Bit · Biochem
Marfan vs Homocystinuria vs Ehlers-Danlos
Three connective-tissue disorders that all give a tall, thin patient with joint hypermobility. The pivot is lens direction, mental status, and whether vessels rupture.
Mechanism
All three involve defects in extracellular matrix proteins, producing tall stature, long limbs, and joint hypermobility. They split on the specific protein and the additional features:
- Marfan syndrome — autosomal dominant mutation in fibrillin-1 (FBN1). Fibrillin is the scaffold for elastin, so elastic tissues fail: aortic root, lens zonules, lungs. Lens dislocation is upward and temporal. Major concern: aortic root dilation → dissection or rupture. Mitral valve prolapse common. Tall, long limbs (arm span > height), arachnodactyly, pectus deformity, scoliosis, spontaneous pneumothorax. Normal intelligence.
- Homocystinuria — autosomal recessive, most commonly cystathionine β-synthase deficiency. Homocysteine accumulates → damages endothelium and crosslinking of connective tissue. Lens dislocation is downward and nasal. Intellectual disability. Hypercoagulable — thrombosis, stroke, MI in young patients. Marfanoid habitus + osteoporosis + ectopia lentis. Treat: methionine restriction, pyridoxine (B6), folate, B12.
- Ehlers-Danlos syndrome (EDS) — group of disorders affecting collagen synthesis. Hyperextensible skin, joint hypermobility, easy bruising. Multiple types; vascular type (Type IV, defect in type III collagen) is the most dangerous — arterial rupture, organ rupture (uterus, bowel), berry aneurysms. Classic type is the joint/skin form.
Differentiator Table
| Marfan | Homocystinuria | Ehlers-Danlos (Vascular type) | |
| Inheritance | Autosomal dominant | Autosomal recessive | Autosomal dominant |
| Defective protein | Fibrillin-1 (FBN1) | Cystathionine β-synthase (most common) | Type III collagen (vascular type); type V collagen (classic) |
| Lens dislocation direction | UPWARD / temporal | DOWNWARD / nasal | Not typically |
| Intelligence | Normal | Intellectual disability (untreated) | Normal |
| Vascular risk | Aortic root dilation → dissection / rupture | Arterial AND venous thrombosis; early MI/stroke | Arterial rupture (sudden death); berry aneurysms |
| Body habitus | Tall, long limbs (arm span > height), arachnodactyly, pectus, scoliosis | Marfanoid; osteoporosis, fair complexion, malar flush | Joint hypermobility, hyperextensible skin, easy bruising |
| Treatment | β-blockers / ARBs to slow aortic dilation; surgical repair | Methionine restriction; B6, B9, B12; aspirin | Avoid contact sports; surgical avoidance; manage vascular events |
The Pivot
Three questions:
- Direction of lens dislocation? Up → Marfan. Down → Homocystinuria.
- Intellectual disability + thrombotic events? → Homocystinuria.
- Hyperextensible skin + hypermobile joints + arterial rupture risk? → EDS (vascular type).
NBME loves the lens-direction split — memorize it.
NBME-Style Stem
A 17-year-old tall, thin boy presents after a stroke. He has bilateral downward and medial lens dislocations on slit-lamp examination. He has fair skin, malar flush, and mild intellectual disability. Plasma homocysteine is markedly elevated. Which of the following is the most likely diagnosis?
Concept Anchor
Three lookalikes — same tall, thin, hypermobile body. Marfan dislocates the lens up and dilates the aorta; homocystinuria dislocates the lens down, scrambles the brain, and clots the arteries; EDS overstretches the skin and ruptures the arteries. The lens direction is the cleanest splitter.