MS 3.docx

MS 3 Hereditary and Developmental “Congenital” Disorders Pathological changes/alterations/growth defects to bone may be due to 1. hereditary or developmental errors 2. disorders of metabolism or endocrine function 3. bacterial or nonbacterial inflammation 4. degeneration and necrosis 5. primary o...

MS 3 Hereditary and Developmental “Congenital” Disorders Pathological changes/alterations/growth defects to bone may be due to 1. hereditary or developmental errors 2. disorders of metabolism or endocrine function 3. bacterial or nonbacterial inflammation 4. degeneration and necrosis 5. primary or metastatic tumor formation Congenital abnormalities frequently result from inherited mutations and first manifested during the earliest stages of bone formation (typically, endochondral stuff not keeping pace chronologically) can result from dysostosis: localized defects in the migration and condensation of mesenchyme result from defects in the formation of mesenchymal condensations and their differentiation in to the cartilage models i.e. complete absence of a bone or digit, or extra bones or digits dysplasia: a global disorganization of bone and/or cartilage arise from mutations in genes that control development or remodeling of the entire skeleton There are more than 350 skeletal dysostoses and dysplasias, and most are very rare. Diseases of Skeletal Growth 4 categories: Failures in formation (regardless of etiology) Abnormalities in the quality of the tissue formed Insufficient growth due to errors in the epiphyseal mechanisms Abnormal growth due to the effect of extra-skeletal substances on the epiphyseal mechanism. Radiological appearance is more helpful than the histological patterns in establishing a diagnosis Congenital anomalies range from minor absences of terminal phalanges of fingers to complete failure of development of a limb some genetic, some random Most common anomaly: Absent portion or all of a bone Second: failure in segmentation to form a joint (creates an entire big bone) the cartilaginous model fails in the embryo to develop the line of degeneration that marks the location of a subsequent joint cleft ossification centers appear, there is no joint formation ossification centers coalesce a solid mass of bone replacing the site of the joint Bone is smaller than normal deformity, stiffness other common anomaly: formation of extra bones, joint, or even entire structures Adjacent tissue is always normal Osteogenesis imperfecta (Type I collagen disorder) formation of osseous tissue is deficient and imperfect most common inherited disorder of CT – autosomal dominant TYPE I collagen disorder – tissues rich in type I collagen (bone, joints, eyes, ears, skin, and teeth) Affects Alpha 1, 2 chains “too little bone, resulting in extreme skeletal fragility” thinness and fragility of the entire skeleton Slate-blue sclerae: decreased collagen renders the sclerae translucent – seeing the choroid stuff progressive deafness: middle ear ossicles (bone) forming incorrectly dentin defect: collagen problems with dentin skin thinning joint hyperlaxity Type 1: mild (at birth) osteogenesis imperfecta tarda: fracturing begins some years after birth normal lifespan Type 2: severe numerous fractures are evident at birth osteogenesis imperfecta fetalis: stillborn limbs short, crooked (deformity of long bones) enlarged head soft neurocranial bones, yielding to pressure – multiple small bones as part of whole ribs, vertebrae fractured Histo: Meager osteoblastic activity – little osseous tissue laid down on cartilage sparse, thin “primitive” trabecular bone thin and spongy cortex bone immature woven fiber bone No pathology in periosteum except slightly less osteoblasts than usual Achondroplasia (dwarfism- a skeletal dysplasia) most common skeletal dysplasia major cause of dwarfism Autosomal dominant disorder resulting from retarded cartilage growth (paternal allele) shortened proximal extremities trunk is normal length enlarged head with a bulging forehead a visible depression of the root of the nose NOT associated with longevity, intelligence, or reproductive status Osteopetrosis (“marble bone disease”) bone stone due to impaired osteoclasts stonelike bone – abnormally brittle and fracture easily, like a piece of chalk reduced bone resorption (osteoclastic) and diffuse symmetric skeletal sclerosis resulting from impaired osteoclasts most from faulty acidification of the osteoclast resorption pit, which is required for the dissolution of calcium hydroxyapatite with the matrix lack medullary canal, ends of the long bones are bulbous and mis-shapen small neural foramina that compress nerves Trabecular bone fills medullary cavity and hematopoietic marrow has no room (normally trabeculation is removed here) Severe infantile osteopetrosis (autosomal recessive and often fatal) Mild is autosomal dominant, may not be detected until adolescence or adulthood These individuals may also have mild cranial nerve deficits and anemia Metabolic Osseous Disorders Osteopenia and continues to become Osteoporosis Osteopenia: decreased bone mass (1 to 2.5 below normal bone mass) Osteoporosis: severe osteopenia with significant risk of FRACTURE (>2.5 below normal) Localized or generalized Primary type (most common) Senile Postmenopausal Secondary occur due to: endocrine disorders (hyperthyroidism) GI disorders (malnutrition) drugs (corticosteroids) Pathogenesis Peak bone mass in young adulthood Influenced by: AGE-RELATED CHANGES PHYSICAL ACTIVITY REDUCED GENETIC FACTORS CALCIUM NUTRITIONAL STATE HORMONAL INFLUENCES Senile osteoporosis low-turnover osteoporosis (not creating new bone) osteoblasts have reduced response to growth factors diminished capacity to make new bone Due to: Decrease physical activity contributes (Weight training better NOT repetitive endurance Calcium deficiency Increased PTH (parathyroid hormone) Reduced vitamin D Postmenopausal Decade after menopause: yearly reductions in bone mass (2% of cortical bone and 9% of medullary bone) 40% of postmenopausal women are affected by osteoporosis Estrogen deficiency decreased estrogen increases secretion of inflammatory cytokines by monocytes. Cytokines stimulate osteoclast recruitment Decreased estrogen levels after menopause, increases bone resorption and formation Bone formation cannot keep up with the resorption In postmenopausal osteoporosis the increase in osteoclast activity affects mainly bones or portion so bone that have increase surface area, such as the cancellous compartment of vertebral bodies. The trabecular plates become perforated, thinned and lose their interconnections, leading to progressive microfractures and eventual vertebral collapse The hallmark of osteoporosis is histologically decrease quantity of normal bone Clinical manifestations based on bone involved: Vertebral fractures (thoracic and lumbar) multiple lead to significant loss of height and various deformities, including lumbar lordosis and kyphoscoliosis immobility following fractures of the femoral, neck, pelvis, or spine pulmonary embolism and pneumonia Not detected through radiographs until 30 % - 40 % of the bone mass is lost Not detected through blood levels of calcium, phosphorus, and alkaline phosphatase Special radiographic techniques measure bone density: dual-energy radiographic absorptiometry quantitative computed tomography (CT) Prevention and treatment: exercise Calcium and vitamin D intake Medications to decrease resorption Major challenge in pharmacotherapy: inability to uncouple bone formation and resorption Rickets and Osteomalacia (Vit D deficiency) Vit D deficiency or abnormal metabolism Rickets: childhood, impaired deposition of bone in the growth plates Osteomalacia: adult, impairment remodeling (mineralization) causing accumulation of unmineralized matrix Hyperparathyroidism (PTH increases blood calcium) parathyroid gland secretes PTH in response to low calcium in the blood. PTH facilitates the synthesis of vitamin D and calcitrol in the kidneys á PTH -> á osteoclastic activity – Leading to bone resorption and osteopenia Although the entire skeleton is affected, the osteopenia in some bones (like phalanges) is more conspicuous radiographically PTH important in calcium homeostasis PTH elevation in serum calcium, which normally inhibits further PTH production excessive or inappropriate levels of PTH from: Primary hyperparathyroidism: altered parathyroid secretion Secondary hyperparathyroidism: from underlying renal disease Untreated primary hyperparathyroidism is symptomatic has 3 interrelated skeletal abnormalities: Osteoporosis Generalized but most severe in phalanges, vertebrae and proximal femur Dissecting osteitis: osteoclasts may tunnel into and dissect centrally along the length of the traveculae, creating the appearance of railroad tracks marrow spaces around the affected surfaces are replaced by fibrovascular tissue. -- appearing radiologically as a decrease in bone mass Brown tumors Bone loss micro-fracturing and secondary hemorrhages influx of macrophages & mass of reactive tissue ingrowth Brown color from vascularity, hemorrhage, etc Osteitis fibrosa cystica cystica degeneration less common b/c early hyperparathyroidism diagnosis/intervention Restoring PTH levels will reverse bone changes Secondary hyperparathyroidism is mild than primary hyperparathyroidism (severe)