Ehlers Danlos Syndrome

Slide 1 · Ehlers–Danlos syndrome

Molecular pathology, connective-tissue fragility and phenotype–genotype relationships

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Trace collagen biosynthesis and identify stages disrupted in EDS.

Differentiate structural collagen, processing-enzyme and extracellular matrix defects.

Relate subtype-associated genes to skin, joint and visceral manifestations.

Explain why vascular EDS requires distinct clinical recognition.

Slide 3 · EDS is a group of heritable matrix disorders

The Ehlers–Danlos syndromes are clinically and genetically heterogeneous.

Defects affect collagen chains, collagen-processing enzymes or interacting extracellular matrix proteins.

The unifying consequence is loss of connective-tissue structural integrity.

Genetic alteration

Defective collagen / matrix

Tissue fragility

Slide 4 · Why collagen defects produce multisystem disease

Collagen-rich tissues transmit and withstand mechanical loads.

A defect in the matrix compromises tensile strength rather than a single organ-specific function.

The dominant clinical manifestation depends on the collagen or pathway involved.

Skin / wounds

Ligaments / joints

Vessels / viscera

Slide 5 · Affected tissues reflect the collagen involved

Tissue

Relevant vulnerability

Clinical expression

Skin

Reduced tensile integrity

Hyperextensibility; Traumatic tears

Joints and ligaments

Reduced passive restraint

Hypermobility; Dislocation

Arteries and bowel

Weak connective-tissue support

Rupture in vascular EDS

Cornea / eye

Ocular tissue fragility

Corneal rupture or retinal detachment in selected EDS forms

Slide 6 · Fibrillar collagen has organized molecular architecture

Collagen α-chains assemble into a triple-helical molecule.

Some fibrillar collagens are heterotrimers; Type III collagen is a homotrimer.

Chain identity and processing determine the properties of the mature fibril.

Original triple-helix schematic

Slide 7 · Different collagen types implicate different tissues

Types I and V

Important in fibrillar connective-tissue assembly.

Relevant to classical and arthrochalasia EDS mechanisms.

Processing and fibril organization are central.

Type III

Prominent in blood vessels and intestines.

COL3A1 variants underlie vascular EDS.

Defects can culminate in spontaneous visceral or arterial rupture.

Slide 8 · Collagen biosynthesis provides multiple disease targets

Synthesize pro-α chains

Hydroxylate and glycosylate

Assemble triple helix

Secrete procollagen

Process propeptides

Form and stabilize fibrils

An inherited defect at any of several steps can reduce functional collagen strength.

Slide 9 · Procollagen precursors require precise chain synthesis

Collagen chains are translated as precursor pro-α chains.

Nonhelical propeptides flank the helical region during synthesis.

Sequence changes can disturb the structure or handling of the assembled molecule.

Collagen gene

Precursor α-chain

Potential abnormal trimer

Slide 10 · Intracellular hydroxylation prepares collagen

Proline and lysine residues undergo hydroxylation.

Lysine can also be glycosylated within the biosynthetic pathway.

These modifications are part of the pathway that yields structurally stable collagen.

Pro-α chains

Hydroxylation

Modified procollagen

Slide 11 · Three chains assemble into a triple helix

Appropriate chains align and fold into a collagen triple helix.

Altered chain structure may interfere with assembly of the multimer.

This explains severe phenotypes from certain heterozygous structural-gene variants.

Original triple-helix schematic

Slide 12 · Secreted procollagen is not yet the mature fibril

Procollagen leaves the cell with propeptide extensions.

Endopeptidases process these noncollagenous regions.

Incorrect cleavage may compromise subsequent fibril organization.

Procollagen secretion

Propeptide cleavage

Mature collagen units

Slide 13 · N-terminal processing is a vulnerable step

N-terminal procollagen cleavage contributes to type I fibrillar collagen maturation.

Mutations affecting the substrate and mutations affecting the enzyme have different inheritance patterns.

Arthrochalasia and dermatosparaxis EDS exemplify these defects.

N-propeptide present

N-propeptide removed

Assembly of mature fibril

Slide 14 · Extracellular assembly generates load-bearing fibrils

Processed helical molecules polymerize into ordered collagen fibrils.

Collagen fibrils serve as a tensile framework in connective tissues.

Impaired collagen assembly is expressed as mechanical weakness under stress.

Collagen molecule

Staggered organization

Tensile fibril

Slide 15 · Cross-linking adds mechanical stability

Cross-links stabilize collagen after secretion.

The biosynthetic pathway relies on appropriately modified residues.

Insufficient molecular stabilization creates structurally weak collagen.

Fibrils

Cross-links

Slide 16 · EDS mutations affect three broad functional classes

Molecular class

Illustrative gene(s)

Consequences

Collagen structural proteins

COL3A1, COL5A1, COL1A1, COL1A2

Defective chain structure / quantity

Collagen-modifying or processing enzymes

PLOD1, ADAMTS2

Defective hydroxylation / cleavage

Extracellular matrix-associated proteins

TNXB

Defective matrix organization / assembly

Slide 17 · Structural-gene defects compromise collagen assemblies

Mutant collagen chains can disrupt formation of stable trimers.

Clinical severity depends on how the particular variant affects the protein.

Autosomal dominant disease is possible even when one normal allele remains.

Mutated chain

Mixed molecular assembly

Reduced matrix strength

Slide 18 · Enzyme defects compromise collagen processing

Enzymes are needed for posttranslational modification and procollagen maturation.

Loss of a processing enzyme can reduce functional collagen even if collagen genes are intact.

A recessive inheritance pattern is common when residual enzyme from one allele is sufficient.

Enzyme deficiency

Incomplete processing

Weak collagen

Slide 19 · Extracellular-matrix defects can resemble collagen defects

Proteins that bind or organize fibrillar collagen influence matrix architecture.

Loss of tenascin X can produce a classical-like EDS phenotype.

Thus a collagenopathy phenotype need not arise from a collagen structural gene.

Matrix-associated protein

Collagen organization

Tissue integrity

Slide 20 · Dominant and recessive inheritance coexist in EDS

Autosomal dominant

Can reflect a mutant structural chain interfering with assembly.

Includes classical, vascular and arthrochalasia EDS classification.

Affected heterozygotes may express disease.

Autosomal recessive

Frequently reflects enzyme or matrix-component deficiency.

Includes dermatosparaxis, classical-like and several rare types.

Two pathogenic alleles are typically needed.

Slide 21 · Dominant-negative effects amplify chain defects

One mutant collagen allele

Mutant α-chains synthesized

Abnormal chains enter assemblies

Collagen multimers destabilized

The effect exceeds a simple reduction in the amount of a normal protein.

Slide 22 · EDS is phenotypically heterogeneous

Multiple genes produce overlapping manifestations of skin and joint laxity.

Different mutations in the same collagen gene can affect synthesis, secretion or molecular structure.

The same broad syndrome label encompasses very different risks of organ rupture.

A subtype-oriented assessment is more informative than hypermobility alone.

Slide 23 · The textbook uses the 2017 classification of 13 EDS types

Robbins organizes EDS into 13 subtypes.

Subtypes differ in involved genes, typical manifestations and inheritance.

The 2017 scheme is the framework used for this lecture; An updated classification was still in development in 2026.

13 types

Molecular classes

Clinical risk patterns

Slide 24 · Autosomal-dominant groups in the 2017 table

Subtype

Gene(s)

Inheritance

Classical

COL5A1; COL1A1 (rare) in Table 5.5

AD

Vascular

COL3A1; COL1A1 (rare)

AD

Hypermobile

No gene established

AD (2017 table)

Arthrochalasia

COL1A1; COL1A2

AD

Periodontal

C1R; C1S

AD

Myopathic

COL12A1

AD or AR

Slide 25 · Autosomal-recessive groups in the 2017 table

Subtype

Associated gene(s)

Inheritance

Classical-like

TNXB

AR

Cardiac-valvular

COL1A2

AR

Dermatosparaxis

ADAMTS2

AR

Kyphoscoliotic

PLOD1; FKBP14

AR

Brittle cornea syndrome

ZNF469; PRDM5

AR

Spondylodysplastic

B4GALT7; B3GALT6; SLC39A13

AR

Musculocontractural

CHST14; DSE

AR

Slide 26 · The classification is not a severity ranking

Subtype names identify particular phenotypic or molecular patterns.

No single finding is sufficient to infer the underlying gene in all cases.

Subtypes with similar joint findings can differ greatly in vascular and visceral risk.

Classification guides investigation; A molecular finding must be interpreted with the phenotype.

Slide 27 · Classical EDS has prominent cutaneous abnormalities

Hyperextensible, fragile skin is a prominent manifestation.

Minor trauma may produce gaping wounds and difficult surgical repair.

Joint hypermobility and dislocation susceptibility can accompany skin disease.

The molecular association centers on type V collagen.

Slide 28 · Type V collagen defects are central to classical EDS

The narrative identifies COL5A1 and COL5A2 variants in most classical cases.

Type V collagen participates in the organization of fibrillar collagen.

Disordered organization diminishes the tensile integrity of skin and supporting tissues.

Type V collagen defect

Fibril organization impaired

Cutaneous fragility

Slide 29 · Classical EDS illustrates mechanical wound failure

Fragile skin can split under relatively minor force.

Wound edges may not hold normal tension during repair.

Surgical closure can be challenging because connective tissue lacks normal strength.

Minor skin injury

Gaping defect

Difficult wound closure

Slide 30 · Vascular EDS has a distinct risk profile

The principal underlying molecule is type III collagen.

Arterial and intestinal tissues are especially susceptible.

Spontaneous rupture or dissection can be a major presentation.

Marked skin hyperextensibility is not generally typical of this subtype.

Slide 31 · COL3A1 abnormalities produce vascular EDS

COL3A1 pathogenic variant

Abnormal type III collagen

Weak vascular / bowel support

Rupture vulnerability

Type III collagen is especially important in blood vessels and intestines.

Slide 32 · Vascular EDS can involve deficient chain synthesis

Some COL3A1 variants reduce production of pro-α1(III) chains.

Fewer normal chains may be available for collagen assembly.

This is one of several molecular paths toward vascular fragility.

Variant alters production

Less pro-α1(III)

Weak tissue support

Slide 33 · Vascular EDS can involve secretion defects

Some COL3A1 variants interfere with secretion of type III procollagen.

Intracellular chain synthesis need not equate to normal extracellular matrix content.

The result may still be loss of tensile strength at the organ level.

Procollagen produced

Secretion impaired

Matrix collagen reduced

Slide 34 · Vascular EDS can involve abnormal collagen structure

Other COL3A1 variants produce structurally abnormal type III collagen.

Abnormal chains may adversely affect assemblies formed with normal chains.

Dominant-negative behavior can contribute to severe disease in heterozygotes.

Abnormal type III chain

Trimer destabilization

Organ fragility

Slide 35 · Type III collagen explains target-organ vulnerability

Arterial wall

Connective tissue resists intraluminal mechanical force.

Impaired type III collagen weakens the structural framework.

Arterial dissection or rupture may occur.

Intestinal wall

Collagen reinforces tissue under distension.

Reduced tensile integrity predisposes to bowel wall failure.

Spontaneous intestinal rupture is a major hazard.

Slide 36 · Do not exclude vascular EDS for lack of stretchy skin

The vascular phenotype differs from the archetypal hyperextensible skin presentation.

Major-organ fragility may dominate the clinical picture.

A relevant history of arterial or intestinal rupture deserves subtype-directed investigation.

Connective-tissue syndromes cannot be safely triaged by a single sign.

Slide 37 · Hypermobile EDS illustrates incomplete gene discovery

Hypermobile EDS is one of the 13 types in the 2017 framework.

Its disease gene as unknown.

Clinical hypermobility does not by itself identify the molecular mechanism.

Avoid assigning a particular collagen-gene mutation to hypermobile EDS without evidence.

Slide 38 · Joint hypermobility is a phenotype, not a genotype

What examination can establish

The range of motion exceeds the usual physiological range.

Joint instability or dislocations may coexist.

Other tissue findings help narrow the differential.

What it cannot establish alone

A specific EDS subtype.

A COL3A1 or COL5A1 pathogenic variant.

The presence or absence of life-threatening vascular fragility.

Slide 39 · Kyphoscoliotic EDS highlights hydroxylation defects

PLOD1 as a key cause of kyphoscoliotic EDS.

PLOD1 encodes lysyl hydroxylase.

The deficit interferes with collagen stabilization.

The 2017 classification also lists FKBP14-associated kyphoscoliotic EDS.

Slide 40 · PLOD1 deficiency impairs lysine hydroxylation

PLOD1 loss of function

Reduced lysyl hydroxylase

Inadequate hydroxylysine

Reduced collagen stability

This is an enzyme-deficiency mechanism with autosomal-recessive inheritance.

Slide 41 · Hydroxylysine is needed for stable collagen

Lysine hydroxylation prepares collagen for normal stabilization.

A severe lysyl hydroxylase deficit can compromise both intra- and intermolecular strength.

This is mechanistically different from a defect in a collagen structural chain.

Lysine modification

Stabilizing interactions

Tissue strength

Slide 42 · Kyphoscoliotic EDS can endanger ocular integrity

The EDS section associates kyphoscoliotic forms with ocular fragility.

Corneal rupture and retinal detachment are important potential complications.

This demonstrates that not all EDS complications are confined to skin and joints.

An ocular phenotype may direct attention toward a specific subtype.

Slide 43 · Arthrochalasia EDS is a substrate-processing defect

Autosomal-dominant arthrochalasia EDS is linked to COL1A1 and COL1A2.

Affected procollagen chains can resist N-terminal propeptide cleavage.

A structurally abnormal substrate is produced despite the presence of processing enzymes.

This disrupts the transition from procollagen to mature collagen.

Slide 44 · Failure of propeptide removal disrupts fibrils

COL1A1 / COL1A2 variant

N-propeptide cleavage resisted

Abnormal type I collagen maturation

Weakened fibrillar matrix

The mutation is in the substrate protein, not necessarily the enzyme.

Slide 45 · Dermatosparaxis EDS is a processing-enzyme defect

Autosomal-recessive dermatosparaxis EDS is linked to ADAMTS2.

ADAMTS2 encodes the procollagen N-peptidase required for collagen processing.

An enzyme defect blocks normal cleavage of procollagen.

Its inheritance differs from arthrochalasia despite a shared biochemical step.

Slide 46 · Same biochemical step, different molecular lesions

Arthrochalasia EDS

Collagen substrate is abnormal.

COL1A1 or COL1A2.

Resistant to N-terminal cleavage.

Autosomal dominant.

Dermatosparaxis EDS

Processing enzyme is deficient.

ADAMTS2.

N-peptidase activity is defective.

Autosomal recessive.

Slide 47 · Classical-like EDS involves tenascin X

Classical-like EDS is associated with TNXB variants.

TNXB encodes tenascin X, an extracellular matrix glycoprotein.

Tenascin X interacts with fibrillar collagens I, III and V.

Loss of a collagen-associated protein can mimic a collagen structural disorder.

Slide 48 · Tenascin X links collagen to matrix organization

Collagen molecules operate within a wider extracellular matrix network.

Tenascin X participates in interactions with fibrillar collagen.

Matrix disorganization is another route to connective-tissue laxity.

Tenascin X abnormal

Collagen association altered

Matrix mechanical weakness

Slide 49 · Other 2017 subtypes extend the molecular spectrum

Subtype

Gene(s) listed

Genetic pattern

Periodontal

C1R, C1S

AD

Myopathic

COL12A1

AD / AR

Cardiac-valvular

COL1A2

AR

Brittle cornea

ZNF469, PRDM5

AR

Slide 50 · Rare subtypes implicate additional matrix pathways

Subtype

Genes

Inheritance

Spondylodysplastic

B4GALT7; B3GALT6; SLC39A13

AR

Musculocontractural

CHST14; DSE

AR

Classical-like

TNXB

AR

Kyphoscoliotic

PLOD1; FKBP14

AR

Slide 51 · Skin hyperextensibility reflects reduced resistance

Skin can be stretched beyond the usual range when its collagen framework is weak.

The sign represents altered material properties of the connective tissue.

Its prominence varies by subtype and should not be used as a universal criterion.

Weak dermal collagen

Mechanical traction

Excess extension

Slide 52 · Easy bruising and skin fragility are related findings

Fragile connective-tissue support is vulnerable to minor trauma.

Visible bruising and skin tears can occur disproportionately to injury.

Severity and combination of cutaneous findings vary across EDS types.

Fragile supporting matrix

Minor force

Bruise / skin injury

Slide 53 · Poor wound repair is a direct clinical consequence

Tissue apposition requires collagen that can withstand tension.

In EDS, inadequate tensile strength can cause gaping or difficult-to-repair wounds.

The clinical problem is structural support during healing, not simply slow cell proliferation.

Injury

Tension on wound edges

Difficult approximation

Slide 54 · Joint hypermobility reflects reduced passive stability

Ligaments and connective tissues normally limit joint range.

Weak connective-tissue support permits excessive motion.

Instability predisposes to recurrent subluxation or dislocation.

Ligament laxity

Excessive excursion

Joint instability

Slide 55 · Dislocation risk links anatomy to functional effects

Abnormal joint range does not necessarily imply functional benefit.

Loss of passive mechanical restraint increases susceptibility to instability.

Repeated dislocations can become a dominant clinical complaint.

Joint findings should be interpreted together with skin and systemic manifestations.

Slide 56 · Visceral rupture is a subtype-specific red flag

Vascular EDS

Large artery rupture or dissection.

Colon rupture.

Type III collagen / COL3A1.

Selected nonvascular subtypes

Kyphoscoliotic: Ocular fragility.

Classical: Diaphragmatic hernia reported.

These patterns differ from arterial/intestinal rupture.

Slide 57 · Clinical assessment must look beyond hypermobility

Characterize skin stretchability, fragility, bruising and wound history.

Ask about recurrent joint dislocations and family history.

Identify arterial, bowel or ocular complications suggesting higher-risk forms.

Use the combined phenotype to select appropriate confirmatory evaluation.

Slide 58 · Genotype, mechanism and organ risk must be integrated

Example

Primary mechanism

Distinguishing consequence

Classical EDS

Type V collagen abnormalities

Skin / wound fragility

Vascular EDS

Type III collagen abnormalities

Arterial / bowel rupture

Kyphoscoliotic EDS

Lysyl hydroxylase deficit

Reduced collagen stability; Ocular risk

Arthrochalasia EDS

Type I procollagen processing resistance

Defective collagen maturation

Dermatosparaxis EDS

Procollagen N-peptidase deficiency

Defective collagen maturation

Slide 59 · A phenotype-first diagnostic pathway avoids overcalling

Clinical skin + joint findings

Screen for visceral / vascular red flags

Map candidate subtype

Select molecular evaluation

A clinical pattern raises suspicion; Subtype confirmation depends on the relevant evidence.

Slide 60 · Vascular EDS merits molecular confirmation

GeneReviews identifies pathogenic or likely pathogenic COL3A1 variants as establishing vascular EDS.

Arterial, intestinal or family-history clues warrant targeted suspicion.

A variant of uncertain significance alone does not confirm or exclude the diagnosis.

Molecular testing should be interpreted in a genetics-informed clinical assessment.

Slide 61 · Interpreting negative or ambiguous testing

A negative result for one gene does not establish an alternative EDS subtype.

Hypermobile EDS has no established single molecular diagnostic gene in the 2017 framework.

An uncertain variant is not equivalent to a pathogenic variant.

Reassess phenotype, test scope and competing disorders when findings conflict.

Slide 62 · Marfan syndrome is an important differential

Ehlers–Danlos syndromes

Core tissue defect involves collagen pathways / matrix proteins.

Skin fragility and joint hypermobility can dominate.

Specific EDS forms threaten bowel and arteries.

Marfan syndrome

Linked to FBN1 / fibrillin.

Skeletal, ocular and cardiovascular manifestations dominate.

Aortic root disease is a major concern.

Slide 63 · Other collagen-related diseases differ by target tissue

EDS

Skin, ligaments, joints and selected viscera.

Collagen structure, maturation or extracellular organization.

Distinct phenotypes and inheritance patterns.

Other disorders

Osteogenesis imperfecta: Particularly skeletal fragility.

Alport syndrome: Collagen-associated renal / auditory disease.

Epidermolysis bullosa: Skin separation from adhesion defects.

Slide 64 · Clinical case: Skin and joint phenotype

CLINICAL PRESENTATION

A patient has markedly stretchable, fragile skin, bruises after minor trauma, and recurrent joint dislocation. Minor cuts produce wide, difficult-to-close wounds.

Which pathophysiologic defect best explains the cutaneous and joint findings?

Deficient tensile integrity of collagen-rich connective tissues. A classical EDS pattern is plausible; Clinical findings alone do not establish a gene.

Slide 65 · Clinical case: Suspected vascular EDS

CLINICAL PRESENTATION

A young adult develops a spontaneous arterial complication. Examination shows easy bruising, but the skin is not strikingly hyperextensible.

Does the absence of pronounced skin hyperextensibility argue against all forms of EDS?

No. Vascular EDS can lack marked skin hyperextensibility. COL3A1-associated type III collagen disease should be considered, followed by appropriate genetics assessment.

Slide 66 · Clinical case: Two different processing defects

CLINICAL PRESENTATION

Two inherited EDS-like disorders affect collagen N-terminal processing. In one the procollagen substrate resists cleavage; In the other the cleavage enzyme is deficient.

Predict the genes and inheritance categories.

Arthrochalasia: COL1A1/COL1A2, autosomal dominant. Dermatosparaxis: ADAMTS2, autosomal recessive.

Slide 67 · Four molecular pathways to tissue fragility

Collagen chain defect → unstable multimer

PLOD1 defect → poor hydroxylation

ADAMTS2 defect → failed cleavage

TNXB defect → matrix disorganization

Different mutations converge on loss of connective-tissue strength.

Slide 68 · High-yield distinctions for examination and practice

Question

High-yield distinction

Is EDS one disorder?

No: Clinically and genetically heterogeneous syndrome family.

Why hypermobility and stretchy skin?

Reduced strength of collagen-rich supporting tissues.

What marks vascular EDS?

Type III collagen abnormality and arterial / intestinal fragility.

Why two inheritance patterns?

Structural dominant-negative effects versus recessive loss of enzyme / matrix function.

Is hypermobile EDS gene-known?

No established causative gene in the 2017 scheme.

Slide 69 · References and classification scope

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 5, pp 130–131; Table 5.5.

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026. Chapter 1, Fig. 1.17 (collagen biosynthesis).

Byers PH. Vascular Ehlers-Danlos Syndrome. GeneReviews. Updated 2025-04-10.

Ehlers-Danlos Support UK. The types of Ehlers-Danlos syndrome. Reviewed 2026-08-29.

Subtype organization follows the textbook’s 2017 classification; changes under development for 2026 are not assumed or retroactively attributed to Robbins.