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.