Ehlers-Danlos USMLE Question: Type V vs III Collagen

Hyperextensible skin, joint hypermobility, easy bruising and wide, thin "cigarette-paper" scars in a patient with an affected parent point to classic Ehlers-Danlos syndrome (EDS), an autosomal dominant type V collagen defect (COL5A1 or COL5A2). Swap the stretchy skin for thin, translucent skin and add arterial, colon or uterine rupture, and the answer becomes vascular EDS, an autosomal dominant type III collagen defect (COL3A1). Hypermobile EDS is the most common type but has no known gene, and the enzyme-deficiency types, such as kyphoscoliotic EDS (lysyl hydroxylase), are autosomal recessive.

The vignette

A 19-year-old woman comes to the clinic after her third ankle sprain in a year; she has also dislocated her right shoulder twice. Since childhood she has bruised easily, and minor cuts over her knees and shins healed as wide, thin, shiny scars. Her skin is soft and velvety, stretches well beyond normal and snaps back when released, and she can bend both thumbs back to touch her forearms. Her mother has the same skin and scars. Her height, eye examination, hearing and cardiac examination are normal, she has never broken a bone, and she eats a varied diet. Which of the following is most likely defective in this patient?

A. Fibrillin-1 B. Lysyl hydroxylase C. Lysyl oxidase D. Prolyl hydroxylase E. Type I collagen F. Type III collagen G. Type IV collagen H. Type V collagen

Correct answer: H. Type V collagen

Skin hyperextensibility with atrophic scarring and generalized joint hypermobility are the two major criteria for classic EDS in the 2017 international classification. Most patients carry a heterozygous variant in COL5A1 or COL5A2, the genes for type V collagen; a specific COL1A1 variant (c.934C>T) rarely causes the same picture. Type V collagen co-assembles with type I collagen and sets the diameter of the fibrils, so functional haploinsufficiency leaves skin and connective tissue built from abnormal fibrils. Inheritance is autosomal dominant: about half of patients have an affected parent, as here, and half have a new variant. Velvety skin and molluscoid pseudotumors complete the picture; mitral valve prolapse and aortic root dilation can occur but are rarely clinically significant.

Why every other choice is wrong

A. Fibrillin-1 (Marfan syndrome). FBN1 on chromosome 15, autosomal dominant; fibrillin microfibrils normally keep TGF-β in check. Look for tall stature with long limbs and arachnodactyly, pectus deformity, lenses displaced upward and temporally, and aortic root dilation or dissection. Stretchy skin with atrophic scars is not Marfan, and her height and eyes are normal; the full picture is in Marfan syndrome for Step 1.

B. Lysyl hydroxylase (kyphoscoliotic EDS). PLOD1 encodes lysyl hydroxylase 1, the vitamin C–dependent enzyme in the rough ER that hydroxylates lysine so that stable cross-links can form later. Its deficiency causes kyphoscoliotic EDS: congenital hypotonia, early-onset kyphoscoliosis, joint hypermobility with dislocations, fragile sclerae and arterial rupture, with a markedly raised urinary deoxypyridinoline-to-pyridinoline ratio (about 6.0 vs 0.2 in controls). It is autosomal recessive, so an affected mother and daughter argue against it, and she has neither hypotonia nor scoliosis.

C. Lysyl oxidase (Menkes disease, copper deficiency). Lysyl oxidase is the extracellular, copper-dependent enzyme that forms the covalent cross-links. Menkes disease, an X-linked recessive defect in the ATP7A copper transporter, lowers its activity: an infant boy with sparse, kinky or steely hair, hypotonia, seizures from 2–3 months of age, loose skin and tortuous vessels, usually fatal by age 3. A healthy young woman with a dominant family history doesn't fit.

D. Prolyl hydroxylase (scurvy). Vitamin C is the cofactor for prolyl and lysyl hydroxylase, so scurvy is an acquired hydroxylation defect: perifollicular hemorrhages, corkscrew hairs, swollen and bleeding gums, poor wound healing and hemarthrosis, typically with alcohol use disorder, a restricted diet or old age. Her problem is lifelong, inherited and hypermobile, and her diet is varied; the step-by-step logic is in this scurvy and collagen breakdown.

E. Type I collagen (osteogenesis imperfecta). COL1A1 or COL1A2 variants cause most osteogenesis imperfecta, usually autosomal dominant: fractures with little trauma, blue sclerae, hearing loss in up to 70% and dentinogenesis imperfecta. She has never had a fracture and hears normally. Type I collagen genes also turn up in rare EDS types: arthrochalasia and cardiac-valvular EDS, and the COL1A1 form of classic EDS.

F. Type III collagen (vascular EDS). COL3A1, autosomal dominant. Type III collagen is a major structural collagen of skin, lungs, intestinal walls and blood vessel walls, so vascular EDS brings thin, translucent skin with visible veins, extensive bruising, and rupture of arteries, the sigmoid colon or the pregnant uterus. It becomes the answer when the stem adds a young relative's sudden arterial death, a spontaneous colon perforation or a carotid-cavernous fistula; this patient's skin is stretchy and velvety, not translucent, and no one in the family has ruptured anything.

G. Type IV collagen (Alport syndrome). Type IV collagen builds basement membranes. Alport syndrome is X-linked (COL4A5) in 80–85% of cases and presents with hematuria progressing to kidney failure, sensorineural hearing loss and anterior lenticonus, with a split, "basket-weave" glomerular basement membrane. Nothing here involves the kidney, ear or lens.

Change one detail, change the answer

The 2017 international classification recognized 13 EDS types (StatPearls now lists 14). Rule of thumb: the testable collagen-chain types are autosomal dominant, while the enzyme-deficiency types are autosomal recessive.

Where each defect sits in collagen synthesis

The structural chain defects sit outside these enzyme steps: type I (osteogenesis imperfecta), type III (vascular EDS), type IV (Alport syndrome) and type V (classic EDS).

Vascular EDS: the type that kills

• Genetics: COL3A1, autosomal dominant; about half of cases arise from a new variant.
• Red flags: arterial aneurysm, dissection or rupture at a young age; spontaneous intestinal perforation, most often of the sigmoid colon; uterine rupture during pregnancy; carotid-cavernous sinus fistula; or a family history of vascular EDS. These features prompt COL3A1 testing, and a pathogenic COL3A1 variant confirms the diagnosis.
• Outlook: median survival is about 50 years. Deaths in the first two decades are almost always from arterial rupture or dissection, and each pregnancy carries about a 5% risk of maternal death.
• Management: avoid conventional arteriography, collision sports and heavy lifting; check blood pressure regularly and image the arteries noninvasively (ultrasound, CT or MR angiography). Celiprolol, a beta-blocker, has shown benefit in reducing arterial events.

Diagnosing and managing EDS

The Beighton score grades generalized joint hypermobility out of 9. A score of 5 or more is positive in adults up to age 50; the hypermobile EDS criteria accept 4 or more after age 50, and 6 or more is used in children. Molecular testing confirms every type except hypermobile EDS, which remains a clinical diagnosis. Care is supportive: physical therapy, avoiding contact sports and high-impact activity, tension-free layered wound closure, and a baseline echocardiogram in classic EDS.

Exam traps

• Hydroxylase vs oxidase: lysyl hydroxylase works in the rough ER with vitamin C (scurvy, kyphoscoliotic EDS); lysyl oxidase works outside the cell with copper (Menkes disease).
• Classic vs vascular: stretchy, velvety skin with atrophic scars means type V; thin, translucent skin with ruptures means type III.
• No arteriogram in vascular EDS: conventional angiography can injure the vessel, so use noninvasive imaging.
• Scurvy is acquired: bleeding gums, perifollicular hemorrhage and a poor diet point to vitamin C, not a gene.
• Marfan vs vascular EDS: both dissect, but Marfan brings tall stature, arachnodactyly and upward lens dislocation.
• Most common is not most testable: hypermobile EDS accounts for most diagnoses but has no known gene; the named collagen answers belong to classic (V) and vascular (III) EDS.

Key takeaways

• Classic EDS: type V collagen (COL5A1/COL5A2), autosomal dominant; hyperextensible skin, atrophic scars, hypermobility.
• Vascular EDS: type III collagen (COL3A1), autosomal dominant; thin, translucent skin; arterial, sigmoid colon and uterine rupture; median survival about 50 years.
• Hypermobile EDS: most common, no known gene, diagnosed clinically with help from the Beighton score.
• Kyphoscoliotic (lysyl hydroxylase) and dermatosparaxis (ADAMTS2) EDS are autosomal recessive.
• Look-alikes: fibrillin-1 (Marfan), type I (osteogenesis imperfecta), type IV (Alport), vitamin C (scurvy), lysyl oxidase and copper (Menkes).

Sources

• Vascular Ehlers-Danlos Syndrome — GeneReviews, NCBI Bookshelf
• Classic Ehlers-Danlos Syndrome — GeneReviews, NCBI Bookshelf
• Ehlers-Danlos Syndromes — StatPearls, NCBI Bookshelf
• Hypermobile Ehlers-Danlos Syndrome — GeneReviews, NCBI Bookshelf
• Ehlers-Danlos syndrome — MedlinePlus Genetics
• Biochemistry, Collagen Synthesis — StatPearls, NCBI Bookshelf