Genetic Disorders of Bone Growth and Formation

ACHONDROPLASIA

• Impaired cartilage proliferation in growth plates, leading to dwarfism
• Caused by activating mutation in fibroblast growth factor receptor 3 (FGFR3), an autosomal dominant trait
• FGFR3 overexpression inhibits growth
• Many mutations are sporadic, linked to increased paternal age
• Clinical features: short extremities, normal head and chest
• Endochondral bone formation (long bones): cartilage matrix formation replaced by bone
• Intramembranous bone formation (flat bones): bone develops without cartilage precursor
• Mental function, lifespan, and fertility are not affected

OSTEOGENESIS IMPERFECTA

• Congenital bone formation defect, resulting in weak bones
• Primarily due to an autosomal dominant defect in collagen type I synthesis
• Clinical features: multiple bone fractures (can mimic child abuse), blue sclera (thinning of collagen), and hearing loss (middle ear easily fractures)

OSTEOPETROSIS

• Inherited bone resorption defect, causing abnormally thick, heavy bones prone to fractures
• Due to poor osteoclast function
• Multiple genetic variants exist; carbonic anhydrase II mutation linked to loss of acidic microenvironment required for bone resorption
• Clinical features: bone fractures, anemia, thrombocytopenia, leukopenia, extramedullary hematopoiesis (marrow replacement), impaired vision and hearing, hydrocephalus, and renal tubular acidosis

RICKETS/OSTEOMALACIA

• Defective mineralization of osteoid (unmineralized bone matrix)
• Osteoblasts produce osteoid that's mineralized with calcium and phosphate to form bone
• Low vitamin D levels cause low serum calcium and phosphate, hindering mineralization
• Vitamin D activation requires 25-hydroxylation by the liver and 1-alpha-hydroxylation by the kidney
• Vitamin D increases calcium and phosphate absorption in the gut, reabsorption in the kidneys, and release from bone
• Vitamin D deficiency is due to decreased sun exposure, poor diet, malabsorption, liver failure, or renal failure
• Rickets (children): abnormal bone mineralization, presenting as pigeon-breast deformity, frontal bossing, rachitic rosary, and bowing of legs
• Osteomalacia (adults): weak bones, increased fracture risk

OSTEOPOROSIS

• Reduction in trabecular bone mass, leading to porous bone and increased fracture risk
• Risk factors: low peak bone mass (achieved by 30), genetic predisposition, poor diet, lack of exercise, and reduced estrogen (e.g., menopause)
• Bone loss accelerates after peak bone mass

AVASCULAR (ASEPTIC) NECROSIS

• Ischemic necrosis of bone and bone marrow
• Causes include trauma, fractures, steroid use, sickle cell anemia, and caisson disease
• Osteoarthritis and fractures are major complications.