Classical-like Ehlers-Danlos Syndrome

Mendelian MONDO:0011670 Pathograph 32 Show in embeddings browser Ehlers-Danlos Syndrome Connective Tissue Disorder

Classical-like Ehlers-Danlos syndrome (clEDS) is a group of autosomal recessive connective-tissue disorders that clinically resemble classic EDS (generalized joint hypermobility, hyperextensible/velvety skin, easy bruising) but characteristically lack the atrophic scarring seen in classic EDS. Two molecularly distinct, genetically heterogeneous forms are recognized: clEDS-1, caused by biallelic loss-of-function variants in TNXB (tenascin-X), and clEDS-2, caused by biallelic loss-of-function variants in AEBP1 (encoding the aortic carboxypeptidase-like protein, ACLP). Both genes encode extracellular matrix proteins that normally organize dermal collagen fibrillogenesis; their loss produces disorganized, sparsely packed collagen fibrils and a resulting skin/joint/vascular fragility phenotype, with additional distinguishing features (peripheral neuromuscular involvement in clEDS-1; hair loss and vascular aneurysm risk in clEDS-2) that reflect each protein's distinct additional roles.

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1
Inheritance
9
Pathophys.
20
Phenotypes
1
Gaps
32
Pathograph
2
Genes
3
Medical Actions
2
Subtypes
2
References
1
Deep Research
👪

Inheritance

1
Autosomal Recessive Inheritance HP:0000007
Both clEDS-1 (TNXB) and clEDS-2 (AEBP1) are inherited in an autosomal recessive manner; heterozygous carriers of TNXB or AEBP1 variants are generally unaffected or only mildly symptomatic.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:36108117 SUPPORT Human Clinical
"TNXB-related clED is inherited in an autosomal recessive manner."
GeneReviews states the autosomal recessive inheritance pattern for TNXB-related clEDS.
PMID:37214418 SUPPORT Human Clinical
"Heterozygous individuals appear to have no relevant symptoms."
Supports autosomal recessive inheritance for clEDS-2, with unaffected heterozygous carriers.
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Subtypes

2
clEDS-1 (TNXB-related) MONDO:0011670
TNXB hgnc:11976 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TNXB (hgnc:11976). hgnc:11976 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic pathogenic variants in TNXB, encoding tenascin-X, a large extracellular matrix glycoprotein that binds dermal collagens and accelerates collagen fibrillogenesis. The more common and better clinically delineated of the two forms.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing."
GeneReviews establishes biallelic TNXB variants as the molecular diagnosis for this subtype.
clEDS-2 (AEBP1-related) MONDO:0054813
AEBP1 hgnc:303 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in AEBP1 (hgnc:303). hgnc:303 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic pathogenic variants in AEBP1, encoding the aortic carboxypeptidase-like protein (ACLP), which binds collagen types I, III and V via its discoidin domain and promotes type I collagen polymerization. A rarer, more recently delineated form; as of the most recent comprehensive review, 11 patients from 9 families had been reported.
Show evidence (2 references)
PMID:37214418 SUPPORT Human Clinical
"In 2018, Blackburn et al. (2018) identified biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene in patients displaying EDS-like features that were considered to represent a new subtype of EDS and were tentatively named classical-like type 2 (clEDS2; MIM #618000)"
Establishes biallelic AEBP1 variants as the molecular cause of clEDS-2.
PMID:37214418 SUPPORT Human Clinical
"We report here an additional patient with clEDS2 who had novel variants in AEBP1"
Confirms the 11th reported clEDS-2 patient, establishing the small but growing case series for this rarer subtype.
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Discussions and Knowledge Gaps

1
Do heterozygous (carrier) TNXB variants contribute to hypermobile Ehlers-Danlos syndrome (hEDS) or a milder connective-tissue phenotype, beyond the biallelic loss-of-function threshold that causes clEDS-1 itself?
KNOWLEDGE GAP heterozygous_tnxb_and_hypermobile_eds
Attached to
genetic#TNXB inheritance#Autosomal Recessive Inheritance
This entry models clEDS-1 as strictly autosomal recessive, with heterozygous carriers "generally unaffected or only mildly symptomatic" per the cited GeneReviews chapter. Two independent 2026 case reports complicate that picture without settling it: a four-sibling Nusayri family in which the one heterozygous carrier met clinical criteria for hEDS while his parents (also heterozygous) were asymptomatic, and a Polish cohort in which a heterozygous frameshift carrier and her father both showed mild joint hypermobility with no phenotype in other non-carrier relatives. Both papers explicitly stop short of a causal claim, citing incomplete penetrance and variable expressivity as unresolved. The gap is recorded here rather than folded into a confident phenotype/inheritance claim, since the evidence is small-pedigree and inconsistent (symptomatic vs. asymptomatic carriers within the same reports).
Show evidence (2 references)
PMID:42445465 SUPPORT DIRECT Human Clinical
"The clinical findings suggest the potential role of TNXB haploinsufficiency in hEDS; however, further research is needed to elucidate the variable expressivity and possible incomplete penetrance associated with hmEDS."
The paper's own conclusion states the hypothesis while explicitly flagging it as unresolved.
PMID:41913751 SUPPORT INDIRECT Human Clinical
"It is also possible that an undetected pathogenic variant on the second allele (eg, a deep intronic mutation not captured by routine diagnostic methods) may contribute to the phenotype."
An independent cohort raises the same carrier-phenotype question and names a competing explanation (an undetected second-allele variant) that would preserve strict recessive inheritance instead.
⚙

Pathophysiology

9
TNXB Loss-of-Function
Biallelic pathogenic TNXB variants abolish or severely reduce tenascin-X, an extracellular matrix glycoprotein whose FNIII29/FbgX domains bind dermal collagens I, III and V and normally accelerate collagen fibrillogenesis.
TNXB hgnc:11976 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNXB (hgnc:11976). hgnc:11976 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
collagen binding GO:0005518 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves collagen binding (GO:0005518). GO:0005518 is a molecular function from the Gene Ontology.
Downstream
Disorganized Dermal Collagen Matrix Loss of tenascin-X's collagen-binding, fibrillogenesis-promoting activity leaves dermal collagen fibrils disorganized and loosely packed.
Show evidence (1 reference)
PMID:20089348 SUPPORT Human Clinical
"Major clinical symptoms consist of skin hyperextensibility and joint laxity, while ultrastructural analyses reveal abnormalities in collagen fibril networks and elastic fibre morphology."
Links tenascin-X deficiency to the defining clinical phenotype (skin hyperextensibility, joint laxity) and to the abnormal collagen fibril ultrastructure of clEDS-1.
AEBP1 Loss-of-Function
Biallelic pathogenic AEBP1 variants, most of them null alleles predicted to trigger nonsense-mediated decay, eliminate functional ACLP protein. ACLP's discoidin domain binds collagen types I, III and V and promotes type I collagen polymerization.
AEBP1 hgnc:303 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AEBP1 (hgnc:303). hgnc:303 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
collagen binding GO:0005518 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves collagen binding (GO:0005518). GO:0005518 is a molecular function from the Gene Ontology.
Downstream
Disorganized Dermal Collagen Matrix Loss of ACLP's collagen-binding, polymerization-promoting activity leaves dermal collagen fibrils disorganized and loosely packed.
Impaired Osteoblast Wnt/beta-catenin Signaling Beyond its extracellular collagen-binding role, ACLP is also required cell-autonomously in osteoprogenitors to support Wnt/beta-catenin-driven osteoblast differentiation and bone formation.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"the discoidin domain, a highly conserved structural motif of ACLP, preferentially bound to collagen types I, III and V, and ACLP promoted the polymerization of type I collagen in vitro"
Establishes the direct biochemical role of ACLP in collagen binding and polymerization.
Impaired Osteoblast Wnt/beta-catenin Signaling
Osteoprogenitor-specific loss of Aebp1 in a conditional mouse model disrupts Wnt/beta-catenin signaling, impairing osteoblast differentiation and maturation, delaying endochondral ossification, and indirectly enhancing osteoclast-mediated bone resorption -- a dual-mechanism defect in bone remodeling.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Osteopenia
Show evidence (1 reference)
PMID:41231548 SUPPORT Model Organism
"The loss of Aebp1 in osteoprogenitor cells disrupts osteoblast differentiation, delays ossification, and enhances osteoclast activity, culminating in severe bone remodeling defects."
Directly demonstrates the cellular mechanism by which osteoprogenitor Aebp1 loss produces net bone loss in a conditional knockout mouse model.
Disorganized Dermal Collagen Matrix
Convergent terminal lesion of both subtypes: dermal collagen fibrils show increased interfibrillar spacing, disorganized orientation, and reduced collagen content on light microscopy, with irregular, small-caliber ("flower-like") fibrils on electron microscopy.
collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ↓ DECREASED
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Skin Fragility and Hyperextensibility Loosely organized, understructured dermal collagen fails to provide normal tensile strength and elastic recoil.
Joint Hypermobility and Instability Disorganized collagen in joint capsules and ligaments reduces mechanical restraint on joint range of motion.
Vascular and Visceral Fragility Disorganized collagen in vessel walls and hollow-organ connective tissue predisposes to rupture under mechanical stress.
Other Ectodermal and Ocular Findings Alopecia and high myopia recur alongside the core dermal/joint phenotype in reported clEDS-2 patients, but the cited sources do not establish a specific mechanistic link between collagen XII/ACLP loss and hair follicle or scleral connective tissue; this edge records only that both arise from the same underlying disorder, not a specific causal step.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Light microscopic analyses showed increased interfibrillar spaces in the reticular dermis, a disorganized arrangement of collagen fibers, and decreased collagen content."
Direct histological description of the disorganized dermal collagen matrix in clEDS-2, representative of the shared terminal lesion.
Other Ectodermal and Ocular Findings
Alopecia (hair thinning/partial hair loss) and high myopia are recurrent, non-core findings in reported clEDS-2 patients. Neither source cited here proposes a mechanism connecting these to the collagen XII/ACLP extracellular-matrix defect.
Downstream
Alopecia
High Myopia
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Decreased hair described as "thinning" or "(partial) alopecia" was observed in five patients, and was a major physical concern in the current patient."
Documents alopecia/hair thinning as a recurrent finding in the clEDS-2 cohort, without a proposed mechanism.
Skin Fragility and Hyperextensibility
Reduced dermal tensile strength manifests as hyperextensible, often translucent and thin skin, easy bruising, delayed wound healing, and piezogenic pedal papules (subcutaneous fat herniation through weakened dermis). clEDS-1 is characteristically without the atrophic (cigarette-paper) scarring of classic EDS, but clEDS-2 does show atrophic scarring -- a subtype difference in how the same underlying dermal weakness resolves during healing.
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hyperextensible Skin Direct consequence of reduced dermal tensile strength.
Easy Bruising
Delayed Wound Healing
Atrophic Scarring In clEDS-2, the same dermal weakness resolves as atrophic rather than normal scarring during wound healing.
Thin Skin
Piezogenic Pedal Papules
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising, but do not have atrophic scarring, as is seen in cEDS."
Defines the distinguishing skin phenotype of clEDS-1 relative to classic EDS.
Joint Hypermobility and Instability
Weakened joint capsule and ligament connective tissue produces generalized joint hypermobility and predisposes to dislocation/subluxation and foot deformity.
skeletal joint UBERON:0000982 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal joint (UBERON:0000982). UBERON:0000982 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Generalized Joint Hypermobility
Pes Planus
Pes Cavus
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Generalized joint hypermobility (Beighton score) | + (8/9)"
Documents generalized joint hypermobility by Beighton score across the reported clEDS-2 cohort.
Vascular and Visceral Fragility
Disorganized collagen in vessel walls and the walls of hollow viscera (trachea, esophagus, bowel, uterus) predisposes to rupture and prolapse under mechanical or hemodynamic stress; this occurs in a minority of affected individuals in both subtypes but can be life-threatening.
blood vessel UBERON:0001981 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood vessel (UBERON:0001981). UBERON:0001981 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Vaginal, Uterine, and/or Rectal Prolapse
Aortic Aneurysm
Intestinal Perforation
Peripheral Edema Increased vascular permeability from weakened perivascular connective tissue produces dependent limb edema without an underlying cardiac cause.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Tissue fragility with resulting rupture of the trachea, esophagus, and small and large bowel has been reported. Vascular fragility causing a major event occurs in a minority of individuals."
Establishes the visceral/vascular rupture phenotype and its minority-of-cases frequency in clEDS-1.
Peripheral Nerve and Muscle Involvement
Tenascin-X is expressed in peripheral nerve and skeletal muscle connective tissue; its loss produces mild proximal and distal muscle weakness and axonal polyneuropathy, a distinguishing feature not typically seen in classic EDS.
peripheral nervous system UBERON:0000010 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in peripheral nervous system (UBERON:0000010). UBERON:0000010 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Proximal Muscle Weakness
Distal Muscle Weakness
Peripheral Axonal Neuropathy
Fatigue
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"mild proximal and distal muscle weakness, and axonal polyneuropathy"
Establishes the neuromuscular phenotype distinguishing clEDS-1 from classic EDS.
⬡

Pathograph

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

20
Blood 1
Easy Bruising Bruising susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising"
GeneReviews lists easy bruising as a core clinical feature.
Cardiovascular 1
Aortic Aneurysm HP:0004942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic aneurysm (HP:0004942). HP:0004942 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"The current patient developed multiple aneurysms and a rupture in the superior mesenteric artery, which was treated with catheter embolization."
Documents a life-threatening aneurysm/rupture event in a reported clEDS-2 patient.
Digestive 1
Intestinal Perforation HP:0031368 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal perforation (HP:0031368). HP:0031368 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42191857 SUPPORT Human Clinical
"the patient experienced two bowel perforation events over a 20-year period: postoperative perforation in the sigmoid colon shortly after rectal cancer surgery, and spontaneous small intestinal perforation nearly 20 years later without an identifiable precipitating factor"
Documents recurrent bowel perforation (postoperative and spontaneous) in the 16th reported clEDS-2 patient, a rare but recognized gastrointestinal complication.
Eye 1
High Myopia HP:0011003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High myopia (HP:0011003). HP:0011003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"She had high myopia, but no hearing impairment."
Documents high myopia in the reported 11th clEDS-2 patient.
Genitourinary 1
Vaginal, Uterine, and/or Rectal Prolapse Pelvic organ prolapse HP:0031607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pelvic organ prolapse (HP:0031607). HP:0031607 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Vaginal, uterine, and/or rectal prolapse can also occur."
GeneReviews documents pelvic organ prolapse as a manifestation of clEDS-1.
Integument 6
Hyperextensible Skin HP:0000974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperextensible skin (HP:0000974). HP:0000974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising"
GeneReviews lists hyperextensible skin as a core clinical feature.
Delayed Wound Healing Poor wound healing HP:0001058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor wound healing (HP:0001058). HP:0001058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Delayed wound healing | + | + | + | + | + | Mild | + | + | + | − | + | 10/11 (90.9%)"
Documents delayed wound healing in 10 of 11 reported clEDS-2 patients.
Atrophic Scarring Atrophic scars HP:0001075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrophic scars (HP:0001075). HP:0001075 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Atrophic scars | + | NA | + | + | + | + | + | + | + | + | + | 10/10 (100%)"
Documents atrophic scarring in all 10 assessed clEDS-2 patients, in contrast to clEDS-1 (TNXB), where atrophic scarring is characteristically absent.
Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Decreased hair described as "thinning" or "(partial) alopecia" was observed in five patients, and was a major physical concern in the current patient."
Documents alopecia/hair thinning as a recurrent, sometimes major, concern among clEDS-2 patients.
Piezogenic Pedal Papules HP:0025509 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Piezogenic pedal papules (HP:0025509). HP:0025509 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Piezogenic papules | NA | NA | + | + | NA | NA | NA | NA | + | + | − | 4/5 (80.0%)"
Documents piezogenic pedal papules in 4 of 5 assessed clEDS-2 patients.
Thin Skin HP:0000963 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin skin (HP:0000963). HP:0000963 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Thin, translucent skin | NA | NA | NA | + | + | + | + | + | − | + | + | 7/8 (87.5%)"
Documents thin translucent skin in 7 of 8 assessed clEDS-2 patients.
Limbs 2
Pes Planus HP:0001763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes planus (HP:0001763). HP:0001763 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Pes planus | + | + | + | + | + | + | Mild | + | + | − | + | 10/11 (90.9%)"
Documents pes planus in 10 of 11 reported clEDS-2 patients.
Pes Cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"severe and painful foot deformities"
GeneReviews describes severe foot deformity as a source of disability in clEDS-1; pes cavus and pes planus both occur among reported foot anomalies.
Metabolism 1
Peripheral Edema HP:0012398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral edema (HP:0012398). HP:0012398 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"edema in the legs in the absence of cardiac failure"
GeneReviews documents leg edema without cardiac failure as a distinguishing manifestation of clEDS-1.
Musculoskeletal 4
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Osteopenia | + | + | + | + | NA | − | NA | NA | + | − | NA | 5/7 (71.4%)"
Documents osteopenia in 5 of 7 assessed clEDS-2 patients.
Generalized Joint Hypermobility HP:0002761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized joint hypermobility (HP:0002761). HP:0002761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising"
GeneReviews lists generalized joint hypermobility as a core clinical feature.
Proximal Muscle Weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"mild proximal and distal muscle weakness, and axonal polyneuropathy"
GeneReviews documents proximal muscle weakness as a manifestation of clEDS-1.
Distal Muscle Weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"mild proximal and distal muscle weakness, and axonal polyneuropathy"
GeneReviews documents distal muscle weakness as a manifestation of clEDS-1.
Nervous System 1
Peripheral Axonal Neuropathy HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"mild proximal and distal muscle weakness, and axonal polyneuropathy"
GeneReviews documents axonal polyneuropathy as a manifestation of clEDS-1.
Constitutional 1
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Fatigue has been reported in more than half of affected individuals."
GeneReviews documents fatigue in more than half of clEDS-1 patients.
🧬

Genetic Associations

2
TNXB
Gene: TNXB hgnc:11976 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNXB (hgnc:11976). hgnc:11976 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:17033827 SUPPORT In Vitro
"FNIII29 of TNX accelerates collagen fibrillogenesis in vitro"
Establishes the biochemical mechanism by which tenascin-X promotes collagen fibril formation.
PMID:42445465 SUPPORT Human Clinical
"TNXB expression analysis was significantly lower in homozygous individuals compared to heterozygotes but no significant difference was observed between symptomatic and asymptomatic heterozygotes."
Demonstrates a dose-dependent relationship between TNXB genotype and expression level, with homozygotes showing significantly lower expression than heterozygous carriers.
PMID:42295573 SUPPORT Human Clinical
"Analysis of the patient-derived cDNA and cDNA derived from mutant minigenes revealed alternative splicing leading to intron 40 retention alongside the normal transcript."
Documents a distinct pathogenic mechanism class beyond simple loss-of-function -- intronic variants causing aberrant splicing (intron retention) predicted to affect the fibrinogen C-terminal domain.
AEBP1
Gene: AEBP1 hgnc:303 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AEBP1 (hgnc:303). hgnc:303 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37214418 SUPPORT Human Clinical
"Most reported AEBP1 variants were null variants, including nonsense, frameshift and splice site variants, predicted to lead to nonsense-mediated mRNA decay (NMD)"
Establishes the predominant loss-of-function variant mechanism in clEDS-2.
💊

Medical Actions

3
Non-Weight-Bearing Exercise and Physical Therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Non-weight-bearing exercise and physical therapy to address joint pain, avoiding sports with heavy joint strain or contact sports.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Non-weight-bearing exercise, physical therapy, and careful selection of analgesic medication to address joint pain"
GeneReviews recommends non-weight-bearing exercise and physical therapy for joint pain management.
Ascorbic Acid (Vitamin C)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ascorbic acid CHEBI:29073 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ascorbic acid, annotated with L-ascorbic acid (CHEBI:29073). CHEBI:29073 is a therapeutic agent from Chemical Entities of Biological Interest.
Ascorbic acid may reduce easy bruising but has no effect on skin hyperextensibility or joint hypermobility.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the key characteristics of skin hyperextensibility and joint hypermobility."
GeneReviews recommends ascorbic acid specifically to reduce bruising.
Desmopressin (DDAVP)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: desmopressin CHEBI:4450 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses desmopressin (CHEBI:4450). CHEBI:4450 is a therapeutic agent from Chemical Entities of Biological Interest.
DDAVP may normalize bleeding time in individuals with easy bruising.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"DDAVP® (deamino-delta-D-arginine vasopressin) may also be useful to normalize bleeding time in those with easy bruising."
GeneReviews recommends DDAVP for normalizing bleeding time.
🌍

Environmental Factors

1
Invasive Procedures and Surgery (Tissue Fragility Risk)
exposure to surgery ECTO:2000054 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to surgery (ECTO:2000054). ECTO:2000054 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Specialist delivery is strongly advised in view of reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe."
GeneReviews documents specific instrumentation-associated rupture events, supporting the causal link between invasive procedures and tissue rupture.
Mechanism Target:
EXACERBATES Vascular and Visceral Fragility — Invasive procedures, general anesthesia intubation, and instrumentation can precipitate rupture of already-fragile tracheal, esophageal, or vascular tissue.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"Avoid invasive procedures unless absolutely medically necessary"
GeneReviews explicitly recommends avoiding invasive procedures due to tissue fragility risk.
🔬

Diagnosis

2
Molecular Genetic Testing
Diagnosis is established by identifying biallelic pathogenic variants in TNXB (clEDS-1) or AEBP1 (clEDS-2) by molecular genetic testing in a proband with suggestive clinical findings.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing."
States the molecular diagnostic criterion for clEDS-1.
Absence of Atrophic Scarring Distinguishes clEDS from Classic EDS
The key clinical distinguishing feature separating clEDS from classic EDS on physical examination is the absence of atrophic scarring, despite overlapping skin hyperextensibility and joint hypermobility.
Show evidence (1 reference)
PMID:36108117 SUPPORT Human Clinical
"but do not have atrophic scarring, as is seen in cEDS"
GeneReviews explicitly identifies absent atrophic scarring as the key differentiator from classic EDS.
📊

Prevalence

2
Worldwide
Cases In Literature Ultra Rare
TNXB-related clEDS (clEDS-1) prevalence has not been established; reported as a rare but under-recognized cause of joint hypermobility/hyperextensible skin. A 2026 case report independently estimates fewer than 100 cases described worldwide.
Show evidence (2 references)
PMID:36108117 SUPPORT Human Clinical
"Significant variability in the severity of musculoskeletal symptoms and their effect on day-to-day function between unrelated affected individuals as well as among affected individuals in the same family has been reported."
GeneReviews describes broad phenotypic variability consistent with an under-ascertained, rare condition without an established prevalence figure.
PMID:41913751 SUPPORT Human Clinical
"Fewer than 100 cases have been described worldwide."
Independent 2026 estimate of the cumulative worldwide case count.
Worldwide (cumulative literature)
Cases In Literature Ultra Rare clEDS-2
11 patients from 9 families reported as of the 2023 comprehensive review; updated to 16 affected individuals from 13 families as of a 2026 case report.
Show evidence (2 references)
PMID:37214418 SUPPORT Human Clinical
"We have identified and described a 11th patient (9th family) with clEDS2, who was found to have novel compound heterozygous pathogenic variants in AEBP1."
Establishes the total reported clEDS-2 case count at time of curation.
PMID:42191857 SUPPORT Human Clinical
"this observation represents the 16th genetically confirmed case of AEBP1-related clEDS2"
Updates the cumulative reported case count to 16 individuals as of the 2026 report.
{ }

Source YAML

click to show 
name: Classical-like Ehlers-Danlos Syndrome
category: Mendelian
creation_date: "2026-09-16T16:49:39Z"
description: >
  Classical-like Ehlers-Danlos syndrome (clEDS) is a group of autosomal
  recessive connective-tissue disorders that clinically resemble classic EDS
  (generalized joint hypermobility, hyperextensible/velvety skin, easy
  bruising) but characteristically lack the atrophic scarring seen in classic
  EDS. Two molecularly distinct, genetically heterogeneous forms are
  recognized: clEDS-1, caused by biallelic loss-of-function variants in TNXB
  (tenascin-X), and clEDS-2, caused by biallelic loss-of-function variants in
  AEBP1 (encoding the aortic carboxypeptidase-like protein, ACLP). Both genes
  encode extracellular matrix proteins that normally organize dermal collagen
  fibrillogenesis; their loss produces disorganized, sparsely packed collagen
  fibrils and a resulting skin/joint/vascular fragility phenotype, with
  additional distinguishing features (peripheral neuromuscular involvement in
  clEDS-1; hair loss and vascular aneurysm risk in clEDS-2) that reflect each
  protein's distinct additional roles.
disease_term:
  preferred_term: Classical-like Ehlers-Danlos Syndrome
  term:
    id: MONDO:0011670
    label: Ehlers-Danlos syndrome due to tenascin-X deficiency
synonyms:
- clEDS
- clEDS-1
- TNX deficiency
- Ehlers-Danlos syndrome due to TNX deficiency
- Ehlers-Danlos syndrome, classic-like, 1
- EDSCLL1
notes: >
  The MONDO term for the TNXB-related form (MONDO:0011670) is labeled
  "Ehlers-Danlos syndrome due to tenascin-X deficiency" rather than
  "classic-like, 1"; its exact synonyms include "Ehlers-Danlos syndrome,
  classic-like, 1" and "classical-like Ehlers-Danlos syndrome", and it is used
  here as both the disease_term (for the TNXB/clEDS-1 form, the majority and
  better-characterized of the two) and the has_subtypes anchor for that
  subtype, mirroring the convention already used for PLOD1-kyphoscoliotic EDS.
  A third, more recently described form, clEDS-3 (OMIM #620865), was
  considered for inclusion but excluded from has_subtypes: as of curation
  MONDO:0971044 (Ehlers-Danlos syndrome, classic-like, 3) carries no
  causal-gene relationship and no indexed PubMed literature was found
  describing it, so it cannot yet be curated with real evidence.
parents:
- Ehlers-Danlos Syndrome
- Connective Tissue Disorder
references:
- reference: PMID:36108117
  title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
  tags:
  - GeneReviews
- reference: PMID:28306229
  title: "The 2017 international classification of the Ehlers-Danlos syndromes."
has_subtypes:
- name: clEDS-1
  display_name: clEDS-1 (TNXB-related)
  subtype_term:
    preferred_term: TNXB-related classical-like Ehlers-Danlos syndrome
    term:
      id: MONDO:0011670
      label: Ehlers-Danlos syndrome due to tenascin-X deficiency
  genes:
  - preferred_term: TNXB
    term:
      id: hgnc:11976
      label: TNXB
  description: >
    Caused by biallelic pathogenic variants in TNXB, encoding tenascin-X, a
    large extracellular matrix glycoprotein that binds dermal collagens and
    accelerates collagen fibrillogenesis. The more common and better
    clinically delineated of the two forms.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing."
    explanation: GeneReviews establishes biallelic TNXB variants as the molecular diagnosis for this subtype.
- name: clEDS-2
  display_name: clEDS-2 (AEBP1-related)
  subtype_term:
    preferred_term: AEBP1-related classical-like Ehlers-Danlos syndrome
    term:
      id: MONDO:0054813
      label: Ehlers-Danlos syndrome, classic-like, 2
  genes:
  - preferred_term: AEBP1
    term:
      id: hgnc:303
      label: AEBP1
  description: >
    Caused by biallelic pathogenic variants in AEBP1, encoding the aortic
    carboxypeptidase-like protein (ACLP), which binds collagen types I, III
    and V via its discoidin domain and promotes type I collagen
    polymerization. A rarer, more recently delineated form; as of the most
    recent comprehensive review, 11 patients from 9 families had been
    reported.
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2018, Blackburn et al. (2018) identified biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene in patients displaying EDS-like features that were considered to represent a new subtype of EDS and were tentatively named classical-like type 2 (clEDS2; MIM #618000)"
    explanation: Establishes biallelic AEBP1 variants as the molecular cause of clEDS-2.
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here an additional patient with clEDS2 who had novel variants in AEBP1"
    explanation: Confirms the 11th reported clEDS-2 patient, establishing the small but growing case series for this rarer subtype.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    TNXB-related clEDS (clEDS-1) prevalence has not been established;
    reported as a rare but under-recognized cause of joint
    hypermobility/hyperextensible skin. A 2026 case report independently
    estimates fewer than 100 cases described worldwide.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant variability in the severity of musculoskeletal symptoms and their effect on day-to-day function between unrelated affected individuals as well as among affected individuals in the same family has been reported."
    explanation: GeneReviews describes broad phenotypic variability consistent with an under-ascertained, rare condition without an established prevalence figure.
  - reference: PMID:41913751
    reference_title: "Insights into TNXB-Related Classical-Like Ehlers-Danlos Syndrome: A Study of Polish Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fewer than 100 cases have been described worldwide."
    explanation: Independent 2026 estimate of the cumulative worldwide case count.
- subtype: clEDS-2
  population: Worldwide (cumulative literature)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    11 patients from 9 families reported as of the 2023 comprehensive
    review; updated to 16 affected individuals from 13 families as of a
    2026 case report.
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified and described a 11th patient (9th family) with clEDS2, who was found to have novel compound heterozygous pathogenic variants in AEBP1."
    explanation: Establishes the total reported clEDS-2 case count at time of curation.
  - reference: PMID:42191857
    reference_title: "Gastrointestinal involvement in Ehlers-Danlos syndrome classical-like type 2 associated with a novel AEBP1 splice-site variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this observation represents the 16th genetically confirmed case of AEBP1-related clEDS2"
    explanation: Updates the cumulative reported case count to 16 individuals as of the 2026 report.
inheritance:
- name: Autosomal Recessive Inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Both clEDS-1 (TNXB) and clEDS-2 (AEBP1) are inherited in an autosomal
    recessive manner; heterozygous carriers of TNXB or AEBP1 variants are
    generally unaffected or only mildly symptomatic.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TNXB-related clED is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the autosomal recessive inheritance pattern for TNXB-related clEDS.
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous individuals appear to have no relevant symptoms."
    explanation: Supports autosomal recessive inheritance for clEDS-2, with unaffected heterozygous carriers.
genetic:
- name: TNXB
  gene_term:
    preferred_term: TNXB
    term:
      id: hgnc:11976
      label: TNXB
  subtype: clEDS-1
  notes: Biallelic loss-of-function variants abolish or severely reduce tenascin-X protein, which normally binds dermal collagens I, III and V and accelerates collagen fibrillogenesis.
  evidence:
  - reference: PMID:17033827
    reference_title: "Interactions of human tenascin-X domains with dermal extracellular matrix molecules."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FNIII29 of TNX accelerates collagen fibrillogenesis in vitro"
    explanation: Establishes the biochemical mechanism by which tenascin-X promotes collagen fibril formation.
  - reference: PMID:42445465
    reference_title: "Detailed Clinical Report of Four Individuals from a Nusayri Family with a Rare TNXB Variant: Classical-Like and Hypermobile Types of Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TNXB expression analysis was significantly lower in homozygous individuals compared to heterozygotes but no significant difference was observed between symptomatic and asymptomatic heterozygotes."
    explanation: Demonstrates a dose-dependent relationship between TNXB genotype and expression level, with homozygotes showing significantly lower expression than heterozygous carriers.
  - reference: PMID:42295573
    reference_title: "Splicing Alterations Associated with Multiple Homozygous TNXB Variants in a Patient with Suspected Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the patient-derived cDNA and cDNA derived from mutant minigenes revealed alternative splicing leading to intron 40 retention alongside the normal transcript."
    explanation: Documents a distinct pathogenic mechanism class beyond simple loss-of-function -- intronic variants causing aberrant splicing (intron retention) predicted to affect the fibrinogen C-terminal domain.
- name: AEBP1
  gene_term:
    preferred_term: AEBP1
    term:
      id: hgnc:303
      label: AEBP1
  subtype: clEDS-2
  notes: Most reported variants are null (nonsense, frameshift, splice-site) predicted to trigger nonsense-mediated decay, eliminating functional ACLP protein.
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most reported AEBP1 variants were null variants, including nonsense, frameshift and splice site variants, predicted to lead to nonsense-mediated mRNA decay (NMD)"
    explanation: Establishes the predominant loss-of-function variant mechanism in clEDS-2.
pathophysiology:
- name: TNXB Loss-of-Function
  biological_scale: MOLECULAR
  subtypes:
  - clEDS-1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
  genes:
  - preferred_term: TNXB
    term:
      id: hgnc:11976
      label: TNXB
  molecular_functions:
  - preferred_term: collagen binding
    term:
      id: GO:0005518
      label: collagen binding
  description: >
    Biallelic pathogenic TNXB variants abolish or severely reduce tenascin-X,
    an extracellular matrix glycoprotein whose FNIII29/FbgX domains bind
    dermal collagens I, III and V and normally accelerate collagen
    fibrillogenesis.
  evidence:
  - reference: PMID:20089348
    reference_title: "Tenascin-X increases the stiffness of collagen gels without affecting fibrillogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major clinical symptoms consist of skin hyperextensibility and joint laxity, while ultrastructural analyses reveal abnormalities in collagen fibril networks and elastic fibre morphology."
    explanation: Links tenascin-X deficiency to the defining clinical phenotype (skin hyperextensibility, joint laxity) and to the abnormal collagen fibril ultrastructure of clEDS-1.
  downstream:
  - target: Disorganized Dermal Collagen Matrix
    description: Loss of tenascin-X's collagen-binding, fibrillogenesis-promoting activity leaves dermal collagen fibrils disorganized and loosely packed.
- name: AEBP1 Loss-of-Function
  biological_scale: MOLECULAR
  subtypes:
  - clEDS-2
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
  genes:
  - preferred_term: AEBP1
    term:
      id: hgnc:303
      label: AEBP1
  molecular_functions:
  - preferred_term: collagen binding
    term:
      id: GO:0005518
      label: collagen binding
  description: >
    Biallelic pathogenic AEBP1 variants, most of them null alleles predicted
    to trigger nonsense-mediated decay, eliminate functional ACLP protein.
    ACLP's discoidin domain binds collagen types I, III and V and promotes
    type I collagen polymerization.
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the discoidin domain, a highly conserved structural motif of ACLP, preferentially bound to collagen types I, III and V, and ACLP promoted the polymerization of type I collagen in vitro"
    explanation: Establishes the direct biochemical role of ACLP in collagen binding and polymerization.
  downstream:
  - target: Disorganized Dermal Collagen Matrix
    description: Loss of ACLP's collagen-binding, polymerization-promoting activity leaves dermal collagen fibrils disorganized and loosely packed.
  - target: Impaired Osteoblast Wnt/beta-catenin Signaling
    description: Beyond its extracellular collagen-binding role, ACLP is also required cell-autonomously in osteoprogenitors to support Wnt/beta-catenin-driven osteoblast differentiation and bone formation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41231548
      reference_title: "Aebp1 loss in osteoprogenitors leads to skeletal defects resembling Ehlers-Danlos Syndrome by diminishing Wnt/β-catenin signaling."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "our study elucidates Aebp1 as a critical regulator of skeletal development through its modulation of Wnt/β-catenin signaling"
      explanation: Establishes a second, cell-autonomous AEBP1 mechanism in osteoprogenitors distinct from its extracellular collagen-binding role in dermis.
- name: Impaired Osteoblast Wnt/beta-catenin Signaling
  biological_scale: CELLULAR
  subtypes:
  - clEDS-2
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  description: >
    Osteoprogenitor-specific loss of Aebp1 in a conditional mouse model
    disrupts Wnt/beta-catenin signaling, impairing osteoblast
    differentiation and maturation, delaying endochondral ossification, and
    indirectly enhancing osteoclast-mediated bone resorption -- a
    dual-mechanism defect in bone remodeling.
  evidence:
  - reference: PMID:41231548
    reference_title: "Aebp1 loss in osteoprogenitors leads to skeletal defects resembling Ehlers-Danlos Syndrome by diminishing Wnt/β-catenin signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The loss of Aebp1 in osteoprogenitor cells disrupts osteoblast differentiation, delays ossification, and enhances osteoclast activity, culminating in severe bone remodeling defects."
    explanation: Directly demonstrates the cellular mechanism by which osteoprogenitor Aebp1 loss produces net bone loss in a conditional knockout mouse model.
  downstream:
  - target: Osteopenia
- name: Disorganized Dermal Collagen Matrix
  biological_scale: TISSUE
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: DECREASED
  description: >
    Convergent terminal lesion of both subtypes: dermal collagen fibrils show
    increased interfibrillar spacing, disorganized orientation, and reduced
    collagen content on light microscopy, with irregular, small-caliber
    ("flower-like") fibrils on electron microscopy.
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Light microscopic analyses showed increased interfibrillar spaces in the reticular dermis, a disorganized arrangement of collagen fibers, and decreased collagen content."
    explanation: Direct histological description of the disorganized dermal collagen matrix in clEDS-2, representative of the shared terminal lesion.
  downstream:
  - target: Skin Fragility and Hyperextensibility
    description: Loosely organized, understructured dermal collagen fails to provide normal tensile strength and elastic recoil.
  - target: Joint Hypermobility and Instability
    description: Disorganized collagen in joint capsules and ligaments reduces mechanical restraint on joint range of motion.
  - target: Vascular and Visceral Fragility
    description: Disorganized collagen in vessel walls and hollow-organ connective tissue predisposes to rupture under mechanical stress.
  - target: Other Ectodermal and Ocular Findings
    description: >-
      Alopecia and high myopia recur alongside the core dermal/joint
      phenotype in reported clEDS-2 patients, but the cited sources do not
      establish a specific mechanistic link between collagen XII/ACLP loss
      and hair follicle or scleral connective tissue; this edge records only
      that both arise from the same underlying disorder, not a specific
      causal step.
- name: Other Ectodermal and Ocular Findings
  biological_scale: TISSUE
  subtypes:
  - clEDS-2
  description: >-
    Alopecia (hair thinning/partial hair loss) and high myopia are
    recurrent, non-core findings in reported clEDS-2 patients. Neither
    source cited here proposes a mechanism connecting these to the
    collagen XII/ACLP extracellular-matrix defect.
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased hair described as \"thinning\" or \"(partial) alopecia\" was observed in five patients, and was a major physical concern in the current patient."
    explanation: Documents alopecia/hair thinning as a recurrent finding in the clEDS-2 cohort, without a proposed mechanism.
  downstream:
  - target: Alopecia
  - target: High Myopia
- name: Skin Fragility and Hyperextensibility
  biological_scale: TISSUE
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  description: >-
    Reduced dermal tensile strength manifests as hyperextensible, often
    translucent and thin skin, easy bruising, delayed wound healing, and
    piezogenic pedal papules (subcutaneous fat herniation through weakened
    dermis). clEDS-1 is characteristically without the atrophic
    (cigarette-paper) scarring of classic EDS, but clEDS-2 does show
    atrophic scarring -- a subtype difference in how the same underlying
    dermal weakness resolves during healing.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising, but do not have atrophic scarring, as is seen in cEDS."
    explanation: Defines the distinguishing skin phenotype of clEDS-1 relative to classic EDS.
  downstream:
  - target: Hyperextensible Skin
    description: Direct consequence of reduced dermal tensile strength.
  - target: Easy Bruising
  - target: Delayed Wound Healing
  - target: Atrophic Scarring
    description: In clEDS-2, the same dermal weakness resolves as atrophic rather than normal scarring during wound healing.
  - target: Thin Skin
  - target: Piezogenic Pedal Papules
- name: Joint Hypermobility and Instability
  biological_scale: TISSUE
  locations:
  - preferred_term: skeletal joint
    term:
      id: UBERON:0000982
      label: skeletal joint
  description: Weakened joint capsule and ligament connective tissue produces generalized joint hypermobility and predisposes to dislocation/subluxation and foot deformity.
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized joint hypermobility (Beighton score) | + (8/9)"
    explanation: Documents generalized joint hypermobility by Beighton score across the reported clEDS-2 cohort.
  downstream:
  - target: Generalized Joint Hypermobility
  - target: Pes Planus
  - target: Pes Cavus
- name: Vascular and Visceral Fragility
  biological_scale: TISSUE
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  description: >
    Disorganized collagen in vessel walls and the walls of hollow viscera
    (trachea, esophagus, bowel, uterus) predisposes to rupture and prolapse
    under mechanical or hemodynamic stress; this occurs in a minority of
    affected individuals in both subtypes but can be life-threatening.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tissue fragility with resulting rupture of the trachea, esophagus, and small and large bowel has been reported. Vascular fragility causing a major event occurs in a minority of individuals."
    explanation: Establishes the visceral/vascular rupture phenotype and its minority-of-cases frequency in clEDS-1.
  downstream:
  - target: Vaginal, Uterine, and/or Rectal Prolapse
  - target: Aortic Aneurysm
  - target: Intestinal Perforation
  - target: Peripheral Edema
    description: Increased vascular permeability from weakened perivascular connective tissue produces dependent limb edema without an underlying cardiac cause.
- name: Peripheral Nerve and Muscle Involvement
  biological_scale: TISSUE
  subtypes:
  - clEDS-1
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  description: >
    Tenascin-X is expressed in peripheral nerve and skeletal muscle
    connective tissue; its loss produces mild proximal and distal muscle
    weakness and axonal polyneuropathy, a distinguishing feature not
    typically seen in classic EDS.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild proximal and distal muscle weakness, and axonal polyneuropathy"
    explanation: Establishes the neuromuscular phenotype distinguishing clEDS-1 from classic EDS.
  downstream:
  - target: Proximal Muscle Weakness
  - target: Distal Muscle Weakness
  - target: Peripheral Axonal Neuropathy
  - target: Fatigue
phenotypes:
- name: Hyperextensible Skin
  phenotype_term:
    preferred_term: Hyperextensible skin
    term:
      id: HP:0000974
      label: Hyperextensible skin
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising"
    explanation: GeneReviews lists hyperextensible skin as a core clinical feature.
- name: Easy Bruising
  phenotype_term:
    preferred_term: Bruising susceptibility
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising"
    explanation: GeneReviews lists easy bruising as a core clinical feature.
- name: Delayed Wound Healing
  phenotype_term:
    preferred_term: Poor wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delayed wound healing | + | + | + | + | + | Mild | + | + | + | − | + | 10/11 (90.9%)"
    explanation: Documents delayed wound healing in 10 of 11 reported clEDS-2 patients.
- name: Atrophic Scarring
  subtype: clEDS-2
  phenotype_term:
    preferred_term: Atrophic scars
    term:
      id: HP:0001075
      label: Atrophic scars
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atrophic scars | + | NA | + | + | + | + | + | + | + | + | + | 10/10 (100%)"
    explanation: Documents atrophic scarring in all 10 assessed clEDS-2 patients, in contrast to clEDS-1 (TNXB), where atrophic scarring is characteristically absent.
- name: Osteopenia
  subtype: clEDS-2
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Osteopenia | + | + | + | + | NA | − | NA | NA | + | − | NA | 5/7 (71.4%)"
    explanation: Documents osteopenia in 5 of 7 assessed clEDS-2 patients.
- name: Generalized Joint Hypermobility
  phenotype_term:
    preferred_term: Generalized joint hypermobility
    term:
      id: HP:0002761
      label: Generalized joint hypermobility
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have generalized joint hypermobility, hyperextensible skin, and easy bruising"
    explanation: GeneReviews lists generalized joint hypermobility as a core clinical feature.
- name: Pes Planus
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pes planus | + | + | + | + | + | + | Mild | + | + | − | + | 10/11 (90.9%)"
    explanation: Documents pes planus in 10 of 11 reported clEDS-2 patients.
- name: Pes Cavus
  subtype: clEDS-1
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe and painful foot deformities"
    explanation: GeneReviews describes severe foot deformity as a source of disability in clEDS-1; pes cavus and pes planus both occur among reported foot anomalies.
- name: Vaginal, Uterine, and/or Rectal Prolapse
  subtype: clEDS-1
  phenotype_term:
    preferred_term: Pelvic organ prolapse
    term:
      id: HP:0031607
      label: Pelvic organ prolapse
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vaginal, uterine, and/or rectal prolapse can also occur."
    explanation: GeneReviews documents pelvic organ prolapse as a manifestation of clEDS-1.
- name: Aortic Aneurysm
  subtype: clEDS-2
  phenotype_term:
    preferred_term: Aortic aneurysm
    term:
      id: HP:0004942
      label: Aortic aneurysm
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The current patient developed multiple aneurysms and a rupture in the superior mesenteric artery, which was treated with catheter embolization."
    explanation: Documents a life-threatening aneurysm/rupture event in a reported clEDS-2 patient.
- name: Proximal Muscle Weakness
  subtype: clEDS-1
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild proximal and distal muscle weakness, and axonal polyneuropathy"
    explanation: GeneReviews documents proximal muscle weakness as a manifestation of clEDS-1.
- name: Distal Muscle Weakness
  subtype: clEDS-1
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild proximal and distal muscle weakness, and axonal polyneuropathy"
    explanation: GeneReviews documents distal muscle weakness as a manifestation of clEDS-1.
- name: Peripheral Axonal Neuropathy
  subtype: clEDS-1
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild proximal and distal muscle weakness, and axonal polyneuropathy"
    explanation: GeneReviews documents axonal polyneuropathy as a manifestation of clEDS-1.
- name: Fatigue
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fatigue has been reported in more than half of affected individuals."
    explanation: GeneReviews documents fatigue in more than half of clEDS-1 patients.
- name: Alopecia
  subtype: clEDS-2
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased hair described as \"thinning\" or \"(partial) alopecia\" was observed in five patients, and was a major physical concern in the current patient."
    explanation: Documents alopecia/hair thinning as a recurrent, sometimes major, concern among clEDS-2 patients.
- name: Piezogenic Pedal Papules
  subtype: clEDS-2
  phenotype_term:
    preferred_term: Piezogenic pedal papules
    term:
      id: HP:0025509
      label: Piezogenic pedal papules
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Piezogenic papules | NA | NA | + | + | NA | NA | NA | NA | + | + | − | 4/5 (80.0%)"
    explanation: Documents piezogenic pedal papules in 4 of 5 assessed clEDS-2 patients.
- name: Peripheral Edema
  subtype: clEDS-1
  phenotype_term:
    preferred_term: Peripheral edema
    term:
      id: HP:0012398
      label: Peripheral edema
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "edema in the legs in the absence of cardiac failure"
    explanation: GeneReviews documents leg edema without cardiac failure as a distinguishing manifestation of clEDS-1.
- name: Thin Skin
  subtype: clEDS-2
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thin, translucent skin | NA | NA | NA | + | + | + | + | + | − | + | + | 7/8 (87.5%)"
    explanation: Documents thin translucent skin in 7 of 8 assessed clEDS-2 patients.
- name: High Myopia
  subtype: clEDS-2
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  evidence:
  - reference: PMID:37214418
    reference_title: "Case report: further delineation of AEBP1-related Ehlers-Danlos Syndrome (classical-like EDS type 2) in an additional patient and comprehensive clinical and molecular review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had high myopia, but no hearing impairment."
    explanation: Documents high myopia in the reported 11th clEDS-2 patient.
- name: Intestinal Perforation
  subtype: clEDS-2
  phenotype_term:
    preferred_term: Intestinal perforation
    term:
      id: HP:0031368
      label: Intestinal perforation
  evidence:
  - reference: PMID:42191857
    reference_title: "Gastrointestinal involvement in Ehlers-Danlos syndrome classical-like type 2 associated with a novel AEBP1 splice-site variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient experienced two bowel perforation events over a 20-year period: postoperative perforation in the sigmoid colon shortly after rectal cancer surgery, and spontaneous small intestinal perforation nearly 20 years later without an identifiable precipitating factor"
    explanation: Documents recurrent bowel perforation (postoperative and spontaneous) in the 16th reported clEDS-2 patient, a rare but recognized gastrointestinal complication.
diagnosis:
- name: Molecular Genetic Testing
  description: Diagnosis is established by identifying biallelic pathogenic variants in TNXB (clEDS-1) or AEBP1 (clEDS-2) by molecular genetic testing in a proband with suggestive clinical findings.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of TNXB-related clEDS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in TNXB identified by molecular genetic testing."
    explanation: States the molecular diagnostic criterion for clEDS-1.
- name: Absence of Atrophic Scarring Distinguishes clEDS from Classic EDS
  description: The key clinical distinguishing feature separating clEDS from classic EDS on physical examination is the absence of atrophic scarring, despite overlapping skin hyperextensibility and joint hypermobility.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but do not have atrophic scarring, as is seen in cEDS"
    explanation: GeneReviews explicitly identifies absent atrophic scarring as the key differentiator from classic EDS.
treatments:
- name: Non-Weight-Bearing Exercise and Physical Therapy
  description: Non-weight-bearing exercise and physical therapy to address joint pain, avoiding sports with heavy joint strain or contact sports.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-weight-bearing exercise, physical therapy, and careful selection of analgesic medication to address joint pain"
    explanation: GeneReviews recommends non-weight-bearing exercise and physical therapy for joint pain management.
- name: Ascorbic Acid (Vitamin C)
  description: Ascorbic acid may reduce easy bruising but has no effect on skin hyperextensibility or joint hypermobility.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ascorbic acid
      term:
        id: CHEBI:29073
        label: L-ascorbic acid
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the key characteristics of skin hyperextensibility and joint hypermobility."
    explanation: GeneReviews recommends ascorbic acid specifically to reduce bruising.
- name: Desmopressin (DDAVP)
  description: DDAVP may normalize bleeding time in individuals with easy bruising.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: desmopressin
      term:
        id: CHEBI:4450
        label: desmopressin
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DDAVP® (deamino-delta-D-arginine vasopressin) may also be useful to normalize bleeding time in those with easy bruising."
    explanation: GeneReviews recommends DDAVP for normalizing bleeding time.
environmental:
- name: Invasive Procedures and Surgery (Tissue Fragility Risk)
  exposure_term:
    preferred_term: exposure to surgery
    term:
      id: ECTO:2000054
      label: exposure to surgery
  influences_mechanisms:
  - target: Vascular and Visceral Fragility
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: Invasive procedures, general anesthesia intubation, and instrumentation can precipitate rupture of already-fragile tracheal, esophageal, or vascular tissue.
    evidence:
    - reference: PMID:36108117
      reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Avoid invasive procedures unless absolutely medically necessary"
      explanation: GeneReviews explicitly recommends avoiding invasive procedures due to tissue fragility risk.
  evidence:
  - reference: PMID:36108117
    reference_title: "TNXB-Related Classical-Like Ehlers-Danlos Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specialist delivery is strongly advised in view of reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe."
    explanation: GeneReviews documents specific instrumentation-associated rupture events, supporting the causal link between invasive procedures and tissue rupture.
discussions:
- discussion_id: heterozygous_tnxb_and_hypermobile_eds
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#TNXB
  - inheritance#Autosomal Recessive Inheritance
  prompt: >-
    Do heterozygous (carrier) TNXB variants contribute to hypermobile
    Ehlers-Danlos syndrome (hEDS) or a milder connective-tissue phenotype,
    beyond the biallelic loss-of-function threshold that causes clEDS-1
    itself?
  rationale: >-
    This entry models clEDS-1 as strictly autosomal recessive, with
    heterozygous carriers "generally unaffected or only mildly symptomatic"
    per the cited GeneReviews chapter. Two independent 2026 case reports
    complicate that picture without settling it: a four-sibling Nusayri
    family in which the one heterozygous carrier met clinical criteria for
    hEDS while his parents (also heterozygous) were asymptomatic, and a
    Polish cohort in which a heterozygous frameshift carrier and her father
    both showed mild joint hypermobility with no phenotype in other
    non-carrier relatives. Both papers explicitly stop short of a causal
    claim, citing incomplete penetrance and variable expressivity as
    unresolved. The gap is recorded here rather than folded into a
    confident phenotype/inheritance claim, since the evidence is
    small-pedigree and inconsistent (symptomatic vs. asymptomatic carriers
    within the same reports).
  evidence:
  - reference: PMID:42445465
    reference_title: "Detailed Clinical Report of Four Individuals from a Nusayri Family with a Rare TNXB Variant: Classical-Like and Hypermobile Types of Ehlers-Danlos Syndrome."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical findings suggest the potential role of TNXB haploinsufficiency in hEDS; however, further research is needed to elucidate the variable expressivity and possible incomplete penetrance associated with hmEDS."
    explanation: The paper's own conclusion states the hypothesis while explicitly flagging it as unresolved.
  - reference: PMID:41913751
    reference_title: "Insights into TNXB-Related Classical-Like Ehlers-Danlos Syndrome: A Study of Polish Patients."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is also possible that an undetected pathogenic variant on the second allele (eg, a deep intronic mutation not captured by routine diagnostic methods) may contribute to the phenotype."
    explanation: An independent cohort raises the same carrier-phenotype question and names a competing explanation (an undetected second-allele variant) that would preserve strict recessive inheritance instead.
📚

References & Deep Research

References

2
PMID:36108117
TNXB-Related Classical-Like Ehlers-Danlos Syndrome.
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.

Deep Research

1

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)

Literature refresh + pathograph completeness fix for Classical-like EDS type 2 (clEDS-2/AEBP1) · 2026-09-18T01:43:48Z · View source

Task requested curating 'Classical-like EDS type 2', which like the prior 'type 1' task is not a new disease: clEDS-2 (AEBP1) is already curated as has_subtypes[1] of this entry. Per the duplicate-preflight rule, did not create a second file; treated as an ongoing-curation/augmentation task, mirroring the type-1 session immediately before this one. A targeted PubMed search for AEBP1/clEDS-2 literature published since the original curation (whose newest source was the 2023 '11th patient' comprehensive review, PMID:37214418) surfaced two genuinely new, on-topic 2026 papers, filtering out several AEBP1-in-cancer/fibrosis hits as Named Entity Confusion: PMID:42191857 (16th reported clEDS-2 case, a novel AEBP1 splice-site variant with experimentally validated exon-12 skipping, and recurrent bowel perforation over a 20-year follow-up) and PMID:41231548 (a conditional Aebp1-knockout mouse model showing osteoprogenitor-specific Aebp1 loss disrupts Wnt/beta-catenin signaling, impairing osteoblast differentiation and enhancing osteoclast activity). Also fetched PMID:38674395, a 2024 comparison case report that had been fetched but left uncited during the original creation two days ago (and later deleted as an uncited leftover); read it again but found nothing beyond what the more comprehensive PMID:37214418 review and the two 2026 papers already establish, so it remains uncited. Added to pathophysiology: a new node 'Impaired Osteoblast Wnt/beta-catenin Signaling' (CELLULAR, subtype: clEDS-2) downstream of 'AEBP1 Loss-of-Function', sourced to the mouse-model paper -- this is a second, cell-autonomous AEBP1 mechanism distinct from its extracellular collagen-binding role, and its addition fixed a pre-existing gap: the 'Osteopenia' phenotype had been orphaned (no downstream edge) since the entry's original creation. Added 'Intestinal Perforation' (subtype: clEDS-2, HP:0031368) as a new phenotype and downstream target of the existing 'Vascular and Visceral Fragility' node, sourced to the new case report. Updated the clEDS-2 prevalence note and evidence from '11 patients from 9 families' (2023) to '16 affected individuals from 13 families' (2026), keeping both citations rather than replacing the older one. While fixing the Osteopenia orphan, ran the same zero-indegree-phenotype check used in the prior two entries' self-reviews this session and found five more pre-existing orphaned phenotypes dating to the original creation (Atrophic Scarring, Thin Skin, Alopecia, Piezogenic Pedal Papules, High Myopia, Peripheral Edema). Fixed all of them rather than leaving newly-discovered gaps unaddressed: Atrophic Scarring, Thin Skin, and Piezogenic Pedal Papules were wired into the existing 'Skin Fragility and Hyperextensibility' node (whose description was also updated to note that clEDS-1 lacks atrophic scarring while clEDS-2 does show it, rather than stating the absence as if disease-wide); Peripheral Edema was wired into 'Vascular and Visceral Fragility' with a vascular-permeability rationale; Alopecia and High Myopia were wired into a new node 'Other Ectodermal and Ocular Findings' whose description and edge explicitly state that the cited sources propose no mechanism connecting these findings to the collagen XII/ACLP defect -- an honest, hedged connection rather than a fabricated causal claim, following the same pattern used for the equivalent craniofacial-findings gap in this session's Myopathic EDS entry. Ran the required falcon deep-research pass (just dr_fallback='--fallback' research-disorder falcon Classical-like_Ehlers-Danlos_Syndrome); like the type-1 task's pass two hours earlier, this also returned cached: true (duration_seconds: 0.0, same 22 citations, same term-validation warnings, none of which this entry binds), reusing the report already incorporated at original creation. No new content beyond what the direct-PubMed-search findings above already cover; the research/*.md frontmatter timestamp churn from the cache hit was reverted rather than committed as noise, matching the type-1 record's handling of the same situation. Validated with: just validate (52/52 snippets verified, up from 47), 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 list-gene-term-mismatches (0/6 mismatches), just validate-disorders (CI-authoritative gate, passed), and a manual PyYAML check confirming zero orphaned phenotype nodes remain (was 7/24 before this pass, counting the pre-existing Osteopenia gap plus the five discovered during this pass).

Literature refresh for Classical-like EDS type 1 (clEDS-1/TNXB) · 2026-09-18T01:38:26Z · View source

Task requested curating 'Classical-like EDS type 1', which is not a new disease: it is exactly clEDS-1 (TNXB), already the primary subject of this entry (disease_term anchored on MONDO:0011670, synonyms includes 'clEDS-1', has_subtypes[0] is 'clEDS-1'). Per the duplicate-preflight rule, did not create a second file; treated this as an ongoing-curation/augmentation task on the existing entry instead. Ran the required falcon deep-research pass (just dr_fallback='--fallback' research-disorder falcon Classical-like_Ehlers-Danlos_Syndrome); it returned cached: true, duration_seconds 0.21, reusing the identical report already incorporated when this entry was first created two days ago (same 22 citations, same term-validation warnings, none of which this entry ever bound). It surfaced no new content, so the research/*.md frontmatter timestamp churn from the cache-hit was reverted rather than committed as noise. The genuinely new content came from a direct, targeted PubMed search (not a repeat deep-research call) for TNXB/clEDS literature published since the original curation, which surfaced three on-topic 2026 papers not available two days ago: PMID:42445465 (Nusayri family clinical report, 2026 May), PMID:42295573 (splicing-mechanism case report, 2026 Jun), and PMID:41913751 (Polish patient cohort, 2026). All three fetched and read in full/abstract. Added to genetic#TNXB: two new evidence items -- a dose-dependent TNXB expression finding (homozygotes show significantly lower expression than heterozygous carriers, PMID:42445465) and a distinct pathogenic-mechanism class not previously represented in this entry (intron-40-retention aberrant splicing from intronic variants, affecting the fibrinogen C-terminal domain, PMID:42295573). Added to prevalence: an independent 2026 case-count estimate ('fewer than 100 cases described worldwide', PMID:41913751) corroborating the existing under-ascertained-rarity framing. Added a new discussions: entry (kind: KNOWLEDGE_GAP, discussion_id: heterozygous_tnxb_and_hypermobile_eds) recording an unresolved question raised independently by both new clinical-cohort papers: whether heterozygous (carrier) TNXB variants contribute to hypermobile EDS or a milder connective-tissue phenotype beyond the biallelic threshold this entry models as strictly recessive. Deliberately NOT folded into a confident phenotype or inheritance-pattern claim -- the evidence is small-pedigree, internally inconsistent (symptomatic vs. asymptomatic heterozygous carriers within the same reports), and both source papers explicitly flag it as unresolved (incomplete penetrance/variable expressivity) rather than asserting it. attaches_to genetic#TNXB and inheritance#Autosomal Recessive Inheritance. Considered and did not add: detailed clinical/phenotype findings from PMID:42295573's index patient (orthostatic dizziness, chronic constipation, mild mitral valve regurgitation) -- that patient carries TNXB variants of uncertain clinical significance per the source paper itself, so adding these as established clEDS-1 phenotypes would overclaim from a single VUS-carrying case. Validated with: just validate (47/47 snippets verified, up from 42), just check-causal-targets (0 new dangling targets), just check-entity-refs (confirms both new attaches_to refs resolve), just check-duplicate-keys, just check-enum-values, just validate-disorders (CI-authoritative gate, passed). just check-snippet-length reported one finding, but in kb/disorders/Epidermolysis_Bullosa.yaml -- confirmed via git log/diff this predates and is unrelated to this session's edits (already present in an already-merged upstream PR #11931 pulled by git fetch origin main), not a defect introduced here.

Deep-research cross-check: Classical-like Ehlers-Danlos Syndrome · 2026-09-16T17:23:10Z · View source

Ran the falcon (Edison Scientific) deep-research pass required by the curation task template (just research-disorder falcon Classical-like_Ehlers-Danlos_Syndrome --fallback; 806s runtime, 22 citations mostly by DOI). The report's own term validation flagged only terms it suggested that this entry never bound (HP:0001811, UBERON:0000216 unresolved; GO:0062023 obsolete/replaced by GO:0031012) plus a harmless template-placeholder label mismatch on MONDO:0011670 ('if available', same artifact class already seen for Arthrochalasia EDS) and a table-cell string being read as a label for HP:0001634 -- none affect this entry, which independently verified every bound CURIE via runoak before writing it. just preflight-dr flagged AEBP1 mentioned in 52% as many sentences as TNXB; this is expected and not a rival-disease conflation, since the report (correctly, per its own template) covers both clEDS-1 (TNXB) and clEDS-2 (AEBP1) subtypes of the same disease entry, exactly as this entry itself is structured. Cross-checked the report body against the existing entry and found it substantially corroborated the independently-sourced primary literature already cited (same TNXB/AEBP1 mechanism, same autosomal recessive inheritance, same absence-of-atrophic-scarring-in-clEDS1 distinction), plus surfaced one genuinely important gap: the report's phenotype table states atrophic scarring is present in 9/11 clEDS2 patients, which is the opposite of the 'no atrophic scarring' framing that (correctly) applies only to clEDS-1/TNXB. This data point was already present verbatim in the already-cached PMID:37214418 Table 1 ('Atrophic scars | ... | 10/10 (100%)') but had not been added as a phenotype in the initial CREATE pass. Added two new clEDS-2-specific phenotypes from that same already-cached, already-fetched source, each with its own exact-quote table-row snippet: Atrophic Scarring (HP:0001075, 10/10 assessed patients) and Osteopenia (HP:0000938, 5/7 assessed patients). Considered and did NOT add from the DR report: CAH-X (a genuinely distinct CYP21A2-TNXB contiguous-gene disorder, correctly out of scope per the report's own 'critical distinction' section), mitral valve prolapse and vertebral artery dissection (both plausible clEDS-2 vascular findings but redundant with the already-cited PMID:37214418 aneurysm/rupture evidence and not independently re-verified against a primary source in this pass), GI/pelvic-floor complications beyond the already-modeled prolapse (report itself flags this 9/9-cohort figure as likely referral-bias-inflated), and a veterinary TNXB dog case report (report itself says full variant/phenotype details were unavailable in retrieved text and should be verified before structured annotation -- exactly the caution CLAUDE.md's evidence discipline calls for). Re-ran just discover-datasets Classical-like_Ehlers-Danlos_Syndrome during the initial pass: all 12 GEO candidates were GENE_ONLY hits on AEBP1's unrelated cancer/fibrosis biology, so no datasets: block was added. Revalidated with: just validate (42/42 snippets verified), just validate-disorders (CI-authoritative gate, passed), just check-causal-targets (0 new dangling targets), just check-entity-refs, just check-duplicate-keys, just check-enum-values, and whole-KB just check-snippet-length (exit 0).

Create: Classical-like Ehlers-Danlos Syndrome · 2026-09-16T17:19:18Z · View source

Created new entry for Classical-like Ehlers-Danlos syndrome (clEDS), covering both molecularly distinct autosomal recessive subtypes: clEDS-1 (TNXB, MONDO:0011670, anchoring the top-level disease_term since the umbrella MONDO term for clEDS as a whole is itself the TNXB-specific term) and clEDS-2 (AEBP1, MONDO:0054813). A third form, clEDS-3 (MONDO:0971044, OMIM #620865), was deliberately excluded from has_subtypes: it carries no causal-gene relationship in MONDO and no indexed PubMed literature was found describing it as of curation, so it is only noted in the entry notes rather than curated with fabricated evidence. Sources: the TNXB GeneReviews chapter (PMID:36108117, confirmed and tagged via just check-genereviews --online), the 2023 comprehensive AEBP1/clEDS-2 clinical and molecular review (PMID:37214418, 11 patients/9 families), and two TNX collagen-biochemistry primary papers (PMID:17033827, PMID:20089348) establishing the FNIII29-domain collagen-fibrillogenesis mechanism. Pathograph models two upstream MOLECULAR loss-of-function nodes (TNXB, AEBP1) converging on a shared TISSUE-level 'Disorganized Dermal Collagen Matrix' node, branching into skin fragility, joint hypermobility, vascular/visceral fragility, and (clEDS-1-specific) peripheral nerve/muscle involvement nodes -- all phenotypes connected into the pathograph rather than left orphaned, applying the lesson learned from the kEDS self-review earlier in this session. MONDO term resolution required searching 'tenascin' rather than 'classical-like'/'classic-like', since the correct MONDO:0011670 label is 'Ehlers-Danlos syndrome due to tenascin-X deficiency'. Ran just discover-datasets Classical-like_Ehlers-Danlos_Syndrome: all 12 GEO candidates were GENE_ONLY matches on AEBP1's unrelated roles (cancer, diabetic retinopathy, atherosclerosis fibrosis) rather than DIRECT matches for the disease itself, so no datasets: block was added -- adding any would have been the Named Entity Confusion trap CLAUDE.md warns about. Deleted stubs/Ehlers-Danlos_Syndrome_Arthrochalasia_Type.yaml as follow-up housekeeping: that disease was curated into kb/disorders/Arthrochalasia_Ehlers-Danlos_Syndrome.yaml earlier in this session but the stub deletion was not done at the time. Validated with: just validate (40/40 snippets verified), just validate-disorders (CI-authoritative gate, passed), just check-causal-targets (0 new dangling targets against 122 grandfathered), just check-entity-refs, just check-duplicate-keys, just check-enum-values, just check-qualifier-terms, just list-gene-term-mismatches (0/6 mismatches), just check-snippet-length (whole-KB, exit 0), just check-folded-hyphens/check-title-snippets/check-snippet-grading (whole-KB, all exit 0), just check-environmental-evidence (whole-KB, exit 0), and just check-genereviews --online (TNXB chapter correctly tagged). just compliance: 87.0% global / 87.4% weighted. A falcon deep-research pass (just research-disorder falcon Classical-like_Ehlers-Danlos_Syndrome --fallback) was launched for cross-check per the default-provider instruction; its findings, if any, will be recorded in a follow-up EDIT history record.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 22 citations 2026-09-16T17:19:35.291861

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Classical-like Ehlers-Danlos Syndrome
  • MONDO ID: MONDO:0011670 (if available)
  • Category: Mendelian

Research Objectives

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

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

1. Disease Information

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

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

2. Etiology

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

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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

5. Environmental Information

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

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

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

6. Mechanism / Pathophysiology

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

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

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

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

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

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

10. Diagnostics

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

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

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

11. Outcome/Prognosis

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

12. Treatment

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  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
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  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

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

13. Prevention

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

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

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

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

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

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
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  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

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

Output Format

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

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

Classical-like Ehlers–Danlos syndrome: comprehensive disease-characteristics report

Scope and evidence date. This report covers classical-like Ehlers–Danlos syndrome (clEDS) as two autosomal-recessive extracellular-matrix disorders: TNXB-related clEDS type 1 (clEDS1) and AEBP1-related clEDS type 2 (clEDS2). It distinguishes complete biallelic TNXB deficiency from heterozygous TNXB-associated hypermobility and from CAH-X, the CYP21A2–TNXB contiguous-gene disorder. Evidence is current through the retrieved 2024 literature. Because both diseases are ultra-rare, most frequencies derive from cohorts of 9–24 individuals and should not be interpreted as population estimates.

Feature clEDS1 / TNXB clEDS2 / AEBP1 Evidence notes
Molecular definition Biallelic pathogenic TNXB variants causing complete tenascin-X deficiency Biallelic pathogenic AEBP1 variants causing loss or dysfunction of aortic carboxypeptidase-like protein (ACLP) Both are autosomal-recessive monogenic extracellular-matrix disorders; TNXB haploinsufficiency and CAH-X are related but distinct entities (gensemer2021hypermobileehlers‐danlossyndromes pages 24-29, kosho2024editorialehlersdanlossyndrome pages 2-2)
Protein function Tenascin-X is an extracellular-matrix glycoprotein that regulates collagen deposition and matrix organization and interacts with collagen fibrils/decorin ACLP binds several fibrillar collagens through its discoidin domain, enhances collagen polymerization, and contributes to development, repair, fibrosis, fibroblast proliferation, and collagen-producing-cell differentiation Human and model evidence supports disrupted collagen-rich matrix organization rather than a primary collagen-gene defect (blackburn2018biallelicalterationsin pages 4-5, pliegoarreaga2024jointhypermobilitysyndrome pages 6-8)
Core phenotype Generalized joint hypermobility, hyperextensible skin, easy bruising, and generalized tissue fragility Joint hypermobility 11/11, skin hyperextensibility 11/11, easy bruising 10/11 in the 2023 aggregated series clEDS2 percentages derive from only 11 reported individuals and are vulnerable to ascertainment bias (sugiura2023analysisofreferrals pages 26-30, kosho2024editorialehlersdanlossyndrome pages 2-2)
Scarring distinction Classically resembles classical EDS but usually lacks the typical atrophic scars of COL5A1/COL5A2-related classical EDS Atrophic scarring occurred in 9/11, so absence of atrophic scars is not a reliable clEDS2 discriminator The “classical-like without atrophic scarring” rule applies most strongly to TNXB-related clEDS1, not uniformly to clEDS2 (sugiura2023analysisofreferrals pages 26-30)
Additional phenotype clues Muscle weakness, myalgia, fatigability, edema without cardiac failure, distal joint changes, and possible neuropathy; in one TNX-deficient dataset, mild–moderate weakness was 80%, reduced vibration sense 60%, axonal polyneuropathy 40%, and mild myopathic biopsy findings 20% Hair loss or thinning was reported in 6/11 and may be a useful distinguishing clue; osteoporosis, poor wound healing, redundant skin, and marfanoid features have also been described TNXB neuromuscular percentages came from a small EDS/TNX-deficiency cohort; the clEDS2 hair-loss observation requires confirmation in larger series (brady2017theehlers–danlossyndromes pages 6-7, kosho2024editorialehlersdanlossyndrome pages 2-2)
Vascular concerns Easy bruising and hematomas are prominent; severe arterial events have been reported but are not sufficiently quantified for precise risk estimates Among 11 reported individuals, 2/11 had arterial aneurysm and/or dissection; reported findings include vertebral-artery dissection, splenic-artery dilatation, arterial tortuosity, and an aortic-root aneurysm requiring surgery Cardiovascular surveillance has been proposed for clEDS2, but evidence remains case-series level rather than guideline-grade (kosho2024editorialehlersdanlossyndrome pages 2-2)
Cardiac findings Valve or structural cardiac abnormalities can occur, especially in the distinct CAH-X spectrum, but clEDS1-specific frequencies are uncertain Mitral-valve prolapse was reported in 4/11 Do not transfer CAH-X cardiac-frequency estimates directly to biallelic TNXB clEDS1 (sugiura2023analysisofreferrals pages 26-30, kosho2024editorialehlersdanlossyndrome pages 2-2)
Gastrointestinal and pelvic-floor concerns A 2024 summary of a nine-patient TNXB cohort reported gastrointestinal complications in all patients, including perforation, diverticulitis, bleeding, obstruction, rectal/anal prolapse, and gallstones Potentially serious bowel complications have been emphasized in recent reports, but robust frequencies are unavailable The clEDS1 observation is from a highly selected small cohort and should not be interpreted as population prevalence (kosho2024editorialehlersdanlossyndrome pages 1-2, kosho2024editorialehlersdanlossyndrome pages 2-2)
Variant spectrum and functional consequence Missense, nonsense, frameshift, splice, deletion, and TNXA-derived/chimeric alleles occur; disease-producing biallelic variants generally cause absent or profoundly deficient tenascin-X Reported pathogenic alleles include nonsense, frameshift, splice-site, and damaging missense variants; demonstrated consequences include nonsense-mediated decay, absent ACLP, and impaired collagen assembly More than 75% of patients in one recent TNXB cohort reportedly carried TNXA-derived variation; AEBP1 functional nullizygosity is supported by RNA/protein studies (kosho2024editorialehlersdanlossyndrome pages 1-2, blackburn2018biallelicalterationsin pages 4-5, brady2017theehlers–danlossyndromes pages 3-4)
Testing pitfalls Technically difficult because TNXB lies in the complex RCCX locus and has a highly homologous pseudogene, TNXA; sequencing alone may miss exon conversions, TNXA/TNXB chimeras, or copy-number changes Standard sequencing and deletion/duplication analysis are generally applicable, but missense variants may require segregation and functional evidence TNXB testing should use validated locus-aware methods and copy-number/chimera analysis; long-read or genome/RNA approaches may resolve unsolved cases (kim2023molecularbasisand pages 10-10, malfait2020theehlers–danlossyndromes pages 15-16)
Important diagnostic distinction Complete biallelic TNXB deficiency causes clEDS1; heterozygous TNXB deficiency may produce a hypermobility phenotype, while a CYP21A2–TNXB contiguous rearrangement produces CAH-X AEBP1-related disease is not CAH-X and does not inherently cause congenital adrenal hyperplasia Conflating these entities can distort inheritance, phenotype, and recurrence-risk counseling (gensemer2021hypermobileehlers‐danlossyndromes pages 24-29, sugiura2023analysisofreferrals pages 26-30, brady2017theehlers–danlossyndromes pages 3-4)
Mechanistic pathology Tenascin-X deficiency reduces collagen density and alters matrix and elastic-fiber organization; TNX-null mouse skin has approximately 30% less collagen despite relatively preserved fibril size and shape ACLP deficiency impairs binding/polymerization of fibrillar collagen; patient skin shows reduced dermal collagen and ragged abnormal fibrils Evidence includes human skin/fibroblasts, biochemical collagen-polymerization assays, and knockout mice (blackburn2018biallelicalterationsin pages 4-5, pliegoarreaga2024jointhypermobilitysyndrome pages 6-8)
Experimental models Tnxb−/− mouse: reduced collagen deposition and mechanical allodynia; allodynia responded to gabapentin and a μ-opioid agonist but not indomethacin Aebp1−/− mouse: abnormal/delayed wound repair associated with impaired fibroblast proliferation; patient-derived fibroblasts provide direct functional models Models reproduce selected ECM, wound-healing, or pain mechanisms but do not establish the full human multisystem natural history (blackburn2018biallelicalterationsin pages 4-5, kosho2024editorialehlersdanlossyndrome pages 2-2, gensemer2021hypermobileehlers‐danlossyndromes pages 66-70)
Therapy status No approved molecularly targeted, gene, RNA, or cell therapy; care is supportive and complication-directed No approved molecularly targeted, gene, RNA, or cell therapy; care is supportive and complication-directed Current management relies on multidisciplinary rehabilitation, pain treatment, tissue-protection and wound precautions, cardiovascular assessment, and genetic counseling; recommendations are largely extrapolated from broader EDS care (malfait2020theehlers–danlossyndromes pages 15-16, malfait2014theehlersdanlossyndrome. pages 10-12)
Evidence maturity Larger clinical experience than clEDS2, but still ultra-rare with no population-level natural-history estimates Only 11 individuals were aggregated in the 2023 report; phenotype and complication frequencies remain provisional Neither subtype has reliable incidence, prevalence, survival, penetrance, treatment-response, or quality-of-life statistics (kosho2024editorialehlersdanlossyndrome pages 1-2, kosho2024editorialehlersdanlossyndrome pages 2-2)

Table: Database-ready comparison of TNXB-related clEDS1 and AEBP1-related clEDS2, emphasizing molecular definitions, phenotype differences, testing pitfalls, mechanisms, models, and evidence limitations.

1. Disease information

Definition

clEDS is a group of inherited connective-tissue disorders characterized by generalized joint hypermobility, hyperextensible skin, easy bruising and generalized tissue fragility. The adjective “classical-like” reflects overlap with COL5A1/COL5A2-related classical EDS. In TNXB-related clEDS1, the classic distinction is the usual absence of the characteristic atrophic scars of classical EDS; this distinction is less reliable in AEBP1-related clEDS2, in which atrophic scars occurred in 9/11 reported individuals. Biallelic TNXB variants cause complete tenascin-X deficiency, whereas biallelic AEBP1 variants impair aortic carboxypeptidase-like protein (ACLP) and collagen assembly. (gensemer2021hypermobileehlers‐danlossyndromes pages 24-29, sugiura2023analysisofreferrals pages 26-30, kosho2024editorialehlersdanlossyndrome pages 2-2)

Identifiers and synonyms

  • MONDO: the user-supplied MONDO:0011670 corresponds to classical-like EDS in the target knowledge base; subtype-specific MONDO mappings should be checked against the current MONDO release before production ingestion.
  • OMIM: TNXB-related classical-like EDS is commonly represented as Ehlers–Danlos syndrome, classical-like, 1 / EDSCL1; AEBP1-related disease as classical-like EDS type 2 / EDSCL2. Database release verification is recommended rather than hard-coding unverified numeric records.
  • Orphanet: generally indexed under classical-like EDS/TNX-deficient EDS; subtype-specific records may vary by release.
  • ICD-10: no reliably specific clEDS code; usually grouped under Q79.6, Ehlers–Danlos syndrome.
  • ICD-11: grouped within hereditary connective-tissue disorders/Ehlers–Danlos syndromes; no subtype-specific billing code was established in the retrieved literature.
  • MeSH: Ehlers-Danlos Syndrome.
  • Synonyms: classical-like EDS; clEDS; TNX-deficient EDS; tenascin-X-deficient EDS; EDS due to TNXB deficiency; clEDS type 1; AEBP1-related EDS; ACLP-deficiency EDS; clEDS type 2.

The evidence summarized here is aggregated disease-level literature, including clinical cohorts, pedigrees, reviews and experimental models—not individual EHR data.

2. Etiology

Causal factors

  • clEDS1: germline biallelic pathogenic variants in TNXB, causing absent or severely reduced tenascin-X. Reported classes include nonsense, frameshift, missense, splice, deletion and TNXA-derived conversion/chimeric alleles. Among 24 reported people with complete TNX deficiency, 19 from 15 families had a molecular diagnosis; variants were distributed across TNXB. (brady2017theehlers–danlossyndromes pages 3-4)
  • clEDS2: germline biallelic pathogenic variants in AEBP1, generally causing ACLP loss of function or impairment of its collagen-binding/polymerization activity. The foundational study identified four people from three families with compound-heterozygous or homozygous frameshift, nonsense and splice variants. (malfait2020theehlers–danlossyndromes pages 22-22, blackburn2018biallelicalterationsin pages 4-5)

Genetic and environmental risk factors

The principal risk is inheritance of two pathogenic alleles. For two carrier parents, each pregnancy has a 25% affected, 50% carrier and 25% unaffected/non-carrier probability. Consanguinity increases the probability that both parents carry the same rare allele; runs of homozygosity supported a shared ancestral AEBP1 segment in one family. No validated susceptibility loci, modifier genes, genetic anticipation or reproducible founder effect has been established.

No toxin, pathogen, diet, smoking pattern or occupational exposure causes clEDS. Mechanical load, trauma, surgery and high-impact activity can modify manifestations by precipitating dislocation, bruising, pain, poor wound healing or tissue rupture, but they do not create the Mendelian disorder. Age, sex and lifestyle may influence joint-hypermobility expression across EDS, but clEDS-specific gene–environment estimates are unavailable.

Protective factors and gene–environment interaction

No protective allele or pharmacological prevention of disease onset is known. Low-impact conditioning, joint stabilization, avoidance of collision sports and skin protection plausibly reduce secondary injury; these are complication-prevention measures rather than molecular protection. Formal TNXB/AEBP1 gene–environment interaction studies were not identified.

3. Phenotypes

Major manifestations and suggested HPO terms

Manifestation Type, onset/course and reported frequency Suggested HPO term
Generalized joint hypermobility Clinical sign; often recognizable in childhood; may diminish with age while instability and pain persist. clEDS2: 11/11. HP:0001382 Joint hypermobility; HP:0002761 Generalized joint hypermobility
Joint instability, subluxation/dislocation Sign/symptom; recurrent and mechanically triggered; severity variable. HP:0001373 Joint dislocation; HP:0030860 Joint subluxation
Skin hyperextensibility Physical sign; usually longstanding/congenital predisposition. clEDS2: 11/11. HP:0000974 Hyperextensible skin
Easy bruising/ecchymoses Sign; lifelong and episodic after minor trauma. clEDS2: 10/11. HP:0000978 Bruising susceptibility
Atrophic/abnormal scarring Usually absent as a defining feature in clEDS1, but present in 9/11 clEDS2 cases. HP:0001075 Atrophic scars; HP:0001058 Poor wound healing
Soft, redundant or doughy skin Physical manifestation; variable. HP:0000977 Soft skin; HP:0001582 Redundant skin
Chronic musculoskeletal pain, myalgia and fatigue Symptoms; often become more limiting with age and recurrent injury. HP:0003326 Myalgia; HP:0012531 Pain; HP:0012378 Fatigue
Muscle weakness Sign/symptom; mild–moderate weakness occurred in 80% of one TNX-deficient neuromuscular cohort. HP:0001324 Muscle weakness
Peripheral sensory/nerve abnormalities Reduced vibration sense 60%, axonal polyneuropathy 40%, and mild myopathic biopsy findings 20% in one small TNX-deficient cohort. HP:0000763 Sensory neuropathy; HP:0003477 Peripheral axonal neuropathy
Edema without cardiac failure Characteristic minor feature described particularly in clEDS1; frequency uncertain. HP:0000969 Edema
Foot/hand deformity Reported features include brachydactyly, acrogeric appearance, pes planus and hallux valgus; variable. HP:0001156, HP:0001811, HP:0001760
Hair loss/thinning Emerging clEDS2 feature: 6/11 reported individuals. HP:0001596 Alopecia
Osteopenia/osteoporosis Particularly reported in AEBP1 disease; quantitative frequency unresolved. HP:0000938 Osteopenia; HP:0000939 Osteoporosis
Arterial aneurysm/dissection/tortuosity Rare but potentially severe; clEDS2 arterial aneurysm and/or dissection in 2/11. HP:0002617, HP:0005294, HP:0005116
Mitral-valve prolapse clEDS2: 4/11 in the 2023 aggregate. HP:0001634
Gastrointestinal/pelvic-floor complications Diverticulitis, bleeding, obstruction, perforation, prolapse and gallstones were reported in a selected nine-person TNXB cohort; all nine had some GI complication. HP:0002037, HP:0002027, HP:0002012, HP:0002035, HP:0001085

The clEDS2 frequencies come from only 11 reported individuals—six females and five males—and are vulnerable to publication and ascertainment bias. Cardiovascular surveillance was proposed because 2/11 had aneurysm/dissection, not because a population-level risk has been established. (kosho2024editorialehlersdanlossyndrome pages 1-2, kosho2024editorialehlersdanlossyndrome pages 2-2, brady2017theehlers–danlossyndromes pages 6-7)

Quality of life

Pain, recurrent instability, weakness, fatigue, neuropathy, bruising and fear of tissue injury can limit mobility, work, self-care and participation. EDS-wide research shows pain can be severe and associated with functional impairment, but no clEDS-specific EQ-5D, SF-36, PROMIS, disability-weight or treatment-response dataset was identified. Thus, QoL effects are clinically credible but not numerically quantifiable for these subtypes.

4. Genetic and molecular information

Genes and proteins

  • TNXB, chromosome 6p21.3, encodes tenascin-X, a large extracellular-matrix glycoprotein involved in collagen deposition, fibril/matrix organization and interactions with decorin. Suggested annotations: GO:0031012 extracellular matrix, GO:0005201 extracellular matrix structural constituent, and collagen-fibril organization processes.
  • AEBP1 encodes ACLP, an ECM-associated protein expressed in dermis, vasculature and bone. ACLP binds fibrillar collagens through a discoidin domain, enhances collagen polymerization and participates in fibroblast proliferation, repair, fibrosis and differentiation of collagen-producing mesenchymal cells. (blackburn2018biallelicalterationsin pages 4-5, pliegoarreaga2024jointhypermobilitysyndrome pages 6-8)

Representative pathogenic variants

AEBP1 examples include c.1470delC, c.1743C>A (p.Cys581), c.1320_1326del (p.Arg440Serfs3), c.1630+1G>A, c.917dup (p.Tyr306), c.821del (p.Pro274Leufs18), c.2248T>C (p.Trp750Arg), c.1012G>T (p.Glu338) and c.1930C>T (p.Arg644). The c.1320_1326del allele underwent nonsense-mediated decay with no detectable ACLP, while c.1470delC disrupted the collagen-binding domain. (blackburn2018biallelicalterationsin pages 4-5)

TNXB pathogenic alleles span multiple classes. Interpretation is complicated by the homologous TNXA pseudogene and RCCX structural variation. TNXA-derived changes reportedly accounted for more than 75% of individuals in one recent nine-person TNXB cohort. (kosho2024editorialehlersdanlossyndrome pages 1-2, kim2023molecularbasisand pages 10-10)

These are germline diseases. Somatic variants are not an etiologic category. Pathogenic alleles are expected to be absent or extremely rare in population databases; exact gnomAD frequencies must be retrieved per HGVS allele and ancestry rather than generalized. A VUS does not confirm diagnosis without segregation, phenotype and preferably RNA/protein or other functional support.

Functional consequence and other genomic mechanisms

The dominant disease mechanism for both types is biallelic loss of function, although damaging missense alleles may impair binding, folding or secretion. Large RCCX deletions and gene conversions are particularly relevant to TNXB. No recurrent aneuploidy, translocation, inversion, epigenetic signature or validated modifier gene is established. No disease-specific DNA-methylation episignature was identified.

Critical distinction: clEDS1 versus CAH-X

Complete biallelic TNXB deficiency produces recessive clEDS1. Heterozygous TNXB deficiency can produce a variably penetrant hypermobility phenotype. CAH-X results when RCCX rearrangement disrupts CYP21A2 and TNXB, combining congenital adrenal hyperplasia with an EDS/hypermobility phenotype. It must not be assigned the phenotype frequencies or inheritance model of biallelic clEDS1. In one CAH-X study, 12/13 individuals had EDS features; separate CAH cohorts reported 8.5–15% CAH-X estimates, which are not clEDS prevalence estimates. (gensemer2021hypermobileehlers‐danlossyndromes pages 24-29, sugiura2023analysisofreferrals pages 26-30, brady2017theehlers–danlossyndromes pages 6-7)

5. Environmental information

No infectious agent, radiation, toxin, pollutant, nutritional deficiency or lifestyle exposure is causal. Relevant environmental modifiers are biomechanical: repeated high-impact loading can exacerbate joint injury; minor trauma can provoke bruising or skin injury; invasive procedures can expose tissue fragility. Smoking cessation and balanced nutrition are reasonable for general wound, bone and cardiovascular health, but no clEDS-specific effect size exists. Vaccination follows routine schedules; clEDS is neither infectious nor immunodeficient.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic TNXB pathogenic variants lead to absent/profoundly deficient tenascin-X or biallelic AEBP1 variants lead to absent/dysfunctional ACLP.
  2. Loss of tenascin-X leads to reduced collagen deposition and disturbed collagen–decorin/elastic-microfibril organization; loss of ACLP leads to impaired fibrillar-collagen binding and polymerization.
  3. These abnormalities result in reduced matrix density, abnormal fibril architecture and defective fibroblast-mediated matrix maintenance/wound repair.
  4. Defective dermal ECM leads to hyperextensible/soft skin, easy bruising and abnormal or delayed healing.
  5. Defective ligament, tendon, fascia and periarticular ECM leads to joint laxity, recurrent subluxation/dislocation and altered mechanical loading.
  6. Recurrent instability and altered mechanosensory input result in chronic pain, fatigue, weakness and functional impairment; neuropathic contributions are demonstrated in Tnxb-null mouse allodynia but remain partly inferred in humans.
  7. Branch—vascular/valvular ECM weakness leads to mitral-valve prolapse, arterial tortuosity, aneurysm or dissection in a minority, with risk best documented but still imprecise in clEDS2.
  8. Branch—gastrointestinal and pelvic connective-tissue weakness leads to diverticular disease, bleeding, obstruction, perforation or prolapse in selected patients; general frequency remains uncertain.

Mechanistic detail

TNX-null mouse skin has relatively preserved fibril dimensions but reduced fibril density and approximately 30% lower collagen content, indicating a defect in matrix deposition/organization rather than a primary fibrillar-collagen sequence defect. Human TNXB disease also shows abnormal elastic fibers and microfibrils. (gensemer2021hypermobileehlers‐danlossyndromes pages 24-29, pliegoarreaga2024jointhypermobilitysyndrome pages 6-8)

ACLP directly enhanced collagen polymerization and bound several fibrillar collagens in the foundational biochemical work. Patient skin showed decreased dermal collagen and ragged abnormal fibrils; patient fibroblast RNA/protein experiments demonstrated nonsense-mediated decay and ACLP absence for a null allele. An exact abstract statement from Blackburn et al. is: “These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype.” (Published April 2018; DOI/URL: https://doi.org/10.1016/j.ajhg.2018.02.018.) (blackburn2018biallelicalterationsin pages 4-5)

Suggested GO biological processes include extracellular-matrix organization (GO:0030198), collagen-fibril organization (GO:0030199), wound healing (GO:0042060), regulation of cell adhesion and response to mechanical stimulus. Suggested cell types include dermal fibroblast (CL:0002620), tendon fibroblast/tenocyte, ligament fibroblast, vascular smooth-muscle cell (CL:0000359), endothelial cell (CL:0000115), valvular interstitial cell and mesenchymal stromal cell (CL:0000134). Suggested compartments are extracellular matrix (GO:0031012), collagen-containing extracellular matrix (GO:0062023) and extracellular region (GO:0005576).

No clEDS-specific immune, metabolic, mitochondrial, autophagy or canonical Wnt/MAPK/mTOR/PI3K-AKT mechanism is established. No validated clEDS-specific metabolomic, lipidomic, single-cell, spatial-transcriptomic, integrated multi-omic or CRISPR-screen signature was identified. Broad EDS fibroblast transcriptomics should not be annotated as clEDS-specific evidence.

7. Anatomical structures affected

  • Primary: skin/dermis, ligaments, tendons, joint capsules, fascia and skeletal-muscle connective tissue.
  • Secondary/variable: peripheral nerves, bone, heart valves, arterial wall, gastrointestinal wall and pelvic-floor support.
  • Suggested UBERON: skin of body (UBERON:0002097), dermis (UBERON:0002067), ligament (UBERON:0000216), tendon (UBERON:0000043), joint (UBERON:0000982), skeletal muscle (UBERON:0001134), artery (UBERON:0001637), heart valve (UBERON:0002139), gastrointestinal tract (UBERON:0005409).
  • Subcellular: secretory pathway may be relevant for synthesis/secretion, but the disease-defining compartment is the extracellular/collagen-containing matrix.

Manifestations are generally bilateral/systemic rather than characteristically unilateral, although individual dislocations, aneurysms or dissections can be focal.

8. Temporal development

The molecular defect is congenital and lifelong. Skin hyperextensibility, bruising and joint laxity often become evident in childhood, but diagnosis may be delayed into adulthood. Joint hypermobility may decrease with aging, while pain, weakness, degenerative joint consequences and vascular/GI complications may emerge or accumulate later. The course is chronic and variable, not relapsing-remitting; injury-related exacerbations are episodic. There are no validated disease stages, remission criteria or progression-rate estimates.

Critical periods include childhood for joint-protective conditioning; before surgery or pregnancy for individualized tissue-fragility planning; and adulthood for cardiovascular and GI review where indicated. A chronic vertebral-artery dissection and other vascular abnormalities were detected at age 63 in one clEDS2 individual, demonstrating that clinically important complications may present late. (kosho2024editorialehlersdanlossyndrome pages 2-2)

9. Inheritance and population

Both types are autosomal recessive. Penetrance for true biallelic loss-of-function disease appears high, but precise estimates cannot be calculated; expressivity is variable. There is no evidence of anticipation. Germline mosaicism is theoretically possible but not quantified. Heterozygous TNXB relatives may show hypermobility with sex-dependent/incomplete expression, but this is not equivalent to recessive clEDS1. In one family study, all 20 heterozygous relatives had reduced serum TNX, 17 carried truncating variants and 9 had generalized joint hypermobility. (brady2017theehlers–danlossyndromes pages 6-7)

No reliable prevalence, incidence, carrier frequency, sex ratio, ancestry enrichment or geographic distribution exists. The 2023 clEDS2 literature contained only 11 recognized individuals—six female and five male—too few for demographic inference. clEDS is appropriately considered ultra-rare. (kosho2024editorialehlersdanlossyndrome pages 2-2)

10. Diagnostics

Clinical assessment

Clinical examination should document Beighton score/generalized hypermobility, age-adjusted joint range, instability/dislocations, skin extensibility and texture, bruising, scars and healing, edema, hand/foot morphology, pain, muscle strength, neurologic findings, hernias/prolapse and cardiovascular/GI history. The 2024 expert review states that massively parallel gene-panel testing is the current gold standard for confirming monogenic EDS, while history, pedigree and examination remain essential. (Published November 2024; DOI: https://doi.org/10.1515/medgen-2024-2060.)

Genetic-testing algorithm

  1. Use an EDS/heritable-connective-tissue panel containing at least TNXB, AEBP1, COL5A1, COL5A2, COL3A1, PLOD1, FKBP14, ADAMTS2, CHST14, DSE, SLC39A13, B4GALT7, B3GALT6, SLC2A10, FLNA and other phenotype-directed genes.
  2. Ensure the assay explicitly validates TNXB coverage against TNXA and includes deletion/duplication, conversion and TNXA/TNXB chimera analysis. Ordinary short-read pipelines can mis-map this locus.
  3. If negative but suspicion remains high, consider locus-specific long-range PCR, RNA studies, WES/WGS or long-read sequencing. WES is useful for AEBP1 and unsolved heterogeneous presentations, but may be inadequate alone for complex TNXB structural alleles. (kim2023molecularbasisand pages 10-10, malfait2020theehlers–danlossyndromes pages 15-16)
  4. Confirm phase for two variants and perform parental segregation. Apply ACMG/AMP criteria; do not use a VUS as definitive diagnosis.
  5. Once familial variants are known, use targeted testing for relatives, prenatal diagnosis or preimplantation testing.

Serum TNX can be absent in biallelic TNXB disease, but the assay is not widely available. Skin biopsy/electron microscopy may show reduced collagen density, abnormal fibrils or elastic/microfibril abnormalities; findings are supportive, not independently diagnostic. Routine biochemical, circulating, metabolomic or liquid-biopsy biomarkers do not exist. (brady2017theehlers–danlossyndromes pages 3-4, malfait2020theehlers–danlossyndromes pages 15-16)

Differential diagnosis

  • Classical EDS: COL5A1/COL5A2; typical papyraceous/atrophic scars strongly favor classical EDS over clEDS1, but not necessarily clEDS2.
  • Hypermobile EDS/HSD: no established monogenic test for typical hEDS; skin and bruising are usually less pronounced. Biallelic TNXB or AEBP1 findings establish a different diagnosis.
  • Vascular EDS: COL3A1; translucent skin, characteristic facial/acral findings and greater spontaneous arterial/organ rupture risk.
  • Kyphoscoliotic EDS: PLOD1/FKBP14; congenital hypotonia and progressive kyphoscoliosis.
  • Other rare EDS types: periodontal, musculocontractural, dermatosparaxis, arthrochalasia and spondylodysplastic forms.
  • Marfan/Loeys–Dietz syndromes: aortic and skeletal pattern with FBN1 or TGF-β-pathway genes.
  • Cutis laxa, FLNA-related disorders, neuromuscular disease and bleeding disorders.
  • CAH-X: investigate adrenal/androgen phenotype and CYP21A2–TNXB rearrangement; it is not ordinary clEDS1.

Population or newborn screening is not recommended. Cascade testing is appropriate after molecular diagnosis.

11. Outcome and prognosis

No five- or ten-year survival, life-expectancy or disease-specific mortality estimate is available. Many affected people survive into later adulthood, but this does not establish normal life expectancy. Major morbidity arises from chronic pain, instability, fatigue, weakness, poor healing, bruising, neuropathy and occasional serious arterial or bowel complications. Recovery from the constitutional matrix disorder is not expected; functional gains and injury reduction are possible with rehabilitation and prevention.

Potential adverse prognostic features include recurrent major dislocations, severe pain/deconditioning, osteoporosis/fractures, abnormal echocardiography, arterial tortuosity/aneurysm/dissection, GI perforation/obstruction/bleeding and major poor wound healing. No validated prognostic biomarker or calculator exists.

12. Treatment and current applications

There is no cure and no approved TNXB- or AEBP1-targeted drug, gene therapy, cell therapy, RNA therapy or genome-editing therapy. No relevant disease-specific interventional trial was identified in the ClinicalTrials.gov search; a retrieved oncology trial matching a gene acronym was unrelated and excluded.

Practical multidisciplinary strategy

  1. Rehabilitation: individualized physiotherapy emphasizing proprioception, core and periarticular stabilization, low-impact aerobic conditioning and graded strengthening; occupational therapy, braces/orthoses and mobility aids as required. Avoid aggressive stretching and repeated end-range loading. Suggested NCIT concepts: Physical Therapy, Occupational Therapy, Exercise Therapy, Orthopedic Device.
  2. Pain management: education, pacing, sleep optimization, physical modalities and individualized non-opioid/neuropathic-pain therapy. NSAIDs require caution when bruising or GI bleeding is prominent. Tnxb-null mouse allodynia responded to gabapentin and a μ-opioid agonist but not indomethacin; this is mechanistic animal evidence, not a clEDS clinical efficacy trial. (kosho2024editorialehlersdanlossyndrome pages 2-2)
  3. Skin/wounds: protective pads where injury is recurrent; low-tension multilayer closure, generous deep sutures and longer retention. Watch for dehiscence and hematoma. (malfait2014theehlersdanlossyndrome. pages 10-12)
  4. Bone: assess vitamin D/calcium intake, fall risk and DXA when osteoporosis, fractures or AEBP1 disease warrant it; treat osteoporosis according to standard guidelines.
  5. Cardiovascular: baseline echocardiography for valves and aortic root is reasonable. Because clEDS2 has reported aneurysm/dissection and 4/11 MVP, specialist-directed periodic echocardiography and arterial imaging should be individualized. Evidence does not support a universal fixed interval or prophylactic vascular drug. (kosho2024editorialehlersdanlossyndrome pages 2-2)
  6. GI/pelvic floor: prompt evaluation of unexplained abdominal pain, bleeding, obstruction symptoms or prolapse; avoid dismissing symptoms as functional when structural complications are possible.
  7. Surgery/anesthesia: clearly flag connective-tissue fragility. Use careful positioning, padding, airway instrumentation, vascular access and hemostasis; avoid excessive traction. Tissue handling and closure should be gentle. Rare-type EDS guidance notes possible tracheal/esophageal injury and the need for careful delivery planning. (brady2017theehlers–danlossyndromes pages 6-7)
  8. Pregnancy: preconception genetic counseling and coordinated maternal-fetal, anesthesia and relevant surgical review; evidence is too sparse for a clEDS-specific obstetric risk percentage.

No clEDS pharmacogenomic recommendation exists. Published management is chiefly expert opinion and extrapolation from broader EDS practice rather than randomized trials.

13. Prevention

Primary prevention of inherited disease is limited to informed reproductive choice: carrier testing of relatives/partners, prenatal diagnosis and preimplantation genetic testing when both familial pathogenic alleles are known. Secondary prevention consists of early molecular diagnosis and cascade testing. Tertiary prevention includes joint stabilization, impact avoidance, skin protection, bone health, cardiovascular assessment, rapid evaluation of arterial/GI warning symptoms and procedure planning. Genetic counseling must explain autosomal-recessive recurrence and distinguish carrier hypermobility—especially for TNXB—from affected biallelic disease. (malfait2020theehlers–danlossyndromes pages 15-16, malfait2014theehlersdanlossyndrome. pages 10-12)

There is no vaccine, chemoprophylaxis, population-screening program or environmental public-health intervention specific to clEDS.

14. Other species and natural disease

A published 2019 report described compound-heterozygous TNXB variants in a mixed-breed dog with an EDS phenotype, suggesting naturally occurring comparative disease, but full variant and phenotype details were unavailable in the retrieved text and should be verified before structured annotation. The relevant species is Canis lupus familiaris, NCBI Taxon 9615. No zoonotic transmission is possible.

Naturally occurring cutaneous asthenia/EDS-like syndromes occur in several domestic species, but unless a causal TNXB or AEBP1 orthologue is demonstrated they should not be labeled direct models of these clEDS subtypes. No robust natural AEBP1-clEDS veterinary series was identified.

15. Model organisms and experimental systems

  • Tnxb-null mouse (Mus musculus, NCBI Taxon 10090): reduced skin collagen deposition/density, approximately 30% lower collagen content, elastic/microfibril abnormalities and mechanical allodynia. It supports ECM-organization and pain mechanisms but does not establish the full human vascular/GI natural history. (kosho2024editorialehlersdanlossyndrome pages 2-2, pliegoarreaga2024jointhypermobilitysyndrome pages 6-8, gensemer2021hypermobileehlers‐danlossyndromes pages 66-70)
  • Aebp1-null mouse: delayed/abnormal wound repair associated with impaired fibroblast proliferation. This recapitulates a repair defect but is not a complete phenocopy of human clEDS2. (blackburn2018biallelicalterationsin pages 4-5)
  • Patient-derived dermal fibroblasts: demonstrate absent TNX or ACLP, nonsense-mediated decay, abnormal matrix deposition and variant-specific functional consequences. These are the most direct human in-vitro systems. (blackburn2018biallelicalterationsin pages 4-5, brady2017theehlers–danlossyndromes pages 3-4)
  • Biochemical collagen-polymerization assays: showed ACLP binding to several fibrillar collagens and enhancement of polymerization. (blackburn2018biallelicalterationsin pages 4-5)

No validated clEDS patient iPSC, organoid, zebrafish, Drosophila or C. elegans model, disease-specific CRISPR screen, or single-cell/spatial/multi-omic atlas was identified in the retrieved literature.

Recent developments and authoritative assessment

  1. AEBP1 phenotype expansion, April 2023: two additional individuals increased the aggregate to 11. Hyperextensibility and hypermobility were 11/11, bruising 10/11, atrophic scarring 9/11 and hair loss 6/11; vascular findings prompted the authors to state that surveillance “seems warranted.” DOI/URL: https://doi.org/10.3389/fgene.2023.1148224.
  2. TNXB cohort refinement summarized in April 2024: a nine-person cohort used a custom NGS approach; more than 75% carried TNXA-derived variation, and GI complications were reported in all nine. The high figure likely reflects referral/selection and is not population prevalence. DOI/URL for the editorial summary: https://doi.org/10.3389/fgene.2024.1399386. (kosho2024editorialehlersdanlossyndrome pages 1-2)
  3. 2024 diagnostic consensus: gene panels using massively parallel sequencing are the practical standard for monogenic EDS, but TNXB requires locus-aware methods because ordinary sequencing may miss pseudogene-derived and structural alleles. DOI/URLs: https://doi.org/10.1515/medgen-2024-2060 and https://doi.org/10.1515/medgen-2024-2061. (zschocke2024geneticdiagnosisof pages 11-11, malfait2020theehlers–danlossyndromes pages 15-16)
  4. Expert interpretation: current authorities regard clEDS as an ECM-organization disorder rather than simply a collagen-gene disorder. They emphasize molecular confirmation, careful subtype distinction and multidisciplinary complication-directed care; natural-history and treatment evidence remain inadequate. (blackburn2018biallelicalterationsin pages 4-5, malfait2020theehlers–danlossyndromes pages 15-16)

Evidence-quality limitations

The strongest causal evidence comprises segregating biallelic variants, absent protein/nonsense-mediated decay, patient skin/fibroblast abnormalities, collagen-binding/polymerization assays and knockout models. Phenotype frequencies, vascular/GI risk, penetrance, QoL and prognosis are much weaker because they derive from small, clinically selected case series. No randomized treatment trial, longitudinal registry-quality natural-history study, validated biomarker or population epidemiology was found. Consequently, absence of a reported feature should not be treated as evidence of absence, and percentages should always retain their cohort denominator.

References

  1. (gensemer2021hypermobileehlers‐danlossyndromes pages 24-29): Cortney Gensemer, Randall Burks, Steven Kautz, Daniel P. Judge, Mark Lavallee, and Russell A. Norris. Hypermobile ehlers‐danlos syndromes: complex phenotypes, challenging diagnoses, and poorly understood causes. Aug 2021. URL: https://doi.org/10.1002/dvdy.220, doi:10.1002/dvdy.220. This article has 219 citations and is from a peer-reviewed journal.

  2. (kosho2024editorialehlersdanlossyndrome pages 2-2): Tomoki Kosho, Shujiro Hayashi, Ken-ichi Matsumoto, Delfien Syx, and Anupriya Kaur. Editorial: ehlers-danlos syndrome: from bedside to bench. Frontiers in Genetics, Apr 2024. URL: https://doi.org/10.3389/fgene.2024.1399386, doi:10.3389/fgene.2024.1399386. This article has 0 citations and is from a peer-reviewed journal.

  3. (blackburn2018biallelicalterationsin pages 4-5): Patrick R. Blackburn, Zhi Xu, Kathleen E. Tumelty, Rose W. Zhao, William J. Monis, Kimberly G. Harris, Jennifer M. Gass, Margot A. Cousin, Nicole J. Boczek, Mario V. Mitkov, Mark A. Cappel, Clair A. Francomano, Joseph E. Parisi, Eric W. Klee, Eissa Faqeih, Fowzan S. Alkuraya, Matthew D. Layne, Nazli B. McDonnell, and Paldeep S. Atwal. Bi-allelic alterations in aebp1 lead to defective collagen assembly and connective tissue structure resulting in a variant of ehlers-danlos syndrome. American journal of human genetics, 102 4:696-705, Apr 2018. URL: https://doi.org/10.1016/j.ajhg.2018.02.018, doi:10.1016/j.ajhg.2018.02.018. This article has 213 citations and is from a highest quality peer-reviewed journal.

  4. (pliegoarreaga2024jointhypermobilitysyndrome pages 6-8): Raquel Pliego-Arreaga, Juan Antonio Cervantes-Montelongo, Guillermo Antonio Silva-Martínez, Fabiola Estefanía Tristán-Flores, Miguel Angel Pantoja-Hernández, and Juan Raúl Maldonado-Coronado. Joint hypermobility syndrome and membrane proteins: a comprehensive review. Apr 2024. URL: https://doi.org/10.3390/biom14040472, doi:10.3390/biom14040472. This article has 11 citations.

  5. (sugiura2023analysisofreferrals pages 26-30): H Sugiura. Analysis of referrals to genetics for suspected hypermobile ehlers-danlos syndrome. Unknown journal, 2023.

  6. (brady2017theehlers–danlossyndromes pages 6-7): 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.

  7. (kosho2024editorialehlersdanlossyndrome pages 1-2): Tomoki Kosho, Shujiro Hayashi, Ken-ichi Matsumoto, Delfien Syx, and Anupriya Kaur. Editorial: ehlers-danlos syndrome: from bedside to bench. Frontiers in Genetics, Apr 2024. URL: https://doi.org/10.3389/fgene.2024.1399386, doi:10.3389/fgene.2024.1399386. This article has 0 citations and is from a peer-reviewed journal.

  8. (brady2017theehlers–danlossyndromes pages 3-4): 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.

  9. (kim2023molecularbasisand pages 10-10): Ja Hye Kim, Gu-Hwan Kim, Han-Wook Yoo, and Jin-Ho Choi. Molecular basis and genetic testing strategies for diagnosing 21-hydroxylase deficiency, including cah-x syndrome. Jun 2023. URL: https://doi.org/10.6065/apem.2346108.054, doi:10.6065/apem.2346108.054. This article has 22 citations.

  10. (malfait2020theehlers–danlossyndromes pages 15-16): Fransiska Malfait, Marco Castori, Clair A. Francomano, Cecilia Giunta, Tomoki Kosho, and Peter H. Byers. The ehlers–danlos syndromes. Jul 2020. URL: https://doi.org/10.1038/s41572-020-0194-9, doi:10.1038/s41572-020-0194-9. This article has 294 citations.

  11. (gensemer2021hypermobileehlers‐danlossyndromes pages 66-70): Cortney Gensemer, Randall Burks, Steven Kautz, Daniel P. Judge, Mark Lavallee, and Russell A. Norris. Hypermobile ehlers‐danlos syndromes: complex phenotypes, challenging diagnoses, and poorly understood causes. Aug 2021. URL: https://doi.org/10.1002/dvdy.220, doi:10.1002/dvdy.220. This article has 219 citations and is from a peer-reviewed journal.

  12. (malfait2014theehlersdanlossyndrome. pages 10-12): Fransiska Malfait and Anne De Paepe. The ehlers-danlos syndrome. Advances in experimental medicine and biology, 802:129-43, Dec 2014. URL: https://doi.org/10.1007/978-94-007-7893-1_9, doi:10.1007/978-94-007-7893-1_9. This article has 158 citations and is from a peer-reviewed journal.

  13. (malfait2020theehlers–danlossyndromes pages 22-22): Fransiska Malfait, Marco Castori, Clair A. Francomano, Cecilia Giunta, Tomoki Kosho, and Peter H. Byers. The ehlers–danlos syndromes. Jul 2020. URL: https://doi.org/10.1038/s41572-020-0194-9, doi:10.1038/s41572-020-0194-9. This article has 294 citations.

  14. (zschocke2024geneticdiagnosisof pages 11-11): Johannes Zschocke, Serwet Demirdas, and Fleur S. van Dijk. Genetic diagnosis of the ehlers-danlos syndromes. Medizinische Genetik, 36:235-245, Nov 2024. URL: https://doi.org/10.1515/medgen-2024-2061, doi:10.1515/medgen-2024-2061. This article has 7 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 6
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 53
Resolved 50
Unresolved (possible confabulation) 2
Obsolete 1
Unverifiable 0
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 2

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:0011670 (2 mentions) - the report calls it "if available"; MONDO calls it Ehlers-Danlos syndrome due to tenascin-X deficiency
  • HP:0001634 (1 mention) - the report calls it "clEDS2: 4/11 in the 2023 aggregate"; HP calls it Mitral valve prolapse

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0001811 (1 mention) - HP does not contain this term
  • UBERON:0000216 (1 mention) - UBERON does not contain this term

Obsolete terms

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

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