Congenital diseases of bone

1. Terminology

• Dysostoses: developmental abnormalities from localized problems in mesenchymal cell migration / condensation formation.
• Aplasia: congenital absence of a digit or rib.
• Dysplasia: mutations interfering with bone or cartilage growth or matrix maintenance (NOTE: here dysplasia is NOT pre-cancerous).

2. Osteogenesis Imperfecta (Brittle Bone Disease)

Definition

• Group of hereditary (autosomal dominant) disorders.
• Defective synthesis of type I collagen.

Pathogenesis

• Mutations in genes coding for α1 or α2 collagen chains → disruption of intact triple helix → premature degradation.

Morphology

• Fundamental abnormality: too little bone (osteopenia).
• → Extreme skeletal fragility.

Four Subtypes

Type	Severity	Features
Type I	Mild	Normal lifespan; modestly ↑ fracture susceptibility in childhood
Type II	Lethal	Fatal pre/post-partum — multiple in-utero fractures, respiratory failure
Type III	Severe	Enough but deformed collagen; mild Sx at birth, progressive deformity
Type IV	Moderate	Collagen quantity + quality inadequate

Clinical Features

Skeletal

• Too little bone: cortical thinning, attenuated trabeculae.
• Short stature.
• ↑ Fractures (often after minor trauma).

Extraskeletal

• Blue sclera: ↓ collagen → transparent sclera → visible choroid.
• Hearing loss: middle-ear bone abnormalities (otosclerosis).
• Dental imperfections: dentin deficiency → small, misshapen, translucent teeth (dentinogenesis imperfecta).

3. Achondroplasia

Definition

• Most common skeletal dysplasia → affects all bones formed from cartilaginous framework (endochondral ossification).
• Major cause of dwarfism.

Pathogenesis

• Point mutation in FGFR-3 (fibroblast GF receptor 3) → constitutive activation → inhibition of chondrocyte proliferation → epiphyseal growth plate expansion suppressed.
• Autosomal dominant; heterozygotes affected (homozygous = lethal).
• Most cases sporadic (new mutations); ↑ risk with advanced paternal age.

Morphology

• Shortening of proximal extremities (rhizomelic).
• Bowing of legs.
• Lordotic (sway-back) posture.
• Short extremities with normal-sized head + chest.
• Normal intelligence + lifespan.

4. Osteopetrosis (Marble Bone Disease, Albers-Schönberg)

Definition

• Genetic disorder of reduced osteoclast-mediated bone resorption → defective bone remodeling.
• NOT to be confused with osteoporosis.

Pathogenesis

• Affected bone is very dense + stone-like but paradoxically fragile (like chalk).
• 4 variants; one due to carbonic anhydrase II deficiency (CA II required for osteoclast H⁺ excretion / acidification of resorption lacunae).

Clinical Findings

• Bone fractures (paradoxical fragility).
• Cranial nerve compression (vision/hearing loss) from foraminal narrowing.
• Recurrent infections + pancytopenia — ↓ marrow space → diminished hematopoiesis → extramedullary hematopoiesis.
• Hydrocephalus from thickened foramen magnum.

Treatment

• Bone marrow transplant → re-populates osteoclast precursors.

5. Summary Table

Disease	Inheritance	Defect	Key features
Osteogenesis imperfecta	AD	Type I collagen (α1/α2 chains)	Brittle bones + blue sclera • hearing loss + dental defects
Achondroplasia	AD	FGFR-3 activating mutation	#1 dwarfism; short proximal limbs, normal head/torso
Osteopetrosis	AR/AD	Osteoclast dysfunction (CA II)	Dense brittle bones; pancytopenia; CN compression; BMT Tx

💡 High-yield: Osteogenesis imperfecta = AD, type I collagen defect (α1/α2); brittle bones + blue sclera + hearing loss + dental imperfections; Type II = lethal in utero. Achondroplasia = AD, FGFR-3 activating mutation, inhibits chondrocyte proliferation → short proximal limbs (rhizomelic) + normal head/torso + lordosis; #1 dwarfism; advanced paternal age. Osteopetrosis = osteoclast dysfunction (CA II deficiency) → dense brittle bones, pancytopenia, cranial nerve compression, hydrocephalus; Tx = BMT.