a Near-Term Neonate with Arthrochalasia Type Ehlers-Danlos Syndrome: A Case Report.'
  findings: []
- reference: PMID:35162892
  title: 'Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.'
  findings: []
- reference: PMID:39343458
  title: Syndromic scoliosis in a patient with arthrochalasia Ehlers-Danlos syndrome corrected with a Wood-Rigo-Cheneau derotational brace.
  findings:
  - statement: Full case, discussion and parent perspective read. Brace plus physical therapy; skeletal maturity not reached and no comparator.
- reference: PMID:39629471
  title: Genetic diagnosis of the Ehlers-Danlos syndromes.
  findings: []
- reference: PMID:40227332
  title: Seventeen-year outcome of surgical management of severe early onset kyphoscoliosis in a patient with arthrochalasia-type Ehlers-Danlos.
  findings:
  - statement: Full case and captions read. Traditional then magnetic rods; major bleeding at exchange, scoliosis stable at 100 degrees, kyphosis improved, persistent wheelchair use; genotype not supplied.
- reference: PMID:42353838
  title: 'A Homozygous Missense COL1A1 Variant (p.Glu684Lys) Associated with an Arthrochalasia-like Ehlers-Danlos Syndrome Phenotype: A Case Report.'
  findings:
  - statement: Full body/Table1 and independent peer audit. Single infant with recessive COL1A1 overlap phenotype; no functional mechanism assay or long-term outcome.
- reference: PMID:8081389
  title: Further evidence that the failure to cleave the aminopropeptide of type I procollagen is the cause of Ehlers-Danlos syndrome type VII.
  findings: []
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
  title: https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
  findings:
  - statement: Complete aEDS history, mechanism, allele, phenotype, management and differential section read. Primary identity PMID:28306225; published-case counts are not population rates.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
  title: https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
  findings:
  - statement: Complete aEDS criteria and diagnostic verification section read, including the rare unilateral hip-dislocation footnote; primary bibliographic identity PMID:28306229.

📚

References & Deep Research

References

PMID:10073586

Ehlers-Danlos syndrome type VII: clinical features and molecular defects.

No top-level findings curated for this source.

PMID:1556139

A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII.

No top-level findings curated for this source.

PMID:1990839

A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype.

No top-level findings curated for this source.

PMID:21801164

Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood.

No top-level findings curated for this source.

PMID:23158907

Cardiac valve disease: an unreported feature in Ehlers Danlos syndrome arthrocalasia type?

No top-level findings curated for this source.

PMID:28306225

The Ehlers-Danlos syndromes, rare types.

No top-level findings curated for this source.

PMID:28306229

The 2017 international classification of the Ehlers-Danlos syndromes.

No top-level findings curated for this source.

PMID:28981071

Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review.

No top-level findings curated for this source.

PMID:3082886

Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII.

No top-level findings curated for this source.

PMID:30856599

Fracture incidence in Ehlers-Danlos syndrome - A population-based case-control study.

No top-level findings curated for this source.

PMID:32091183

Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.

No top-level findings curated for this source.

PMID:32162201

Bone Disease in Patients with Ehlers-Danlos Syndromes.

No top-level findings curated for this source.

PMID:32338564

Pathologic Skull Fracture in a Near-Term Neonate with Arthrochalasia Type Ehlers-Danlos Syndrome: A Case Report.

No top-level findings curated for this source.

PMID:35162892

Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review.

No top-level findings curated for this source.

PMID:39343458

Syndromic scoliosis in a patient with arthrochalasia Ehlers-Danlos syndrome corrected with a Wood-Rigo-Cheneau derotational brace.

1 finding

Full case, discussion and parent perspective read. Brace plus physical therapy; skeletal maturity not reached and no comparator.

PMID:39629471

Genetic diagnosis of the Ehlers-Danlos syndromes.

No top-level findings curated for this source.

PMID:40227332

Seventeen-year outcome of surgical management of severe early onset kyphoscoliosis in a patient with arthrochalasia-type Ehlers-Danlos.

1 finding

Full case and captions read. Traditional then magnetic rods; major bleeding at exchange, scoliosis stable at 100 degrees, kyphosis improved, persistent wheelchair use; genotype not supplied.

PMID:42353838

A Homozygous Missense COL1A1 Variant (p.Glu684Lys) Associated with an Arthrochalasia-like Ehlers-Danlos Syndrome Phenotype: A Case Report.

1 finding

Full body/Table1 and independent peer audit. Single infant with recessive COL1A1 overlap phenotype; no functional mechanism assay or long-term outcome.

PMID:8081389

Further evidence that the failure to cleave the aminopropeptide of type I procollagen is the cause of Ehlers-Danlos syndrome type VII.

No top-level findings curated for this source.

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf

https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf

1 finding

Complete aEDS history, mechanism, allele, phenotype, management and differential section read. Primary identity PMID:28306225; published-case counts are not population rates.

url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf

https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf

1 finding

Complete aEDS criteria and diagnostic verification section read, including the rare unilateral hip-dislocation footnote; primary bibliographic identity PMID:28306229.

Deep Research

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 (4)

Record review notes

Reviewed the entire original entry, its matching deep-research narrative/citation inventory, all nine cited available abstracts and actual full scientific bodies. Read the complete 2012 case-series and 2022 review bodies/tables; recovered 2017 classification and rare-types PDFs and read their general framework and complete aEDS sections rather than treating unrelated EDS chapters as aEDS evidence. New full 2019 fracture study and 2024/2025 spine cases were read completely, including the parent narrative and long-term limitations. The 2024 genetic diagnostic review was read for relevant collagen/neuromuscular differential and testing scope. The2026 recessive arthrochalasia-like report was read completely and independently audited; it is kept as an unresolved boundary rather than merged into the classic mechanism. The 2020 cohort remains abstract-only after unsuccessful publisher/repository recovery; unavailable 2008 correspondence and an image-heavy 2021 teaching deck are not used as positive evidence. Published-case totals overlap and differ by inclusion rules; no population frequency or prevalence band is inferred. The 2012 table has inconsistent totals for hips, fractures, criss-cross skin, fontanelles and some other signs; narrative findings and identified patient scope are preferred without reconstructing unsupported denominators. A micrognathia surgery quotation from the mutation-negative mother was removed from the affected-infant phenotype. The 2012 imported lethal-OI mosaic risk is not an aEDS recurrence estimate. The 2025 surgical abstract understates its 1000 cc bleeding and does not state that scoliosis remained 100 degrees. The entire 2012 valve case and 2018 nonvascular-EDS vascular review bodies/tables were also read; individual valvulopathy and bleeding were kept separate from arterial risk in vascular EDS. The neonatal skull-fracture abstract supports a perinatal fracture, not the neonatal death asserted by the 2022 review. Historical exon 46 nomenclature in the 1986 source was not reproduced as modern exon numbering. Generated caches were not hand-edited.

Review arthrochalasia collagen processing, clinical spectrum and supportive care · 2026-09-21T11:35:25Z · View source

Reviewed the entire entry and matching deep-research artifacts against all original available abstracts and cached full bodies. Rebuilt eight atomic collagen-processing and tissue events, separating substrate cleavage-site loss from enzyme deficiency and preserving the partial-deletion crosslink lysine. Added three patient-derived models with assay and specimen limits. Expanded clinical coverage to 39 findings, retaining selected-cohort, overlapping-family and contradictory table limits without unsupported frequency bands. Added molecular diagnosis and twelve supportive-care records, including individual brace/surgical outcomes, cardiac case findings, pregnancy planning and family counseling. Kept the new recessive exon31 COL1A1 arthrochalasia-like report as a boundary discussion without merging its untested mechanism into classic dominant aEDS. Read the complete relevant 2017 classification/rare-types sections, full 2012 and 2024/2025 primary cases, full fracture and vascular systematic studies and the 2026 overlap report; the 2020 cohort remains abstract-only after unsuccessful recovery. Corrected the mutation-negative-mother quote, neonatal-death overstatement, fracture-review mischaracterization and surgical-outcome omissions. Independent source and integration reviews found no material residual mechanism or care issue. Authoritative validation passes schema, live ontology and 188/188 exact excerpts. All 21 integrity guards and 2,189 whole-KB node-class examples pass. Generated caches were not hand-edited and the frozen accession cache was not accessed.

Deep-research cross-check: Arthrochalasia Ehlers-Danlos Syndrome · 2026-09-15T22:45:27Z · View source

Deep research completed successfully this time via falcon (Edison Scientific), 716s runtime, 32 citations, 13 references checked (13/13 resolved, 0 confabulated, 0 off-topic; needs_review:true was driven solely by a harmless template-placeholder artifact where the report's own MONDO:0007525 label field literally read 'if available' -- not a real term error). Cross-checked the report's body against the existing entry and found it substantially corroborated the independently-sourced primary literature already cited, plus surfaced three genuinely new, previously-uncited primary sources which were fetched and verified before use: PMID:35162892 (Martin-Martin et al. 2022, a full-text systematic review) and PMID:28306229 (Malfait et al. 2017, the 2017 international EDS classification, added to the top-level references: block). A third source the report cited, PMID:18409203 (Giunta et al. 2008, EM fibril ultrastructure diagnostic value), was fetched but has no retrievable abstract text in PubMed (content_type: unavailable) so it was not used for evidence -- citing it without a real quotable snippet would have violated the no-title-as-snippet rule already learned earlier in this session. Added from PMID:35162892: four new phenotypes (Kyphoscoliosis, Osteopenia, Hypertelorism, Epicanthal Folds) connected into the pathograph via the existing Joint Capsule and Ligament Laxity and Skeletal Fragility pathophysiology nodes; a corroborating prevalence evidence item (independently confirming the ~42-published-cases figure); and, importantly, a REFUTE-graded evidence item (quote_role: REVIEW_SYNTHESIS) on the Recurrent Fractures phenotype noting that two other studies (Rolfes et al., Basalom et al., synthesized by this review) did not find increased fracture incidence in children or found only a low incidence in adults -- added specifically to avoid overclaiming fracture frequency from the single 9/12 Ayoub-cohort figure already cited. Considered and deliberately did NOT add: an isolated n=1 cardiac valve involvement case report (too weak/preliminary to model as a phenotype), pregnancy/obstetric complications (breech, polyhydramnios, PROM -- maternal/obstetric rather than proband phenotypes), and a falcon-report-synthesized stoichiometric claim about COL1A1-vs-COL1A2 trimer-poisoning probability (could not be traced to a quotable primary-source sentence, so left unsourced rather than fabricated). The whole-KB offline gate just check-snippet-length (not covered by validate-disorders) initially failed on two pre-existing short snippets ('recurrent joint (sub)luxations', 'skin hyperextensibility') that had been added earlier in this session; both were expanded to the full defining sentence from PMID:32091183 and the gate now passes clean. Revalidated with: just validate (schema/term/reference, 38/38 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-qualifier-terms, just check-snippet-length (whole-KB, exit 0), and just list-gene-term-mismatches (0 mismatches). Compliance (just compliance): 81.7% global / 82.1% weighted, up from the initial 80.8%/81.2%.

Create: Arthrochalasia Ehlers-Danlos Syndrome · 2026-09-15T22:27:16Z · View source

New entry for arthrochalasia Ehlers-Danlos syndrome (aEDS, formerly EDS VIIA/B), anchored on MONDO:0007525 (Ehlers-Danlos syndrome, arthrochalasia type), which unlike the recently-curated kyphoscoliotic EDS is a genuine non-obsolete umbrella MONDO term. Two gene-specific has_subtypes entries are anchored on their own MONDO terms: Arthrochalasia Type 1 (COL1A1, MONDO:0020521) and Arthrochalasia Type 2 (COL1A2, MONDO:0040501), following the same pattern used for Musculocontractural_Ehlers-Danlos_Syndrome.yaml and the newly-created Kyphoscoliotic_Ehlers-Danlos_Syndrome.yaml. No GeneReviews chapter exists for this subtype specifically (confirmed via PubMed genereviews[book] search and just check-genereviews --online, both NO_CHAPTER); this is noted in the entry's notes: field, no action needed. Primary literature was fetched directly via PubMed search rather than relying solely on deep research, since a GeneReviews baseline was unavailable: PMID:32091183 (Ayoub et al. 2020, 12-patient clinical/molecular/management cohort -- the richest single source, establishing the core phenotype, genotype-phenotype COL1A1-vs-COL1A2 severity debate, and management data including fracture/bisphosphonate/surgery statistics), PMID:21801164 (Klaassens et al. 2012, full-text phenotype-expansion case series with electron-microscopy fibril morphology data and differential-diagnosis discussion), PMID:10073586 (Giunta et al. 1999, foundational clinical/molecular review establishing COL1A2 type VIIB mechanism and hip-surgery outcomes), and four classic 1986-1994 molecular papers establishing the exon-6-skipping/N-propeptide-retention mechanism for each gene (PMID:3082886 COL1A1, PMID:1990839 and PMID:1556139 COL1A2 splice mutations, PMID:8081389 further COL1A2 confirmation). The pathophysiology chain models two parallel gene-specific upstream nodes (COL1A1 Exon 6 Skipping Variant, COL1A2 Exon 6 Skipping Variant; genetic_context functional_impact_category DOMINANT_NEGATIVE, since only ~half of secreted chains are affected in the heterozygous state yet still produce disease, consistent with poisoning of the heterotrimer) converging on a shared 'Loss of Procollagen N-Proteinase Cleavage Site' node, then 'Retained Procollagen N-Propeptide' and 'Aberrant Collagen Fibril Assembly', explicitly noting in the node description how the resulting irregular-diameter/reduced-density fibril morphology differs from dermatosparaxis EDS's flattened 'hieroglyphic' ribbon morphology (dermatosparaxis is ADAMTS2 enzyme loss, biallelic; arthrochalasia is substrate mutation, heterozygous) -- an explicit cross-reference to the existing Dermatosparaxis_Ehlers-Danlos_Syndrome.yaml entry's terminal node naming convention, though the two entries do not share nodes (per the 'not DRY' module convention, this is not a conforms_to relationship since no module exists for this mechanism). Downstream tissue-level nodes branch to joint-capsule/ligament laxity (congenital hip dislocation, generalized joint hypermobility, recurrent dislocation, and an inferential/uncited link to hypotonia), skin fragility, and skeletal fragility (recurrent fractures, well-supported by the 9/12-patient cohort statistic). A diagnosis: block covers the differential-diagnosis boundary against Larsen syndrome and dermatosparaxis EDS. Deep research (falcon, with just dr_fallback='--fallback' since no EDISON_API_KEY/FUTUREHOUSE_API_KEY is configured in this environment) was launched in the background; this history record and commit reflect validated content built from independently-sourced primary literature and will be revised/re-validated once the deep-research report completes and is cross-checked for content gaps, following the same red-team review process used for the Kyphoscoliotic_Ehlers-Danlos_Syndrome.yaml entry earlier in this session. Validated so far with: just validate (schema/term/reference, 32/32 snippets verified), just check-entity-refs, just check-causal-targets (0 new dangling targets), just check-duplicate-keys, just check-enum-values, just check-qualifier-terms, just list-gene-term-mismatches (0 mismatches across 6 gene bindings), and just check-genereviews --online (NO_CHAPTER, confirming the notes: field claim). just validate-disorders (the CI-authoritative batched gate) has not yet been run for this file and will be run before this is considered final. Compliance (just compliance): 80.8% global / 81.2% weighted. datasets: left empty -- no GEO/other accession search was performed for this entry.

Falcon ▸

Arthrochalasia Ehlers–Danlos Syndrome: Disease Characteristics Report

Edison Scientific Literature 32 citations 2026-09-15T22:36:20.572315

Arthrochalasia Ehlers–Danlos Syndrome: Disease Characteristics Report

Scope and evidence note. Arthrochalasia Ehlers–Danlos syndrome (aEDS) is so rare that most evidence consists of molecularly confirmed case reports, small series, expert consensus, and one 2022 systematic review. Approximately 42 patients had been published worldwide by 2022; consequently, frequencies should not be interpreted as stable population estimates. Claims based on EDS generally rather than aEDS specifically are explicitly labeled as indirect evidence. No substantive aEDS-specific publications from 2023–2024 were identified; the principal recent development is a 2024 EDS-wide review showing that orthopedic surgical evidence remains sparse and inconsistent. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 1-2, schubart2024outcomesoforthopaedic pages 1-2)

The following table provides a compact, ontology-oriented summary before the detailed report.

Domain	Curated finding	Evidence level/source year	Ontology/code suggestions
Identity and aliases	Arthrochalasia Ehlers–Danlos syndrome (aEDS); formerly EDS type VIIA for COL1A1-related disease and type VIIB for COL1A2-related disease; Mendelian, autosomal-dominant heritable connective-tissue disorder (malfait2017the2017international pages 12-13, wenstrup2002prevalenceofaortic pages 1-2)	International expert classification, 2017	MONDO:0007525; labels: arthrochalasia EDS, EDS VIIA, EDS VIIB
Causal gene: COL1A1	Heterozygous pathogenic variants affecting exon 6 of COL1A1, encoding collagen type I α1 chain, cause aEDS; COL1A1-associated disease may be more severe because approximately three quarters of collagen-I molecules can contain an abnormal α1 chain (OpenTargets Search: arthrochalasia Ehlers-Danlos syndrome-COL1A1,COL1A2, martinmartin2022ehlers–danlossyndrometype pages 7-8, giunta2008thearthrochalasiatype pages 1-2)	Human genetic, biochemical, and ultrastructural evidence; 2008–2022	HGNC:2197; NCBI Gene:1277; collagen α1(I) chain
Causal gene: COL1A2	Heterozygous pathogenic variants affecting exon 6 of COL1A2, encoding collagen type I α2 chain, cause aEDS; approximately half of collagen-I molecules may contain an abnormal α2 chain (OpenTargets Search: arthrochalasia Ehlers-Danlos syndrome-COL1A1,COL1A2, giunta2008thearthrochalasiatype pages 1-2)	Human genetic, biochemical, and ultrastructural evidence; 2008–2024	HGNC:2198; NCBI Gene:1278; collagen α2(I) chain
Variant spectrum	Lesions are usually splice-donor, splice-acceptor, or genomic variants producing complete or partial exon-6 loss. A demonstrated COL1A1 IVS5-2A>T variant activated a cryptic splice site and deleted the first 15 nucleotides of exon 6; variants are germline and may be inherited or de novo (malfait2017the2017international pages 12-13, giunta2008thearthrochalasiatype pages 2-3, malfait2020theehlers–danlossyndromes pages 6-7)	Molecularly confirmed human cases; 2008–2020	Sequence Ontology labels: splice-acceptor variant, splice-donor variant, exon loss, in-frame deletion
Molecular mechanism	Exon-6 loss removes the type-I-procollagen N-proteinase cleavage site and may remove the N-telopeptide cross-linking lysine and start of the Gly-X-Y triple-helical region. Failed cleavage produces collagen retaining its N-propeptide—pN-collagen (giunta2008thearthrochalasiatype pages 2-3, malfait2020theehlers–danlossyndromes pages 6-7, brady2017theehlers–danlossyndromes pages 8-9)	Direct patient-fibroblast biochemical evidence and expert synthesis; 2008–2020	GO labels: collagen biosynthetic process, collagen fibril organization, extracellular-matrix organization, protein processing
Fibrillogenesis	Retained pNα1(I) or pNα2(I) chains disturb collagen fibrillogenesis. Skin electron microscopy shows small, loosely or randomly organized fibrils with irregular or ragged contours; dominant-negative interference is strongly inferred but not directly proven in the cited experiment (giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2)	Human in-vitro biochemical and skin-biopsy TEM evidence; 2008	CL:0000057 fibroblast; labels: dermal fibroblast, collagen fibril, dermis, collagen-containing extracellular matrix
Hallmark phenotype	Congenital bilateral hip dislocation is the principal hallmark, accompanied by severe generalized joint hypermobility and recurrent dislocations or subluxations. One molecularly proven but unpublished patient reportedly had unilateral hip dislocation (malfait2017the2017international pages 12-13)	International diagnostic consensus, 2017	HP:0001382 joint hypermobility; HP:0001374 congenital hip dislocation; labels: recurrent joint dislocation, joint subluxation
Minor phenotypes	Skin hyperextensibility, hypotonia, kyphoscoliosis, mild osteopenia, tissue fragility, atrophic scars, easy bruising or hematomas, redundant skin, clubfoot, and congenital knee dislocation occur variably (malfait2017the2017international pages 12-13, martinmartin2022ehlers–danlossyndrometype pages 5-7, giunta2008thearthrochalasiatype pages 2-3)	Consensus criteria and human cases; 2008–2022	HP:0000974 hyperextensible skin; HP:0001252 hypotonia; HP:0002751 kyphoscoliosis; HP:0000938 osteopenia; HP:0001075 atrophic scars; HP:0000978 bruising susceptibility
Epidemiology	Population prevalence and incidence are unknown. The 2022 systematic review identified approximately 42 published patients worldwide, with substantial uncertainty from underdiagnosis and publication bias (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 1-2)	PRISMA systematic review, 2022	MONDO:0007525; rare disease; do not apply aggregate EDS prevalence estimates to aEDS
Vascular and cardiac risk	A vascular complication was reported in 1/17 aEDS patients (6%) in a systematic review. Progressive mitral, aortic, and tricuspid regurgitation has also been reported, but estimates rest on very small samples (dhondt2018vascularphenotypesin pages 3-4, martinmartin2022ehlers–danlossyndrometype pages 4-5)	Systematic review and isolated human case; 2018–2022	Labels: vascular complication, mitral regurgitation, aortic regurgitation, tricuspid regurgitation
Diagnosis	Suggestive findings are congenital bilateral hip dislocation plus either skin hyperextensibility or severe generalized joint hypermobility with multiple dislocations or subluxations, together with at least two minor criteria. Definitive diagnosis requires molecular confirmation (malfait2017the2017international pages 12-13)	International expert classification, 2017	Sequence COL1A1 and COL1A2; connective-tissue multigene panel; deletion/duplication analysis if sequencing is negative
Ancillary diagnostics	Cultured skin-fibroblast collagen analysis can demonstrate abnormal pN-collagen processing. Skin-biopsy transmission electron microscopy may show supportive fibril abnormalities but does not replace molecular confirmation (malfait2017the2017international pages 12-13, giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2)	Human biochemical/TEM evidence and consensus; 2008–2017	NCIT labels: skin biopsy, transmission electron microscopy, fibroblast culture, protein electrophoresis
Treatment and trials gap	No curative or disease-modifying therapy exists. Care is individualized and multidisciplinary: cautious physiotherapy and strengthening, joint protection, orthoses or mobility aids, pain management, wound precautions, and selective orthopedic intervention. No aEDS-specific treatment-response rates or interventional trials were identified (martinmartin2022ehlers–danlossyndrometype pages 1-2, martinmartin2022ehlers–danlossyndrometype pages 5-7, schubart2024outcomesoforthopaedic pages 1-2)	Systematic and scoping reviews; 2022–2024	NCIT labels: physical therapy, occupational therapy, orthotic device, pain management, orthopedic surgery, supportive care, genetic counseling
Surgery evidence	EDS-wide 2024 evidence comprised 71 primary orthopedic studies—38 case reports, 14 case series, and 19 retrospective cohorts—with no randomized trials and inconsistent outcomes. Findings were not aEDS-specific (schubart2024outcomesoforthopaedic pages 15-16, schubart2024outcomesoforthopaedic pages 1-2)	Scoping review, October 2024; indirect evidence	NCIT labels: orthopedic surgery, preoperative assessment, postoperative care; annotate as EDS-wide indirect evidence
Animal and model gap	No validated naturally occurring animal disease or exact COL1A1/COL1A2 exon-6 aEDS model was identified. A combined osteogenesis-imperfecta/EDS mouse is mechanistically adjacent but does not reproduce the defining exon-6 lesion and should not be curated as an aEDS-equivalent model	Targeted literature search through 2024; negative or adjacent evidence	NCBI Taxon:10090 for the adjacent mouse model only; model status: not disease-equivalent

Table: Compact extraction table summarizing the identity, genetics, mechanism, phenotype, epidemiology, diagnosis, management, vascular evidence, and research gaps for arthrochalasia Ehlers–Danlos syndrome.

1. Disease information

Definition and classification

Arthrochalasia EDS is an autosomal-dominant Mendelian connective-tissue disorder caused by abnormal processing of type I procollagen. Its defining manifestations are congenital—usually bilateral—hip dislocation, severe generalized joint hypermobility, recurrent joint dislocations or subluxations, and hyperextensible or fragile skin. It is one of the 13 subtypes recognized by the 2017 International EDS Classification. (malfait2017the2017international pages 12-13, islam2021ehlersdanlossyndromeimmunologic pages 31-33)

A useful exact abstract statement from the 2022 systematic review is: “Ehlers–Danlos syndrome type arthrochalasia (aEDS) is a rare genetic disease characterized by severe generalized joint hypermobility, bilateral congenital hip dislocation, skin hyperextensibility, muscle hypotonia, and mild dysmorphic features.” The same abstract states: “Only about 42 cases have been published worldwide.” The article was published 7 February 2022; DOI URL: https://doi.org/10.3390/ijerph19031870. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 1-2)

Identifiers and synonyms

MONDO: MONDO:0007525, Ehlers-Danlos syndrome, arthrochalasia type.
OMIM: commonly divided historically into EDS type VIIA (COL1A1-related; OMIM phenotype 130060) and EDS type VIIB (COL1A2-related; OMIM phenotype 130060 is often used for the arthrochalasia phenotype in aggregated resources; database implementations should be checked for version-specific mapping).
Orphanet: Arthrochalasia Ehlers–Danlos syndrome; ORPHA mappings should be version-validated before ingestion because legacy VIIA/VIIB records may be handled differently.
ICD-10: no dedicated aEDS code; generally coded under Q79.6, Ehlers–Danlos syndrome.
ICD-11: under the Ehlers–Danlos syndrome/heritable connective-tissue disorder hierarchy; no reliably retrieved subtype-specific code should be asserted without checking the current ICD-11 release.
MeSH: Ehlers-Danlos Syndrome; no separate aEDS MeSH descriptor was established in the retrieved evidence.
Synonyms: arthrochalasia EDS; EDS arthrochalasia type; Ehlers–Danlos syndrome type VIIA; EDS VIIA; Ehlers–Danlos syndrome type VIIB; EDS VIIB; arthrochalasis multiplex congenita. The VIIA/VIIB distinction respectively denotes COL1A1- and COL1A2-related disease. (malfait2017the2017international pages 12-13, wenstrup2002prevalenceofaortic pages 1-2)

This report is built from aggregated disease-level resources and published human cases, not individual EHR records. Open Targets independently associates MONDO:0007525 with COL1A1 and COL1A2 and links supporting human literature including PMIDs 18409203, 9295084, 1867198, 8071956, and 19594296. (OpenTargets Search: arthrochalasia Ehlers-Danlos syndrome-COL1A1,COL1A2)

2. Etiology

Causal factors and genetic risk

The primary cause is a heterozygous germline pathogenic variant in COL1A1 or COL1A2 that produces complete or partial loss of exon 6 from the mature transcript. Exon 6 encodes functionally critical portions of the type I procollagen N-terminal processing region. Both inherited and de novo cases occur; one reviewed case had a de novo COL1A1 exon-skipping variant. (malfait2017the2017international pages 12-13, martinmartin2022ehlers–danlossyndrometype pages 7-8, malfait2020theehlers–danlossyndromes pages 6-7)

Relevant gene annotations are:

COL1A1 — collagen type I α1 chain; HGNC:2197; NCBI Gene 1277; chromosome 17q21.33.
COL1A2 — collagen type I α2 chain; HGNC:2198; NCBI Gene 1278; chromosome 7q21.3. (OpenTargets Search: arthrochalasia Ehlers-Danlos syndrome-COL1A1,COL1A2, martinmartin2022ehlers–danlossyndrometype pages 2-4)

Because the disorder is monogenic and highly penetrant clinically in reported families, the principal risk factor is carrying the causal allele or having an affected parent. Family history may be absent because of a de novo event. No validated susceptibility loci, common-variant polygenic risk score, or modifier gene has been established.

Environmental, lifestyle, infectious, and protective factors

No environmental toxin, infection, diet, smoking exposure, occupation, sex, or lifestyle factor is known to cause aEDS. Mechanical stress does not initiate the disorder but can expose the genetically weakened tissue phenotype by precipitating dislocation, soft-tissue injury, bruising, and pain. This is a gene–mechanical-environment interaction at the level of manifestations, not a demonstrated interaction affecting mutation penetrance.

No protective allele or environmental exposure has been established. Joint protection, appropriately dosed strengthening, avoidance of high-impact/contact activity, and prevention of unnecessary tissue trauma are complication-reduction strategies, not protection against inheriting or developing aEDS.

3. Phenotypes

Core and minor manifestations

The 2017 criteria define three major features: (1) congenital bilateral hip dislocation, (2) severe generalized joint hypermobility with multiple dislocations or subluxations, and (3) skin hyperextensibility. Minor criteria are muscular hypotonia, kyphoscoliosis, radiologically mild osteopenia, tissue fragility including atrophic scars, and easy bruising. Foot deformities and congenital knee dislocation are also reported. (malfait2017the2017international pages 12-13, yonko2021orthopedicconsiderationsand pages 2-3, martinmartin2022ehlers–danlossyndrometype pages 5-7, giunta2008thearthrochalasiatype pages 2-3)

Phenotype	Type, onset, course, and frequency	Suggested HPO annotation
Congenital hip dislocation	Objective musculoskeletal sign; neonatal. Historically bilateral in all published patients used to formulate criteria, although one molecularly proven unpublished patient reportedly had unilateral involvement. Persistent orthopedic consequences are possible.	Congenital hip dislocation, HP:0001374; bilateral congenital hip dislocation label
Generalized joint hypermobility	Physical sign; present at birth, usually severe. Hypotonia and hypermobility may become less marked with age but instability can remain lifelong.	Joint hypermobility, HP:0001382; generalized joint hypermobility
Recurrent dislocation/subluxation	Sign/symptom; childhood onward; episodic and mechanically provoked, with variable sites and severity.	Recurrent joint dislocation; joint subluxation
Skin hyperextensibility/redundancy	Physical manifestation; congenital or early childhood; variable.	Hyperextensible skin, HP:0000974; redundant skin
Tissue/skin fragility and atrophic scars	Physical manifestation; apparent after trauma or procedures; variable and cumulative.	Atrophic scars, HP:0001075; skin fragility
Easy bruising/hematomas	Physical sign; recurrent and trauma-associated.	Bruising susceptibility, HP:0000978
Muscular hypotonia	Neonatal sign, often severe; reported to lessen with age. Motor development can be delayed through weakness and instability, while intellectual development is generally normal.	Hypotonia, HP:0001252
Kyphosis/kyphoscoliosis	Musculoskeletal sign; congenital or developing during growth; variable.	Kyphoscoliosis, HP:0002751
Mild osteopenia	Radiographic laboratory/imaging abnormality; variable. Available reports do not establish a high fracture rate.	Osteopenia, HP:0000938
Clubfoot/foot deformity	Congenital structural sign; variable.	Talipes equinovarus/clubfoot; pes planus where applicable
Dysmorphism	Mild and variable; reported features include large fontanelle, micrognathia, hypertelorism, and epicanthal folds.	Large fontanelle; micrognathia; hypertelorism; epicanthus

The disease’s extreme rarity precludes reliable percentage estimates for most manifestations. The major exception is the historical observation that bilateral congenital hip dislocation was present in all published patients informing the 2017 criteria. Reports of very low fracture incidence argue against automatically equating mild osteopenia in aEDS with the fracture burden of osteogenesis imperfecta. (malfait2017the2017international pages 12-13, martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 5-7)

Quality of life

No validated aEDS-specific EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life cohort was identified. Likely burdens—supported clinically but not quantified specifically for aEDS—include impaired mobility, need for orthoses or assistive devices, recurrent injuries, chronic pain, limitations in self-care and employment, and procedural anxiety. The 2022 review states that treatment focuses on improving quality of life, but does not report response rates or standardized scores. (martinmartin2022ehlers–danlossyndrometype pages 1-2)

4. Genetic and molecular information

Pathogenic variant class and consequences

Causal variants are usually splice-donor or splice-acceptor changes, intragenic deletions, or other variants that cause in-frame complete or partial exon-6 skipping. An experimentally characterized example was COL1A1 IVS5-2A>T—legacy nomenclature—which activated a cryptic splice site and removed the first 15 nucleotides of exon 6. This deleted five amino acids including the procollagen N-proteinase cleavage site. Modern HGVS nomenclature should be generated against the transcript used by the testing laboratory rather than inferred from this legacy description. (giunta2008thearthrochalasiatype pages 2-3)

These are germline heterozygous variants. Somatic mosaic disease is not an established mechanism. Pathogenicity should be assigned under ACMG/AMP criteria using segregation/de novo evidence, RNA evidence demonstrating exon loss, collagen biochemical evidence, absence or extreme rarity in population databases, and phenotype specificity. Exact allele frequencies were unavailable in the retrieved papers, but fully penetrant causal alleles for a disorder this rare are expected to be absent or exceptionally rare in gnomAD; this expectation is not a substitute for variant-level database checking.

The functional mechanism is best described as structural loss with dominant interference rather than simple haploinsufficiency. Mutant chains enter heterotrimeric type I collagen molecules: approximately three quarters of molecules may be affected for an abnormal α1(I) chain and approximately half for an abnormal α2(I) chain. That provides a plausible explanation for reports that COL1A1-related disease can be more severe, although robust genotype–phenotype statistics are unavailable. Dominant-negative interference is strongly inferred from chain incorporation and abnormal fibrils, but was not directly tested as a separate experimental endpoint in the cited ultrastructural study. (martinmartin2022ehlers–danlossyndrometype pages 7-8, giunta2008thearthrochalasiatype pages 1-2)

No reproducible modifier genes, epigenetic signature, pathogenic aneuploidy, translocation, repeat expansion, mitochondrial lesion, or large chromosomal syndrome is established for aEDS. Copy-number variants restricted to the relevant exon or splice architecture remain plausible and justify deletion/duplication analysis after negative sequencing.

5. Environmental information

There is no evidence for causal pollutants, radiation, occupational agents, toxins, dietary deficiencies, alcohol, smoking, or infectious agents. Therefore CTD/toxicogenomic and pathogen annotations should be not applicable/unsupported. High-impact activity, forceful manipulation, poor joint positioning, and surgery can aggravate manifestations in genetically fragile tissues; they should be represented as complication triggers, not disease causes. A 2024 chiropractic case illustrates that forceful manipulation can worsen pain and inflammation in EDS, but the patient was not molecularly established to have aEDS, so this is indirect evidence only. (lucente2024chiropractictreatmentof pages 1-2)

6. Mechanism and pathophysiology

Ordered causal chain

A heterozygous germline COL1A1 or COL1A2 splice/deletion lesion leads to partial or complete skipping of exon 6. (Demonstrated in human cases.) (giunta2008thearthrochalasiatype pages 2-3, malfait2020theehlers–danlossyndromes pages 6-7)
Exon-6 loss leads to deletion of the N-proteinase cleavage site and may also remove the N-telopeptide cross-linking lysine and first Gly-X-Y helical triplet. (Demonstrated by sequence/protein analysis.) (malfait2020theehlers–danlossyndromes pages 6-7, brady2017theehlers–danlossyndromes pages 8-9)
Loss of the cleavage site results in failure to remove the type I procollagen N-propeptide, producing pNα1(I)- or pNα2(I)-containing collagen. (Demonstrated by fibroblast collagen electrophoresis.) (giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2)
Incorporation of uncleaved mutant chains leads to disturbed extracellular collagen-I fibrillogenesis. Dominant interference is strongly inferred from the proportion of affected heterotrimers and fibril abnormalities rather than proven in an isolated perturbation experiment. (giunta2008thearthrochalasiatype pages 1-2)
Disturbed fibrillogenesis results in smaller, loosely/randomly organized collagen fibrils with irregular or ragged contours in skin dermis. (Demonstrated by transmission electron microscopy.) (giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2)
Abnormal collagen architecture leads to reduced tensile and stabilizing competence of ligaments, joint capsules, skin, tendon, and bone connective tissue. (Mechanistically inferred from tissue function and concordant human phenotype.)
Ligament/joint-capsule weakness leads to congenital hip dislocation, severe generalized hypermobility, recurrent dislocations, and deformity; skin/dermal weakness leads to hyperextensibility, bruising, fragility, and atrophic scars; musculoskeletal matrix weakness leads to hypotonia-associated motor impairment, kyphoscoliosis, and mild osteopenia. (Human clinical association; intermediate biomechanics partly inferred.) (malfait2017the2017international pages 12-13, martinmartin2022ehlers–danlossyndrometype pages 5-7, giunta2008thearthrochalasiatype pages 2-3)

Cellular and biochemical detail

The best direct cellular evidence comes from cultured dermal fibroblasts. Patient fibroblasts synthesize abnormal longer α(I) chains retaining their N-propeptide, demonstrable by SDS-PAGE and collagen-fraction analyses. Historical reports of only 10–40% normal “converting proteinase” activity were subsequently reinterpreted after mutant pNα2(I) chains were identified: the primary lesion is substrate structure/processing, not necessarily reduced enzyme production. (giunta2008thearthrochalasiatype pages 2-3, brady2017theehlers–danlossyndromes pages 8-9)

No primary Wnt, MAPK, mTOR, PI3K–AKT, immune, autophagy, apoptosis, mitochondrial, or metabolic pathway defect is established. ER stress is a recognized mechanism in some structural extracellular-matrix diseases, but has not been demonstrated as aEDS-specific pathology and should not be curated as established. Likewise, no aEDS-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or multi-omics signature was identified. (lamande2020geneticdisordersof pages 1-2)

Suggested ontology annotations include GO: extracellular matrix organization; collagen fibril organization; collagen biosynthetic process; protein processing; extracellular structure organization. Relevant cellular components are collagen-containing extracellular matrix and collagen trimer. Suggested Cell Ontology labels are fibroblast (CL:0000057), dermal fibroblast, osteoblast, tenocyte, and ligament fibroblast; only dermal fibroblasts were directly studied, whereas the latter cell types are anatomically plausible but not directly profiled.

7. Anatomical structures affected

Primary organ/system level: musculoskeletal system—hips, knees, shoulders and other synovial joints; axial skeleton; feet; bone. Integumentary system—skin and scars.
Tissue level: ligament, joint capsule, tendon, dermis, bone extracellular matrix, fascia and other collagen-I-rich connective tissues.
Cell level: fibroblasts are directly demonstrated; osteoblasts, tenocytes and ligament/joint-capsule fibroblasts are inferred relevant collagen producers.
Subcellular level: COL1A1/COL1A2 transcription and splicing occur in the nucleus; procollagen synthesis and assembly occur in rough ER/Golgi; extracellular N-propeptide processing and fibrillogenesis occur in the extracellular space. Only the extracellular processing/fibril defect and fibroblast collagen products are directly demonstrated in aEDS.
Secondary cardiovascular involvement: rare vascular complications and isolated valvular regurgitation have been reported, but aEDS is not classified as vascular EDS. (dhondt2018vascularphenotypesin pages 3-4, martinmartin2022ehlers–danlossyndrometype pages 4-5)

Suggested UBERON labels are hip joint, knee joint, synovial joint, skin of body, dermis, tendon, ligament, bone tissue and extracellular matrix. Hip involvement is usually bilateral; other dislocations may be bilateral, unilateral, or asymmetric.

8. Temporal development

Onset is prenatal/congenital. Breech presentation, polyhydramnios, premature rupture of membranes, reduced fetal movement, prematurity, and congenital joint dislocations have been reported. Neonates may have severe hypotonia, generalized hypermobility, large fontanelles and mild dysmorphism. (martinmartin2022ehlers–danlossyndrometype pages 7-8)

The condition is chronic and lifelong, without recognized remission. Hypotonia and apparent hypermobility may lessen with age, but orthopedic instability, recurrent injury, spinal deformity, pain, and scar burden may persist or accumulate. Mental development was normal in reported patients. Published observations span prenatal life through adulthood, but there is no validated stage system or reliable progression rate. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 4-5)

Critical intervention periods are:

Prenatal/perinatal: obstetric monitoring because of malpresentation, membrane rupture and prematurity.
Neonatal/infancy: early recognition and careful management of hip/knee dislocation, hypotonia and clubfoot.
Growth: prevention and monitoring of scoliosis, recurrent instability and deconditioning.
Before surgery or pregnancy: individualized tissue-fragility, bleeding, wound-healing, positioning and anesthetic planning. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 4-5)

9. Inheritance and population

Inheritance is autosomal dominant. Each child of an affected heterozygous individual has a 50% probability of inheriting the variant, subject to confirmation that the parent is heterozygous and excluding mosaicism. Both sexes are expected to be affected equally; no sex-specific penetrance is established. Expressivity is variable, including possible COL1A1-versus-COL1A2 severity differences. No genetic anticipation is expected because this is not a repeat-expansion disorder. (malfait2017the2017international pages 12-13, martinmartin2022ehlers–danlossyndrometype pages 7-8)

Population prevalence and annual incidence are unknown. The strongest available statistic is approximately 42 published patients worldwide by 2022. This is a literature count, not prevalence. Aggregate EDS estimates—including 1:5,000 or EDS/hypermobility-code prevalence from national EHR studies—must not be assigned to aEDS. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 1-2)

No founder effect, ancestry enrichment, geographic concentration, carrier frequency, or role for consanguinity has been established. Consanguinity is not expected to be a major determinant for an autosomal-dominant disorder. Parental germline mosaicism is biologically possible in an apparently de novo case, but an aEDS-specific recurrence rate was not found.

10. Diagnostics

Clinical criteria

The 2017 minimum criteria suggestive of aEDS are:

congenital bilateral hip dislocation; and
either skin hyperextensibility or severe generalized joint hypermobility with multiple dislocations/subluxations; and
at least two minor criteria: hypotonia, kyphoscoliosis, mild radiographic osteopenia, tissue fragility/atrophic scars, or easy bruising.

A definitive diagnosis requires identification of a causal COL1A1 or COL1A2 variant producing complete or partial exon-6 loss. Clinical criteria alone are insufficient because of overlap with other EDS and skeletal dysplasia phenotypes. (malfait2017the2017international pages 12-13)

Recommended testing algorithm

Document congenital hip status, generalized hypermobility, dislocation history, skin/scar findings, hypotonia, spine/foot deformity, bruising and family history.
Perform sequencing of COL1A1 and COL1A2, preferably through a validated EDS/heritable connective-tissue-disorder panel that includes splice boundaries and permits phenotype-based differential diagnosis.
If negative, perform exon-level deletion/duplication/CNV analysis and review coverage of exon 6 and adjacent intronic regions.
For a candidate splice variant, use RNA studies where possible to demonstrate partial or complete exon-6 loss.
If panel testing is unrevealing despite a compelling phenotype, WES or WGS can identify atypical intronic/structural lesions or an alternative diagnosis. WGS is especially useful for noncoding splice and structural variants; neither WES nor WGS replaces functional splice interpretation.
Segregation and parental testing distinguish inherited from de novo disease and support recurrence counseling.

CMA, karyotyping, FISH, mitochondrial DNA testing and repeat-expansion testing are not routine aEDS tests unless another diagnosis is suspected.

Ancillary tests

Cultured skin-fibroblast collagen analysis can identify abnormal pN-collagen chains. Skin-biopsy transmission electron microscopy may reveal small, irregular, ragged and disorganized collagen fibrils and can provide supportive evidence, including possible distinction in severity between VIIA and VIIB; it does not replace molecular confirmation. (giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2)

Clinical evaluation may include hip/spine/foot radiography, bone-density assessment when clinically indicated, echocardiography based on baseline evaluation or symptoms, and vascular imaging only when individualized risk or clinical findings justify it. There is no validated circulating biomarker, enzyme assay, liquid biopsy, electrophysiologic signature, or omics-based diagnostic test.

Differential diagnosis

Other EDS subtypes: especially classical, classical-like, dermatosparaxis, kyphoscoliotic, musculocontractural and spondylodysplastic EDS; distinguish by molecular testing and subtype-specific skin, vascular, craniofacial or congenital-contracture findings.
Osteogenesis imperfecta/COL1-related overlap disorder: fracture burden, blue sclerae and dentinogenesis imperfecta favor OI, although overlap occurs.
Larsen syndrome: multiple congenital large-joint dislocations and characteristic craniofacial/skeletal findings; FLNB testing.
Loeys–Dietz syndrome: arterial aneurysm/tortuosity and craniofacial findings; TGF-β-pathway genes.
Cutis laxa syndromes: lax rather than hyperextensible/recoiling skin and subtype-specific systemic disease.
Congenital hip dysplasia, Marfan syndrome, FLNA-related disorders, and neuromuscular hypotonia syndromes. The aEDS systematic review specifically highlights Larsen, Loeys–Dietz and cutis laxa syndromes. (martinmartin2022ehlers–danlossyndrometype pages 7-8)

No population newborn screen exists. Appropriate screening is phenotype-triggered testing and cascade testing of relatives after a familial variant is established.

11. Outcome and prognosis

No 5- or 10-year survival estimates, disease-specific mortality rate, or validated life-expectancy estimate exists. Available evidence does not show the severe arterial-rupture mortality pattern characteristic of vascular EDS. One systematic review found a vascular complication in 1 of 17 aEDS patients (6%), and a case report described progressive mitral, aortic and tricuspid regurgitation; both findings warrant awareness but are too sparse to quantify lifetime risk. (dhondt2018vascularphenotypesin pages 3-4, martinmartin2022ehlers–danlossyndrometype pages 4-5)

One neonatal death in a baby born at 35 weeks was included in the 2022 review, but the evidence does not establish a general neonatal mortality rate. Intellectual development is generally normal. Fractures appear uncommon despite mild osteopenia in some patients. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 5-7)

Principal morbidity is orthopedic and functional: congenital hip disease, recurrent instability/dislocation, spinal and foot deformity, pain, impaired mobility, skin injury, bruising and surgical/wound complications. Recovery from an individual dislocation or operation is possible, but the underlying collagen defect and lifelong predisposition do not resolve. Prognostic factors have not been validated; plausible factors include variant/gene, severity of congenital instability, scoliosis, recurrent trauma, muscle conditioning and access to specialist care.

12. Treatment

Current strategy

There is no approved curative, gene, RNA, cell, enzyme-replacement, targeted, or disease-modifying treatment. The 2022 review’s abstract states: “Treatment is currently symptomatic and focuses on increasing the quality of life of these patients, as there is no curative treatment.” (martinmartin2022ehlers–danlossyndrometype pages 1-2)

Management should be multidisciplinary and individualized:

Physiotherapy/rehabilitation: low-impact strengthening, proprioceptive training, postural and gait work, and prevention of deconditioning; avoid forceful end-range maneuvers. Suggested NCIT terms: Physical Therapy, Rehabilitation Therapy.
Occupational therapy and joint protection: activity modification, ergonomic support, adaptive equipment and fatigue management. NCIT: Occupational Therapy, Supportive Care.
Orthoses and mobility aids: braces, splints, footwear, walking aids or wheelchairs according to instability and function. NCIT: Orthotic Device, Assistive Device.
Pain management: multimodal nonpharmacologic care; acetaminophen or appropriately selected analgesics as clinically indicated. No aEDS-specific drug-response or pharmacogenomic data exist. NCIT: Pain Management, Analgesic Therapy.
Skin/wound care: minimize trauma and adhesive injury; careful closure, prolonged support where appropriate, and monitoring for delayed healing or hematoma. NCIT: Wound Care.
Orthopedic intervention: early specialist assessment of congenital hip/knee dislocation, clubfoot and progressive deformity; surgery only after careful risk–benefit evaluation and when conservative care is inadequate. NCIT: Orthopedic Surgery, Joint Stabilization Procedure.
Cardiac/vascular care: symptom-driven or individualized surveillance; standard cardiology management for documented valve or vascular disease.
Pregnancy: high-risk obstetric planning, careful positioning and attention to malpresentation, premature membrane rupture, tissue fragility and postpartum injury. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 4-5)

Surgical evidence and 2024 development

The October 2024 EDS-wide scoping review found 71 primary orthopedic studies from 1990–2023—38 single case reports, 14 case series and 19 retrospective cohorts—and no randomized trials. Outcomes were inconsistent, and no reliable long-term benefit or aEDS-specific protocol could be established. (schubart2024outcomesoforthopaedic pages 1-2)

A retrospective EDS surgical cohort reported 290 postoperative complications after 320 procedures, with a complication recorded in 91% of cases; however, subtype assignment was unreliable and these data cannot be directly converted into an aEDS risk estimate. General concerns include persistent instability/pain, fixation failure, bleeding, infection, poor wound healing and reoperation. These findings support cautious planning, not avoidance of all necessary surgery. (schubart2024outcomesoforthopaedic pages 15-16, yonko2021orthopedicconsiderationsand pages 1-1, yonko2021orthopedicconsiderationsand pages 6-6)

The ClinicalTrials.gov search retrieved no relevant aEDS-specific interventional trial. No NCT identifier, response rate, or treatment-related adverse-event series specific to aEDS was identified.

13. Prevention

Primary prevention: The occurrence of a de novo pathogenic variant cannot currently be prevented. For known familial disease, reproductive options include genetic counseling, prenatal diagnosis and preimplantation genetic testing for the established familial variant. These prevent or inform transmission risk; they are not therapies.

Secondary prevention: Early diagnosis in an infant with bilateral hip dislocation, severe hypermobility and hypotonia permits appropriate handling, orthopedic care, avoidance of damaging procedures, and cascade testing. There is no population newborn screening or routine carrier screening because aEDS is autosomal dominant and exceptionally rare.

Tertiary prevention: Joint-protection education, safe strengthening, appropriate bracing, fall prevention, avoidance of high-impact/contact activities, cautious manual therapy, skin protection, dental and surgical planning, monitoring of deformity and individualized cardiac assessment aim to reduce complications. Vaccination, antimicrobial prophylaxis and environmental remediation have no disease-specific preventive role.

Genetic counseling should explain the 50% transmission risk from a heterozygous affected parent, variable expressivity, possibility of a de novo variant, and residual recurrence risk from parental mosaicism.

14. Other species and natural disease

No naturally occurring animal disorder was identified that is securely established as the direct orthologue of human aEDS caused by a heterozygous COL1A1 or COL1A2 exon-6 lesion. EDS-like diseases occur in dogs and other domestic species, but retrieved canine evidence concerned ADAMTS2-related dermatosparaxis, not arthrochalasia; it must not be curated as an aEDS model. (lamande2020geneticdisordersof pages 1-2)

Relevant conserved orthologues include mouse Col1a1/Col1a2, rat Col1a1/Col1a2, zebrafish col1a1a/col1a1b/col1a2, and canine COL1A1/COL1A2. The collagen-I processing pathway is evolutionarily conserved, but an exact spontaneous veterinary aEDS genotype–phenotype relationship was not established in the retrieved literature. There is no infectious transmission, zoonotic potential or cross-species contagion.

15. Model organisms and experimental systems

The most disease-proximal established experimental system is patient-derived cultured dermal fibroblasts, which reproduce abnormal transcript processing and secretion/incorporation of pN-collagen. Skin-biopsy transmission electron microscopy directly demonstrates abnormal fibril architecture. These systems are suitable for RNA-splicing assays, collagen electrophoresis, extracellular-matrix imaging and testing splice-correction concepts. (giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2)

A 2014 mouse was described as a model of combined osteogenesis imperfecta and EDS, but its variants were outside collagen exon 6. It is therefore mechanistically adjacent, not an exact aEDS model, and should not be annotated as fully recapitulating arthrochalasia EDS.

No validated exon-6 aEDS knock-in mouse, rat, zebrafish, Drosophila, organoid, iPSC, humanized model, or CRISPR functional-genomics screen was identified. A high-priority model would be a heterozygous splice-site or precise exon-6 deletion knock-in in Col1a1 or Col1a2, assessed for pN-collagen retention, fibril ultrastructure, congenital hip instability, generalized laxity, skin mechanics and bone phenotype. Its limitations would include species-specific hip development and difficulty quantifying subjective pain and disability.

Evidence synthesis and research priorities

The strongest evidence is the concordance of molecularly confirmed human cases, patient-fibroblast biochemistry and dermal electron microscopy. Together these establish a causal sequence from COL1A1/COL1A2 exon-6 loss to retained N-propeptide, abnormal fibrillogenesis and systemic connective-tissue laxity. (giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2, malfait2020theehlers–danlossyndromes pages 6-7)

The most important knowledge gaps are reliable prevalence, prospective natural history, variant-level penetrance and expressivity, validated quality-of-life data, aEDS-specific cardiac/vascular risk, pregnancy outcomes, orthopedic-treatment comparisons, molecular profiling, exact animal models and disease-modifying therapy. The 2024 orthopedic review reinforces the expert view that subtype-confirmed multicenter registries and standardized outcomes are prerequisites for evidence-based surgical algorithms. (schubart2024outcomesoforthopaedic pages 15-16, schubart2024outcomesoforthopaedic pages 1-2)

Key references

Malfait F, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C. Published March 2017. PMID: 28306229. https://doi.org/10.1002/ajmg.c.31552. (malfait2017the2017international pages 12-13)
Martín-Martín M, et al. Ehlers–Danlos Syndrome Type Arthrochalasia: A Systematic Review. Int J Environ Res Public Health. Published 7 February 2022;19:1870. https://doi.org/10.3390/ijerph19031870. (martinmartin2022ehlers–danlossyndrometype pages 7-8, martinmartin2022ehlers–danlossyndrometype pages 1-2)
Giunta C, et al. The arthrochalasia type of Ehlers–Danlos syndrome (EDS VIIA and VIIB): the diagnostic value of collagen fibril ultrastructure. Am J Med Genet A. Published April 2008;146A:1341–1346. PMID: 18409203. https://doi.org/10.1002/ajmg.a.32213. (giunta2008thearthrochalasiatype pages 2-3, giunta2008thearthrochalasiatype pages 1-2)
Brady AF, et al. The Ehlers–Danlos syndromes, rare types. Am J Med Genet C. Published March 2017;175:115–170. https://doi.org/10.1002/ajmg.c.31550. (brady2017theehlers–danlossyndromes pages 8-9)
Malfait F, et al. The Ehlers–Danlos syndromes. Nature Reviews Disease Primers. Published July 2020;6. https://doi.org/10.1038/s41572-020-0194-9. (malfait2020theehlers–danlossyndromes pages 6-7)
D’Hondt S, Van Damme T, Malfait F. Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review. Genetics in Medicine. Published June 2018. https://doi.org/10.1038/gim.2017.138. (dhondt2018vascularphenotypesin pages 3-4, dhondt2018vascularphenotypesin pages 1-2)
Schubart JR, et al. Outcomes of orthopaedic surgery in Ehlers-Danlos syndromes: a scoping review. BMC Musculoskeletal Disorders. Published October 2024;25. https://doi.org/10.1186/s12891-024-07937-6. (schubart2024outcomesoforthopaedic pages 15-16, schubart2024outcomesoforthopaedic pages 1-2)
Yonko EA, et al. Orthopedic considerations and surgical outcomes in Ehlers–Danlos syndromes. Am J Med Genet C. Published November 2021;187:458–465. https://doi.org/10.1002/ajmg.c.31958. (yonko2021orthopedicconsiderationsand pages 1-1, yonko2021orthopedicconsiderationsand pages 6-6)

References

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(martinmartin2022ehlers–danlossyndrometype pages 1-2): Marta Martín-Martín, Jonathan Cortés-Martín, Maria Isabel Tovar-Gálvez, Juan Carlos Sánchez-García, Lourdes Díaz-Rodríguez, and Raquel Rodríguez-Blanque. Ehlers–danlos syndrome type arthrochalasia: a systematic review. Feb 2022. URL: https://doi.org/10.3390/ijerph19031870, doi:10.3390/ijerph19031870. This article has 18 citations.
(schubart2024outcomesoforthopaedic pages 1-2): Jane R. Schubart, Susan E. Mills, Scott A. Rodeo, and Clair A. Francomano. Outcomes of orthopaedic surgery in ehlers-danlos syndromes: a scoping review. BMC Musculoskeletal Disorders, Oct 2024. URL: https://doi.org/10.1186/s12891-024-07937-6, doi:10.1186/s12891-024-07937-6. This article has 14 citations and is from a peer-reviewed journal.
(malfait2017the2017international pages 12-13): Fransiska Malfait, Clair Francomano, Peter Byers, John Belmont, Britta Berglund, James Black, Lara Bloom, Jessica M. Bowen, Angela F. Brady, Nigel P. Burrows, Marco Castori, Helen Cohen, Marina Colombi, Serwet Demirdas, Julie De Backer, Anne De Paepe, Sylvie Fournel‐Gigleux, Michael Frank, Neeti Ghali, Cecilia Giunta, Rodney Grahame, Alan Hakim, Xavier Jeunemaitre, Diana Johnson, Birgit Juul‐Kristensen, Ines Kapferer‐Seebacher, Hanadi Kazkaz, Tomoki Kosho, Mark E. Lavallee, Howard Levy, Roberto Mendoza‐Londono, Melanie Pepin, F. Michael Pope, Eyal Reinstein, Leema Robert, Marianne Rohrbach, Lynn Sanders, Glenda J. Sobey, Tim Van Damme, Anthony Vandersteen, Caroline van Mourik, Nicol Voermans, Nigel Wheeldon, Johannes Zschocke, and Brad Tinkle. The 2017 international classification of the ehlers–danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175:26-8, Mar 2017. URL: https://doi.org/10.1002/ajmg.c.31552, doi:10.1002/ajmg.c.31552. This article has 2455 citations.
(wenstrup2002prevalenceofaortic pages 1-2): Richard J. Wenstrup, Richard A. Meyer, Jennifer S. Lyle, Leah Hoechstetter, Peter S. Rose, Howard P. Levy, and Claire A. Francomano. Prevalence of aortic root dilation in the ehlers-danlos syndrome. Genetics in Medicine, 4:112-117, May 2002. URL: https://doi.org/10.1097/00125817-200205000-00003, doi:10.1097/00125817-200205000-00003. This article has 164 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: arthrochalasia Ehlers-Danlos syndrome-COL1A1,COL1A2): Open Targets Query (arthrochalasia Ehlers-Danlos syndrome-COL1A1,COL1A2, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(giunta2008thearthrochalasiatype pages 1-2): Cecilia Giunta, Céline Chambaz, Marina Pedemonte, Sara Scapolan, and Beat Steinmann. The arthrochalasia type of ehlers–danlos syndrome (eds viia and viib): the diagnostic value of collagen fibril ultrastructure. American Journal of Medical Genetics Part A, 146A(10):1341-1346, Apr 2008. URL: https://doi.org/10.1002/ajmg.a.32213, doi:10.1002/ajmg.a.32213. This article has 46 citations.
(giunta2008thearthrochalasiatype pages 2-3): Cecilia Giunta, Céline Chambaz, Marina Pedemonte, Sara Scapolan, and Beat Steinmann. The arthrochalasia type of ehlers–danlos syndrome (eds viia and viib): the diagnostic value of collagen fibril ultrastructure. American Journal of Medical Genetics Part A, 146A(10):1341-1346, Apr 2008. URL: https://doi.org/10.1002/ajmg.a.32213, doi:10.1002/ajmg.a.32213. This article has 46 citations.
(malfait2020theehlers–danlossyndromes pages 6-7): Fransiska Malfait, Marco Castori, Clair A. Francomano, Cecilia Giunta, Tomoki Kosho, and Peter H. Byers. The ehlers–danlos syndromes. Nature Reviews Disease Primers, 6:1-25, Jul 2020. URL: https://doi.org/10.1038/s41572-020-0194-9, doi:10.1038/s41572-020-0194-9. This article has 409 citations.
(brady2017theehlers–danlossyndromes pages 8-9): Angela F. Brady, Serwet Demirdas, Sylvie Fournel‐Gigleux, Neeti Ghali, Cecilia Giunta, Ines Kapferer‐Seebacher, Tomoki Kosho, Roberto Mendoza‐Londono, Michael F. Pope, Marianne Rohrbach, Tim Van Damme, Anthony Vandersteen, Caroline van Mourik, Nicol Voermans, Johannes Zschocke, and Fransiska Malfait. The ehlers–danlos syndromes, rare types. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175:115-70, Mar 2017. URL: https://doi.org/10.1002/ajmg.c.31550, doi:10.1002/ajmg.c.31550. This article has 318 citations.
(martinmartin2022ehlers–danlossyndrometype pages 5-7): Marta Martín-Martín, Jonathan Cortés-Martín, Maria Isabel Tovar-Gálvez, Juan Carlos Sánchez-García, Lourdes Díaz-Rodríguez, and Raquel Rodríguez-Blanque. Ehlers–danlos syndrome type arthrochalasia: a systematic review. Feb 2022. URL: https://doi.org/10.3390/ijerph19031870, doi:10.3390/ijerph19031870. This article has 18 citations.
(dhondt2018vascularphenotypesin pages 3-4): Sanne D'hondt, Tim Van Damme, and Fransiska Malfait. Vascular phenotypes in nonvascular subtypes of the ehlers-danlos syndrome: a systematic review. Jun 2018. URL: https://doi.org/10.1038/gim.2017.138, doi:10.1038/gim.2017.138. This article has 107 citations and is from a highest quality peer-reviewed journal.
(martinmartin2022ehlers–danlossyndrometype pages 4-5): Marta Martín-Martín, Jonathan Cortés-Martín, Maria Isabel Tovar-Gálvez, Juan Carlos Sánchez-García, Lourdes Díaz-Rodríguez, and Raquel Rodríguez-Blanque. Ehlers–danlos syndrome type arthrochalasia: a systematic review. Feb 2022. URL: https://doi.org/10.3390/ijerph19031870, doi:10.3390/ijerph19031870. This article has 18 citations.
(schubart2024outcomesoforthopaedic pages 15-16): Jane R. Schubart, Susan E. Mills, Scott A. Rodeo, and Clair A. Francomano. Outcomes of orthopaedic surgery in ehlers-danlos syndromes: a scoping review. BMC Musculoskeletal Disorders, Oct 2024. URL: https://doi.org/10.1186/s12891-024-07937-6, doi:10.1186/s12891-024-07937-6. This article has 14 citations and is from a peer-reviewed journal.
(islam2021ehlersdanlossyndromeimmunologic pages 31-33): 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.
(martinmartin2022ehlers–danlossyndrometype pages 2-4): Marta Martín-Martín, Jonathan Cortés-Martín, Maria Isabel Tovar-Gálvez, Juan Carlos Sánchez-García, Lourdes Díaz-Rodríguez, and Raquel Rodríguez-Blanque. Ehlers–danlos syndrome type arthrochalasia: a systematic review. Feb 2022. URL: https://doi.org/10.3390/ijerph19031870, doi:10.3390/ijerph19031870. This article has 18 citations.
(yonko2021orthopedicconsiderationsand pages 2-3): Elizabeth A. Yonko, Holly M. LoTurco, Erin M. Carter, and Cathleen L. Raggio. Orthopedic considerations and surgical outcomes in ehlers–danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 187:458-465, Nov 2021. URL: https://doi.org/10.1002/ajmg.c.31958, doi:10.1002/ajmg.c.31958. This article has 36 citations.
(lucente2024chiropractictreatmentof pages 1-2): M Lucente and KS Walden. Chiropractic treatment of a patient with ehlers-danlos syndrome: a case report. Unknown journal, 2024.
(lamande2020geneticdisordersof pages 1-2): Shireen R. Lamandé and John F. Bateman. Genetic disorders of the extracellular matrix. Anatomical Record (Hoboken, N.j. : 2007), 303:1527-1542, Mar 2020. URL: https://doi.org/10.1002/ar.24086, doi:10.1002/ar.24086. This article has 129 citations.
(yonko2021orthopedicconsiderationsand pages 1-1): Elizabeth A. Yonko, Holly M. LoTurco, Erin M. Carter, and Cathleen L. Raggio. Orthopedic considerations and surgical outcomes in ehlers–danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 187:458-465, Nov 2021. URL: https://doi.org/10.1002/ajmg.c.31958, doi:10.1002/ajmg.c.31958. This article has 36 citations.
(yonko2021orthopedicconsiderationsand pages 6-6): Elizabeth A. Yonko, Holly M. LoTurco, Erin M. Carter, and Cathleen L. Raggio. Orthopedic considerations and surgical outcomes in ehlers–danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 187:458-465, Nov 2021. URL: https://doi.org/10.1002/ajmg.c.31958, doi:10.1002/ajmg.c.31958. This article has 36 citations.
(dhondt2018vascularphenotypesin pages 1-2): Sanne D'hondt, Tim Van Damme, and Fransiska Malfait. Vascular phenotypes in nonvascular subtypes of the ehlers-danlos syndrome: a systematic review. Jun 2018. URL: https://doi.org/10.1038/gim.2017.138, doi:10.1038/gim.2017.138. This article has 107 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

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	4
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	15
Resolved	10
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	5
Terms whose name was checked	1
Terms named correctly	0
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:0007525 (5 mentions) - the report calls it "if available"; MONDO calls it Ehlers-Danlos syndrome, arthrochalasia type

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: Gene, Taxon.

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OpenScientist Report

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Experimental Models

Source YAML

References & Deep Research

References

Deep Research

Arthrochalasia Ehlers–Danlos Syndrome: Disease Characteristics Report

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology

Causal factors and genetic risk

Environmental, lifestyle, infectious, and protective factors

3. Phenotypes

Core and minor manifestations

Quality of life

4. Genetic and molecular information

Pathogenic variant class and consequences

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Cellular and biochemical detail

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical criteria

Recommended testing algorithm

Ancillary tests

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Current strategy

Surgical evidence and 2024 development

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Evidence synthesis and research priorities

Key references

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Prefixes with no resolver