Skeletal dysplasias

Skeletal Dysplasias: Overview - Blueprint for Bones

• Heterogeneous group of disorders causing abnormal bone & cartilage growth, leading to disproportionate short stature.
• Classified by affected limb segment:
  • Rhizomelic: Proximal (humerus, femur)
  • Mesomelic: Middle (radius/ulna, tibia/fibula)
  • Acromelic: Distal (hands, feet)
  • Micromelic: Entire limb is shortened
• Key genetic culprits: Collagen (COL1A1) & FGFR3 gene mutations.

⭐ Thanatophoric dysplasia, the most common lethal skeletal dysplasia, is linked to FGFR3 gene mutations.

Achondroplasia - The King of Dwarfs

• Genetics & Patho: Most common non-lethal skeletal dysplasia. Autosomal Dominant, but >80% of cases are de novo mutations (advanced paternal age is a risk factor).
  • Cause: Gain-of-function mutation in the FGFR3 gene on chromosome 4p16.3.
  • Effect: Inhibits chondrocyte proliferation in epiphyseal growth plates, impairing endochondral ossification.
• Clinical Features:
  • Limbs: Rhizomelic (proximal) shortening. Genu varum (bow-legs). Trident hand (persistent space between 3rd & 4th digits).
  • Craniofacial: Macrocephaly with frontal bossing & midface hypoplasia.
  • Spine: Thoracolumbar kyphosis, exaggerated lumbar lordosis.
• Radiology:
  • Spine: Caudal narrowing of interpedicular distance.
  • Pelvis: "Champagne-glass" pelvic inlet.

⭐ Foramen magnum stenosis is the most serious complication in infancy, potentially causing hydrocephalus, sleep apnea, or sudden infant death.

Osteogenesis Imperfecta - Brittle Bone Blues

• Patho: Autosomal Dominant defect in Type I collagen (COL1A1/A2 genes).
• Classic Triad:
  • Multiple recurrent fractures with minimal trauma.
  • Blue sclerae.
  • Hearing loss (conductive/mixed).
• Other signs: Dentinogenesis imperfecta (opalescent teeth), joint hypermobility, short stature.
• 📌 Mnemonic (BITE): Bones (fractures), I (Eyes - blue sclera), Teeth (dentinogenesis imperfecta), Ear (hearing loss).
• Types (Sillence):
  • Type I: Mildest, most common.
  • Type II: Lethal perinatal.
  • Type III: Progressive deforming.
• Rx: Bisphosphonates (Pamidronate), physiotherapy.

⭐ Exam Pearl: The characteristic blue sclera is due to the translucency of the thin scleral collagen, revealing the color of the underlying choroidal veins.

Other Key Dysplasias - Rogues' Gallery of Bones

• Cleidocranial Dysostosis

  • Gene: RUNX2 (AD)
  • Features: Aplastic/hypoplastic clavicles (patient can appose shoulders), delayed fontanelle closure, wormian bones, supernumerary teeth.
  • 📌 Mnemonic: CCD → Clavicles, Cranium, Dentition.

• Diastrophic Dysplasia

  • Gene: SLC26A2 (AR)
  • Features: "Hitchhiker thumb" (abducted thumb), cauliflower ear, severe clubfoot, kyphoscoliosis.

• Spondyloepiphyseal Dysplasia (SED)

  • Gene: COL2A1 (Type II Collagen)
  • Features: Affects spine & epiphyses → platyspondyly (flat vertebrae), short trunk dwarfism. Often associated with myopia & retinal detachment.

⭐ Diastrophic Dysplasia is often called "hitchhiker's dysplasia" due to the characteristic abducted, retroflexible thumb, a key diagnostic clue.

High-Yield Points - ⚡ Biggest Takeaways

• Achondroplasia, the most common non-lethal dysplasia, is due to an FGFR3 gene mutation, presenting with trident hands.
• Thanatophoric dysplasia, the most common lethal form, is also an FGFR3 mutation, often showing a cloverleaf skull.
• Osteogenesis Imperfecta is a Type I collagen defect, leading to blue sclera, fractures, and hearing loss.
• Osteopetrosis (“marble bone disease”) involves defective osteoclast function, causing dense, brittle bones and pancytopenia.
• Look for hitchhiker thumb in Diastrophic Dysplasia.