MS 3 Hereditary and Developmental Disorders PDF

MS 3 Hereditary and Developmental “Congenital” Disorders § Pathological changes/altera0ons/growth defects to bone may be due to 1. hereditary or developmental errors 2. disorders of metabolism or endocrine func0on 3. bacterial or nonbacterial inflamma0on 4. degenera0on and necrosis 5. primary or meta...

MS 3 Hereditary and Developmental “Congenital” Disorders § Pathological changes/altera0ons/growth defects to bone may be due to 1. hereditary or developmental errors 2. disorders of metabolism or endocrine func0on 3. bacterial or nonbacterial inflamma0on 4. degenera0on and necrosis 5. primary or metasta0c tumor forma0on • Congenital abnormali0es o frequently result from inherited muta0ons and first manifested during the earliest stages of bone forma0on (typically, endochondral stuff not keeping pace chronologically) o can result from § dysostosis: localized defects in the migra0on and condensa0on of mesenchyme • result from defects in the forma0on of mesenchymal condensa0ons and their differen0a0on in to the car0lage models • i.e. complete absence of a bone or digit, or extra bones or digits § dysplasia: a global disorganiza0on of bone and/or car0lage • arise from muta0ons in genes that control development or remodeling of the en0re skeleton o There are more than 350 skeletal dysostoses and dysplasias, and most are very rare. Diseases of Skeletal Growth • 4 categories: o Failures in formaGon (regardless of eGology) o AbnormaliGes in the quality of the Gssue formed o Insufficient growth due to errors in the epiphyseal mechanisms o Abnormal growth due to the effect of extra-skeletal substances on the epiphyseal mechanism. • Radiological appearance is more helpful than the histological paMerns in establishing a diagnosis • Congenital anomalies o range from minor absences of terminal phalanges of fingers to complete failure of development of a limb o some gene0c, some random o Most common anomaly: Absent porGon or all of a bone o Second: failure in segmentaGon to form a joint (creates an en0re big bone) § the carGlaginous model fails in the embryo to develop the line of degenera0on that marks the loca0on of a subsequent joint cleQ à ossifica0on centers appear, there is no joint forma0on à ossifica0on centers coalesce à a solid mass of bone replacing the site of the joint § Bone is smaller than normal à deformity, s0ffness o other common anomaly: forma0on of extra bones, joint, or even en0re structures o Adjacent Gssue is always normal Osteogenesis imperfecta (Type I collagen disorder) • forma0on of osseous 0ssue is deficient and imperfect • most common inherited disorder of CT – autosomal dominant • TYPE I collagen disorder – Gssues rich in type I collagen (bone, joints, eyes, ears, skin, and teeth) o Affects Alpha 1, 2 chains à “too liMle bone, resul0ng in extreme skeletal fragility” o thinness and fragility of the en0re skeleton o Slate-blue sclerae: decreased collagen renders the sclerae translucent – seeing the choroid stuff o progressive deafness: middle ear ossicles (bone) forming incorrectly o denGn defect: collagen problems with den0n o skin thinning o joint hyperlaxity • Type 1: mild (at birth) o osteogenesis imperfecta tarda: fracturing begins some years aQer birth o normal lifespan • Type 2: severe o numerous fractures are evident at birth o osteogenesis imperfecta fetalis: s0llborn • limbs short, crooked (deformity of long bones) • enlarged head • soQ neurocranial bones, yielding to pressure – mul0ple small bones as part of whole • ribs, vertebrae fractured • Histo: o Meager osteoblasGc acGvity – li[le osseous Gssue laid down on car0lage o sparse, thin “primiGve” trabecular bone o thin and spongy cortex bone o immature woven fiber bone o 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 resul0ng from retarded carGlage growth (paternal allele) • shortened proximal extremi0es • 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 reproducGve status Osteopetrosis (“marble bone disease”) bone stone due to impaired osteoclasts • stonelike bone – abnormally briMle and fracture easily, like a piece of chalk • reduced bone resorpGon (osteoclas0c) and diffuse symmetric skeletal sclerosis resul0ng from impaired osteoclasts • most from faulty acidificaGon of the osteoclast resorp0on pit, which is required for the dissolu0on of calcium hydroxyapa0te 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 hematopoie0c marrow has no room (normally trabecula0on is removed here) • Severe infanGle osteopetrosis (autosomal recessive and oQen fatal) o Mild is autosomal dominant, may not be detected un0l adolescence or adulthood o These individuals may also have mild cranial nerve deficits and anemia Metabolic Osseous Disorders • Osteopenia and con0nues 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) o Senile o Postmenopausal • Secondary occur due to: o endocrine disorders (hyperthyroidism) o GI disorders (malnutri0on) o drugs (cor0costeroids) • Pathogenesis o Peak bone mass in young adulthood o Influenced by: § AGE-RELATED CHANGES § PHYSICAL ACTIVITY REDUCED § GENETIC FACTORS § CALCIUM NUTRITIONAL STATE § HORMONAL INFLUENCES • Senile osteoporosis o low-turnover osteoporosis (not crea0ng new bone) o osteoblasts have reduced response to growth factors à diminished capacity to make new bone o Due to: § Decrease physical ac0vity contributes (Weight training be[er NOT repe00ve endurance § Calcium deficiency § Increased PTH (parathyroid hormone) § Reduced vitamin D • Postmenopausal o Decade aQer menopause: yearly reducGons in bone mass (2% of cor0cal bone and 9% of medullary bone) o 40% of postmenopausal women are affected by osteoporosis o Estrogen deficiency § decreased estrogen increases secreGon of inflammatory cytokines by monocytes. § Cytokines sGmulate osteoclast recruitment § Decreased estrogen levels aQer menopause, increases bone resorpGon and formaGon § Bone forma0on cannot keep up with the resorp0on o In postmenopausal osteoporosis the increase in osteoclast ac0vity affects mainly bones or por0on so bone that have increase surface area, such as the cancellous compartment of vertebral bodies. o The trabecular plates become perforated, thinned and lose their interconnec0ons, leading to progressive microfractures and eventual vertebral collapse • The hallmark of osteoporosis is histologically decrease quanGty of normal bone • Clinical manifesta0ons based on bone involved: o Vertebral fractures (thoracic and lumbar) à mul0ple lead to significant loss of height and various deformi0es, including lumbar lordosis and kyphoscoliosis o immobility following fractures of the femoral, neck, pelvis, or spine à pulmonary embolism and pneumonia • Not detected through radiographs un0l 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: o dual-energy radiographic absorp0ometry o quanGtaGve computed tomography (CT) • Preven0on and treatment: o exercise o Calcium and vitamin D intake o Medica0ons to decrease resorp0on • Major challenge in pharmacotherapy: inability to uncouple bone formaGon and resorpGon Rickets and Osteomalacia (Vit D deficiency) • • • Vit D deficiency or abnormal metabolism Rickets: childhood, impaired deposiGon of bone in the growth plates Osteomalacia: adult, impairment remodeling (mineraliza0on) causing accumula0on 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 osteoclasGc acGvity – Leading to bone resorp0on and osteopenia Although the en0re skeleton is affected, the osteopenia in some bones (like phalanges) is more conspicuous radiographically PTH important in calcium homeostasis PTH à eleva0on in serum calcium, which normally inhibits further PTH produc0on excessive or inappropriate levels of PTH from: o Primary hyperparathyroidism: altered parathyroid secre0on o Secondary hyperparathyroidism: from underlying renal disease Untreated primary hyperparathyroidism is symptoma0c has 3 interrelated skeletal abnormali0es: o Osteoporosis § Generalized but most severe in phalanges, vertebrae and proximal femur § Dissec0ng ostei0s: osteoclasts may tunnel into and dissect centrally along the length of the traveculae, crea0ng the appearance of railroad tracks § marrow spaces around the affected surfaces are replaced by fibrovascular 0ssue. -appearing radiologically as a decrease in bone mass o Brown tumors § Bone loss à micro-fracturing and secondary hemorrhages à influx of macrophages & mass of reac0ve 0ssue ingrowth § Brown color from vascularity, hemorrhage, etc o Ostei0s fibrosa cys0ca § cys0ca degenera0on § less common b/c early hyperparathyroidism diagnosis/interven0on Restoring PTH levels will reverse bone changes Secondary hyperparathyroidism is mild than primary hyperparathyroidism (severe)