Genetics of Achondroplasia and Osteogenesis Imperfecta

Achondroplasia

• A common cause of dwarfism, resulting from impaired cartilage proliferation in growth plates
• Due to an activating mutation in fibroblast growth factor receptor 3 (FGFR3)
• Autosomal dominant inheritance
• Overexpression of FGFR3 inhibits growth
• Most mutations are sporadic, but some are linked to increased paternal age
• Characterized by short extremities, but normal-sized head and chest
• Intramembranous bone formation unaffected; long bone growth via endochondral ossification impaired
• Intramembranous bone formation does not involve cartilage precursor and forms flat bones (e.g., skull)
• Mental function, lifespan, and fertility are normal

Osteogenesis Imperfecta

• Congenital disorder causing weak bones due to defects in collagen type I synthesis
• Autosomal dominant inheritance is most common
• Characterized by multiple fractures (can mimic child abuse but bruising is absent)
• Presence of blue sclera (thinning of sclera showing underlying choroidal veins)
• Often associated with hearing loss due to fragile middle ear bones

Osteopetrosis

• Inherited disorder affecting bone resorption, leading to abnormally thick, heavy bones prone to fracture
• Poor osteoclast function is the underlying cause
• Genetic variants impacting carbonic anhydrase II (a critical enzyme for bone resorption) can cause this condition
• Often characterized by bone fractures, anemia, thrombocytopenia, leukopenia, and extramedullary hematopoiesis
• Visual and auditory impairments can occur due to cranial nerve compression
• Symptoms can include hydrocephalus and renal tubular acidosis
• Treatment may include bone marrow transplant

Rickets/Osteomalacia

• Defective mineralization of osteoid (the bone matrix) leading to abnormal bone formation.
• Caused by vitamin D deficiency, impacting calcium and phosphate absorption.
• Vitamin D is produced in skin upon exposure to sunlight (primary source) and consumed through the diet;
• Active vitamin D increases calcium and phosphate reabsorption in kidney and absorption in intestines to strengthen bones. Deficiency leads to abnormal bone mineralization
• Symptoms in children (rickets) are often noticeable by 1 year of age and can include pigeon breast deformity, frontal bossing, rachitic rosary, bowing of the legs
• Symptoms in adults (osteomalacia) include weak bones that easily fracture
• Diagnosis may involve assessing serum calcium, serum phosphate, parathyroid hormone (PTH), and alkaline phosphatase levels

Osteoporosis

• Characterized by reduced trabecular bone mass, leading to porous bones and increased fracture risk
• Risk factors include genetic predisposition, diet, exercise, and menopause
• Peak bone mass is achieved typically by age 30, after which gradual bone loss occurs.

Paget's Disease of Bone

• Imbalance between osteoclast and osteoblast function affecting bone remodeling
• Resulting in unusually thick and brittle bone often localized in one or more areas of the skeleton.
• Characterized by microfractures causing bone pain, enlarged hat size, hearing loss, and potential for high-output cardiac failure
• Biopsy of affected bone will reveal a characteristic 'mosaic' pattern of lamellar bone.
• Treatable through calcitonin and bisphosphonates.

Avascular (Aseptic) Necrosis

• Ischemic necrosis of bone and marrow often due to reduced blood supply
• Associated with trauma or fracture, use of steroids, conditions like sickle cell anemia, and caisson disease
• Complications include osteoarthritis and fractures

Explore the genetic mechanisms and characteristics of Achondroplasia and Osteogenesis Imperfecta. This quiz delves into the inheritance patterns, physical features, and underlying causes of these conditions. Test your understanding of these important genetic disorders.