MSK Pathology
What caners are associated with paraneoplastic syndrome: Dermatomyositis?
15%-24% of adult patients with dermatomyositis have an associated malignancy: -Adenoacrinomas -Ovarian carcinoma
What is osteoid?
A soft, immature part of the bone matrix that is synthesized by osteoblasts prior to mineralization. Mainly consists of collagen type I. Defective mineralization of osteoid is called osteomalacia.
What is the mechanism by which fractured bones heal?
A. Soon after a fracture is sustained, an extensive blood clot forms in the subperiosteum and soft tissue, as well as in the marrow cavity. The bone at the fracture site is jagged. B. The inflammatory phase of fracture healing is characterized by neovascularization and beginning organization of the blood clot. Because the osteocytes in the fracture site are dead, the lacunae are empty. The osteocytes of the cortex are necrotic well beyond the fracture site, owing to the traumatic interruption of the perforating arteries from the periosteum. C. The reparative phase of fracture healing is characterized by the formation of a callus of cartilage and woven bone near the fracture site. The jagged edges of the original cortex have been remodeled and eroded by osteoclasts. The marrow space has been revascularized and contains reactive woven bone, as does the periosteal area. D. In the remodeling phase, during which the cortex is revitalized, the reactive bone may be lamellar or woven. The new bone is organized along stress lines and mechanical forces. Extensive osteoclastic and osteoblastic cellular activity is maintained.
What are the main causes of avascular necrosis of the bone?
Alcohol abuse Bisphosphonate therapy Corticosteroid administration Sickle Cell Crisis Trauma Chronic atherosclerosis
What are the clinical manifestations of osteitis deformans (paget's disease)?
Also, leontiasis ossea (lion facies) due to enlargement of the craniofacial muscles
What is Becker Muscular Dystrophy?
An X-linked recessive genetic disease typically caused by mutations in the dystrophin gene that leads to dysfunctional protein product, with subsequent degeneration of muscle fibers and progressive proximal muscle weakness. Patients may be ambulatory for part of their adult lives and usually survive past the third decade of life. Mutations and subsequent alterations of the dystrophin protein → partial (Becker MD) or almost complete impairment (DMD) of the protein → disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells and subsequent replacement with connective and fat tissue → muscle appears larger ("pseudohypertrophy")
What is dermatomyositis?
An idiopathic inflammatory myopathy, associated with characteristics dermatologic manifestations Characterized by: 1. deposition of immune complexes of IgG, IgM and compliment components (including the MAC complex(C5b-C9) -The deposit in the walls of capillaries and other blood vessels 2. Due to the deposition of the immune complexes in the vessels, microangiopathy occurs 3. Atrophy to the muscle fibers 4. Perimysial infiltrares of B-cells and CD4+ cells.
What is myotonic dystrophy?
Autosomal dominant multisystem disorder. This is one of the diseases caused by Trinucleotide repeat - Expansion of the CTG triplet repeats in the 3'-noncoding region of the Dystrophia Myotonica protein kinase gene on chromosome 19 -- although the function of this protein is not understood, mutations are implicated in causing myotonic dystrophy. Morphology: Selective atrophy of type 1 muscle fibers Lab Diagnoses: - Glucose intolerance - Increase in serum creatine kinase - Muscle biopsy
What are the tumor and tumor-like conditions that develop in bones with Paget disease (osteitis deformans)
Benign Lesions: -Giant Cell Tumor -Giant Cell Reparative Granuloma -Extraosseous masses of hematopoietic tissue Malignant Lesions: - Sacroma (*Osteosarcoma* or Fibrosarcoma)
What are serum markers for osteoclastic activity and why?
Bone ALP Osteocalcin - this is a glycoprotein that is part of the Bone Matrix. Secreted by osteoblasts to influence bone mineralization Peptides of Collagen Type 1 - Type 1 collagen is the collagen found in bone, so high levels of this would be found in situations where there is high bone turnover
What are the differences in mutation between achondroplasia and thantophoric dysplasia?
Both of this diseases have a autosomal dominant inheritance and both affect the FGFR3 gene on chromosome 4. Achondroplasia is a point mutation that results in the replacement of glycine with arginine at the 380 region of the gene. This leads to hyperactive FGFR-3, causing the growth centers in each bone to ossify before bone growth is complete. Thanatophoric Dysplasia is caused by specific autosomal dominant mutations in the gene that codes for the Fibroblast Growth Factor Receptor 3 (FGFR3). The mutations constitutively activate the tyrosine kinase activity of the receptor. As normally FGFR3 is a negative regulator of bone growth, the gain-of-function mutations associated to TD allow the activated receptor to send negative signals within the cells of the cartilage (chondrocytes), thus leading to the generalized disorganization of endochondral ossification at the bone growth plates
On a histological stain of a bone biopsy, how can one identify osteomalacia?
By using the von Kossa stain, calcified bones can be dyed black while osteoid remains visible.
What are the serum calcium, phosphorus, PTH, and alkaline phosphatase levels for Paget's Disease (Osteitis Deformans)
Calcium: Normal Phosphorus: Normal PTH: Normal Alk. Phosphatase: Increased
What are the serum calcium, phosphorus, PTH, and alkaline phosphatase levels for osteoporosis?
Calcium: Normal Phosphorus: Normal PTH: Normal Alk. Phosphatase: Normal
What are the serum calcium, phosphorus, PTH, and alkaline phosphatase levels for osteomalacia/rickets?
Calcium: decreased Phosphorus: decrease PTH: increase Alkaline Phosphatase: increase
What are the serum calcium, phosphorus, PTH, and alkaline phosphatase levels for Secondary hyperparathyroidism due to Chronic Kidney Disease?
Calcium: decreased Phosphorus: increased PTH: increased Alk. Phosphatase: increased
What are the serum calcium, phosphorus, PTH, and alkaline phosphatase levels for primary hyperparathyroidism?
Calcium: increased Phosphorus: decreased PTH: increased Alk. Phosphatase: increased
What are the serum calcium, phosphorus, PTH, and alkaline phosphatase levels for hypervitaminosis?
Calcium: increased Phosphorus: increased PTH: low Alk. Phosphatase: N/A
What are the clinical features of osteoporosis, diagnostics, and treatments?
Cinical features: -Vertebral fractures: frequently occur in the thoracic and lumbar regions -Mutiple fractures: significant loss of height, lumbar lordosis, and kyphoscoliosis Complications of fractures: Pulmonary embolism an pneumonia (leaked fat from barrow) Diagnosis: DXA scan, Biopsy Treatment: -Exercise -appropriate calcium and Vitamin D intake -Bisphosphonates -Denosumab (RANK-L antibody) -Anti-sclerostin antibodies -Cathepsin K inhibitors
What cover compact (cortical) bone and what covers Cancellous (trabeculated) bone?
Compact (cortical) bone is covered by periosteum Cancellous (trabeculated) bone is covered by endosteum
What is Ricketts?
Deficiency in calcitriol formation that leads to an inability of bone mineralization. Vitamin D3 (cholecalciferol) is obtained from exposure of the skin's stratum basale to the sun and from the ingestion of fish and milk products. The liver hydroxylates vitamin D3 to 25-OH vitamin D3, and the renal proximal convoluted tubule cells convert 25-OH vitamin D3 to 1,25(OH)2 vitamin D3 (calcitriol, active form). Calcitriol increases intestinal absorption of Ca2+ and PO43- and, at lower levels, increases the mineralization of bone. Deficiency can be caused by malabsorption (eg, celiac disease), decreased sun exposure, dark skin, poor diet, breastfeeding without supplementation, and chronic kidney disease.
What are the morphological findings in Rickets? What does the growth plate look like compared to normal?
Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants Growth plate is considered conspicuously thickened, irregular and lobulated *Thickness is a result from no osteoclastic activity due to a lack of mineralized osteoid.*
What is the progression of Duchenne's Dystrophy? What do they each look like on slides?
Early Stage: segmental myofiber degeneration and regeneration, atrophic myofibers Progressive Stage: Fatty replacement of muscles, prominent variation in myofiber size, from small atrophic fibers to large hypertrophied fibers
What is found on the histological examination of someone with Osteopetrosis?
Ends of the long bones are bulbous (Erlenmeyer Flask Deformity) and misshapen There is a lack of the medullary canal, as it is filled with primary spongiosa (woven bone) Since the deposited bone is not remodeled, the woven bone from primary endochondral ossification does not get changed to trabecular bone, and remains in the primary, woven structure. Image: (1) shows that the bone cortex is still present, but 2 shows the medullary cavity filled with primary spongiousa which replaced the bone marrow cavity. *This replacement of the medullary component of the bone is the main cause of anemia and thrombocytopenia in osteopetrosis*
What tissue encloses the entire skeletal muscle?
Epimysium
How is the characteristic x-ray of osteopetrotic long bone?
Erlenmeyer flask characteristic on X-ray Extremely dense radiographic, diffuse, symmertrical sclerosed bones
What is the pathogenesis of post-menopausal osteoporosis?
Estrogen enhances osteoblastic activity Estrogen inhibits osteoclastic activity by inhibiting bone resorptive cytokines such as IL-1, IL-6, and TNF With a lack of estrogen, there are more IL-1, IL-6, and TNF which leads to expression of RANK and RANK-L, and inhibition of Osteoprotegerin expression Leads to osteoclast maturation and recruitment
What morphological findings are associated with Osteomalacia?
Exaggeration of osteoid seams (measured by bone histomorphometry and double tetracycline labeling)
What gene is implicated in achondroplasia?
Gene for Fibroblast Growth Factor Receptor 3 (FGFR3) on chromosome 4 Point mutation that results in the replacement of Glycine with arginine
What autoantibodies are associated with which specific features of dermatomyositis are each one associated with?
Heliotropic rash is associated with Anti-Mi2 autoantibodies Gottron Papules is associated with anti-Mi2 autoantibodies Mechanic's hands are associated with Anti-Jo1 autoantibodies shawl rash also occurs idk which autoantibody
What is the visual findings in osteoporosis?
Histologically normal bone that is decreased in quantity. Reduction in the number and size of trabeculaue "Islands" of isolated bone due to loss of connectivity
What radiological findings can be seen in an X-ray of Rickets?
Looking at the metaphyseal end, one can notice Cupping: end of the metaphysis become concave Splaying: widening of the metaphyseal end of the bone Fraying: Loss of the sharp end of the metaphyseal end Increase in distance between the ends of bone chants and the epiphyseal center
What are the clinical manifestations of Myotonic dystrophy?
Muscle weakness and wasting Myotonia (prolonged muscle contraction) Cataracts Frontal Balding Testicular trophy Arrhythmias *Mnemonic: This helps with remembering the manifestation as well as the trinucleotide repeat "CTG: Cataracts, Toupee (early balding), and gonadal atrophy"*
What are the clinical features of dermatomyositis?
Muscle weakness: slow, symmetric, proximal muscles first, and associated myalgia (Hx: difficulty getting up, climbing steps, combing, lifting heavy objects, buttoning clothes, aka all activities that have to do with proximal muscles. ) Skin: -Heliotropic rash: lilac discoloration of the eyelid associated with periorbital edema (associated with Anti-Mi2 autoantibodies) -Gottron Papules: scaly erythematous eruption, dusky red patches over knuckles elbows and knees (also anti-Mi2 autoantibodies) -Mechanic's Hands: darkening and thickening of fingertips and sides resulting in irregular "dirty" appearing marks (Anti-Jo1 autoantibodies) Histology: - Perimysial Inflammation (CD4+ T-cells) - Perifascicular atrophy
Explain the histology of a bone slide preperation
Newly formed bone tissue decalcified for sectioning and stained with trichrome in which the collagen-rich ECM appears bright blue. The tissue is a combination of mesenchymal regions (M) containing capillaries, fibroblasts, and osteoprogenitor stem cells and regions of normally calcified matrix with varying amounts of collagen and the three major cell types found in all bone tissue
What are the modifiable vs. non-modifiable risk factors of Osteoporosis?
Non Modifiable: - Caucasian ethnicity - Rheumatoid arthritis - Advancing Age - Postmenopausal status - Previous fragility fracture - genetics Modifiable: - Low body weight - Excessive alcohol consumption (direct inhibitor of osteoblasts) - History of heavy/protracted glucocorticoid use - current cigarette smoking (decreases estrogens) - poor diet and exercise
What are the clinical features of achondroplasia?
Normal sized head and vertebral column Shortened arms and legs Short stature, *rhizomelic shortening* (disproportionate length, but normal thickness) of limbs, frontal bossing, mid face deficiency *Normal growth hormone and insulin like growth factor-1* *All of the bones that use endochondral ossification are affected* Micromelic shortening occurs in thanatophoric dwarfism (dysplasia)
What is the pathogenesis of senile osteoporosis?
Older age leads to lower activity of 1alpha-hydroxylase activity, less active Vitamin D (1,25(OH)2D), leading to less absorbed calcium within the intestines, less plasma calcium. Low plasma calcium means high levels of PTH, leading to more bone resorption, causing osteoporosis (This is all in addition to lower osteoblastic activity that comes with age)
What disease is associated with "cotton wool appearance" of the bone?
Osteitis Deformans (Paget's Disease) Radiography of the skull (Panel A) showed thickening of the outer and inner tables of the cranial bones, widening of the diploë, and a "cotton wool" appearance caused by irregular areas of sclerosis (arrows). Computed tomography of the skull (Panel B) confirmed bony expansion, cortical bone thickening, and irregular areas of sclerosis (arrows). These imaging findings reflect the mixed osteolytic and osteoblastic phases of Paget's disease, resulting in accelerated bone turnover with bone deposition and expansion
How do osteoclasts affect bone that has not undergone mineralization?
Osteoclasts can only function if the bone matrix has been mineralized, so osteoid is protected from the action of osteoclasts.
What radiological findings can be seen in an X-ray of osteomalacia?
Osteopenia Psuedofracture of Milkman-Looser syndrome - radiolucent transverse defects that are most common in the concave side of a long bone. - common on the medial side of the neck of the femur, ischial and pubic rami, ribs and scapula
What disease occurs when there is a mutation of CLCN7 gene?
Osteopetrosis Autosomal dominant, adult type (Remember, in children, the autosomal recessive Carbonic Anhydrase mutation is what's causing the inability for osteoclasts to produce an acidic enough environment to do bone resorption).
What are two diseases that manifest with "chalk-stick fractures"?
Osteopetrosis Paget's Disease of Bone
How do osteoblasts regulate bone absorption, and how does this happen?
Osteoprotegrin is a molecule secreted by osteoblasts that acts as a decoy receptor to the RANK-L on the osteoblast, keeping it from being able to bind to the RANK on osteoclasts. Estrogen stimulates the production of osteoprotegerin from osteoblasts. PTH and Glucocorticoids inhibit the production of osteprotegrin
Explain the steps of bone resorption
PTH is released into the blood stream. PTH binds to the PTH-receptor on osteoblast. This triggers the synthesis of RANK-L on osteoblast. RANK-L will bind to RANK on the osteoclast precursor This binding initiates maturation for the osteoclast, which can then form the ruffled border (via beta-integrins), attach to cell surface and create the seal to begin resorption.
What is the manifestation of Duchenne muscular dystrophy?
Patients will be normal at birth. Gower's Sign Delayed walking, clumsiness and inability to keep up with peers Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle Psuedohypertrophy: enlargement of the muscles of the lower leg that is adipose tissue, not muscle, Dialated cardiomyopathy and arrhythmias Cognitive impairment Mean age of death: 25 to 30 Years of age An X-linked recessive genetic disease in which mutations in the dystrophin gene result in a defective protein product
What are two muscle morphologies seen in a biopsy of dermatomyositis?
Perimysial inflammation: this is mononuclear infiltration of the perimysium (Orange arrow) Perifascicular atrophy: myofiber atrophy accentuated at the edges of the fascicles (green arrows)
Each muscle is composed of many muscle fascicles. What are these individual fascicles separated by?
Perimysium
What is the difference between Dermatomyositis and polymyositis?
Polymyositis does not have cutaneous involvement Infiltrates in Polymyositis are CD8+ T-cells (endomysial inflammation) Infiltrates in dermatomyositis are CD4+ T-cells (perimysial inflammation) Polymyositis has elevated ESR/CRP, cretine kinase, aldolase, and myoglobin
What is polymyositis?
Polymyositis is an autoimmune disorder that has progressive onset of proximal muscle weakness without pain. It is commonly associated with other autoimmune diseases. It is caused by endomysial infiltration with CD8+ T cells and is associated with overexpression of major histocompatibility complex (MHC) class I, which allows the muscle to become susceptible to destruction.
What is the difference between Primary and Secondary osteoporosis?
Primary: Idiopathic -Type1: Postmenopausal Women -Type 2: Senile (aging related) Secondary: Associated with a defined cause -Endocrine abnormalities -Genetic abnormalities
What are the differences between the recessive and dominant forms of osteopetrosis
Recessive Form: - Severe infantile form - Fractures, anemia, hydrocephaly - Postpartum mortality - Infancy: repeated infections, optic atrophy, deafness, and facial paralysis - Autosomal recessive Carbonic Anhydrase 2 mutation Dominant Form: - Less severe form - Detected at adolescence or adulthood - Repeated fractures - Mild cranial nerve defects (small neural foramina compress nerves) - anemia - Autosomal Dominant CLCN7 mutation
What are the two Vitamin D related osteopathies? How do they differ?
Rickets and Osteomalacia They are both charcerized by impairment of mineralization and a resultant accumulation of unmineralized matrix. Rickets - refers to the disorder in children where it interferes with the mineralization of cartilagenous growth plates Osteomalacia - adult counterpart, in which mineralization of osteoid is dysfunctional
What are the differences in chemical stains for muscle biopsy in Normal, Duchenne Dystrophy, and Becker Dystrophy?
Stain for Dystrophin Duchenne Dystrophy: In this x-linked recessive mutation of dystrophin, there is a complete absence of dystrophin, and it can be seen that each muscle fiber is not surrounded with dystrophin at all. Normal: In this slide, normal muscle fibers that are stained for dystrophin can be seen. They are each lined with the brown color, which is dystrophin Becker: In this x-linked recessive mutation, dystrophin is partially made, and had limited function. The presence can be seen, but very light and faded compared to the normal one.
What is fibromyalgia?
Syndrome characterized by widespread MSK pain without evidence of muscle inflammation or increase in muscle enzymes This is a disorder of pain regulation (abnormal ascending and descending pain pathways leading to central amplification of pain signals) Clinical features: - Fatigue and sleep disruption - Psychiatric (anxiety depression) - Somatic symptoms (headache) - Cognitive disturbance (learning, memory, perception, problem solving) - Multiple, symmetric tender spots over joints, muscles and tendons. Diagnosis: - 11/18 spots must be involved in order to diagnose (see image) Most common in women between ages 20-55
How is tetracycline used in bone biopsy?
Tetracycline is a fluorescent molecule that binds newly deposited osteoid matrix during mineralization with high affinity and specifically labels new bone under the UV microscope Bone that forms while tetracycline is present appears as fluorescent lamellae The distance between the labeled layers is proportional to the rate of bone appositional growth (bone growth in width) This can be used to see bone growth in patients with rickets or osteomalacia
What chromosome is affected in myotonic dystrophy?
The Myotonic Dystrophy Protein Kinase gene on Chromosome 19 is mutated by CTG repeats in the 3' non-coding region
Each fasicle is composed of many muscle fibers. What are these individual fibers surrounded by? What are the fibers composed of?
The fibers are surrounded by Endomysium They are composed of Myofibrils and satalite cells.
What is the process of bone resorption?
The osteoclasts form a ruffled border and forms a sealing zone, creating a microenvironment between it and the bone. The microenvironment will become very acidic due to Carbonic Anhydrase 2, within the osteoclast, converting CO2 and H2O into H+ and CH3- (Mutated in Childhood, Autosomal Recessive Osteopetrosis). Chloride/Hydrogen Antiporter secretes Cl- into the cleft of the microenvironment, further making it acidic and favorable for bone resorption. (Mutated in Adult, Autosomal Dom Osteopetrosis) H+ is pumped out of the cell and into the microenvironment via Hydrogen ATPases (in the ruffled membrane) and the microenvironment reaches a pH of 4.5 This high acidity environment promotes the dissolution of hydroxyapeptite from bone and stimulates activity of the protein hydrolases, producing localized matrix resorption
What is the histologic presentation of bone affected by osteitis deformans (paget's disease)?
There is a mosaic pattern (jigsaw puzzle) appearance of lamellar bone, seen in the sclerotic phase of the disease. Pieces of bone are joined by "cement lines"
What are the functions of osteoclasts?
These are large, multinucleated cells due to their origin from the fusion of marrow derived monocytes. These are found in small depressions on bone, and their surfaces have Howship Lacunae They contain many lysosomes and are rich in hydrolytic enzymes Role: Bone resorption
What are the characteristics of normal Type 1 muscle fibers?
They are used for sustained force movement, aerobic exercise. Highly resistant to fatigue High lipid content Low glycogen content Low glycolytic capacity, High oxidative capacity High mitochondrial density Enzyme Activity: -NADH-TR, dark staining -ATPase at pH 4.3, dark staining -ATPase at pH 9.4, light staining Gene Expression: Myosin Heavychain 7 (MYH7) Red in color due to high myoglobin content Slow contraction rate Mnemonic: 1 slow red ox
What is the function of osteoblasts?
They secrete osteocalcin, which binds calcium, and they release matrix vesicles rich in Alkaline Phosphatase and raises the local concentration of phosphate ions. Matrix vesicles serve as the foci for the formation of hydroxyapatite crystals, which is the first visible step in calcification. Eventually, each vesicle gets a mineralized outside, and then they all come together to form one confluent mass of calcified materials that embed the collagen fibers and proteoglycans
What is malignant hyperthermia?
This (can be inherited in an autosomal dominant fashion) is an Ion Channelopathy. Mutations in the RYR1 gene, which controls the expression of ryanodine receptors. When patients are exposed to halogenated inhalation agents like succinylcholine or anesthetics, susceptible people will start to have malignant hyperthermia. When the patient is exposed, the mutates receptor allows excess efflux of calcium from the sarcoplasmic reticulum, leading to tetany and excessive heat production (also hypocalcemia) Clinical manifestations: - Tachycardia - Tachypnea - Muscle spasms - Hyperpyrexia - Rhabdomyolysis Tx: Dantrolene - This drug binds to the ryanodine receptor
What is Gower's sign?
This demonstrates the manner of a child with Duchenne's MD gets up off the ground. The child turns prone to rise and begins to use his hands to get upright, then the child pushes off his knees and thighs before standing. *This method of getting up is normal in children learning to walk and only thought to be related to DMD once the child passes age 3*
What is a DXA scan?
This is a Dual-energy X-ray Absorptiometry, which measures the average concentration of mineral in a defined section of bone The Bone Mineral Density (BMD) is measured in m/cm^2 T-score and Z-score for measurements are calculated T-score: The standard deviation by which the BMD of the patient differs from the mean BMD of a young adult reference population of the same ethnicity and sex Z-score: represents the standard deviation by which the BMD of the patient differs from the mean BMD of an age-matched reference population of the same ethnicity and sex
What is an osteocyte and their function?
This is a cell that is found in lacunae in between bone layers (on the edges). They were once osteoblasts that trapped themselves into the bone and are currently surrounded. They contain long cytoplasmic processes that extend into the matrix called canaliculi These cells function as mechanoreceptors and are responsible for upkeep of the bony matrix that surrounds them. Resistance excersizes can result in thickened and increased bone density due to stimulation of the mechanoreceptors. Lack of stimulation leads to loss (think astronauts)
What is a torus fracture?
This is a common pediatric fracture Also known as a buckle fracture It happens when there is an incomplete fracture creating a "buckle" of the cortex Mechanism: an axial loading force along the long axis of the bone Tension (convex) side stays intact
What is a greenstick fracture?
This is a common pediatric fracture that is characterized by an incomplete fracture extending partway through the width of the bone following bending stress. Mechanism: - Occurs when the force applied to a bone overcomes the structural integrity of the convex (broken part) part of the bone, the concave surface of the bent bone remains intact *seen in the distal radius and ulna in particular*
What is osteopetrosis?
This is also called Marble Bone Disease or ALbers-Schonberg disease (in type 2 only) Autosomal recessive form = severe infantile osteopetrosis - more likely to involve Carbonic Anhydrase 2 Mutations Carbonic anhydrase is the enzyme in osteoclasts that creates a methyl group and H+ from CO2 and H2O in order to supply H+ ions to the "microenvironment" created by the osteoclast when attempting to mineralize the calcium hydroxyapatite of bone. Autosomal Dominant form = Adulthood - more likely to involve defects in the CLCN7 gene, leading to defective CLCN7 transporter. CLCN7 is a Chloride/ Hydrogen transporter that sits on the ruffled membrane of the active osteoclast. - It works to acidify the "microenvironment" to establish bone resorption. Without these enzymes, the acidic environment never forms, and bone is not remineralized ever. Leads to Diffuse symmetric skeletal sclerosis due to impaired formation or function of osteoclasts Bones gain stone-like quality, increased density of bone Bones become abnormally brittle and fracture easily like a chalk stick "Chalk stick Fracture" because the break it transverse to the long axis of the bone.
What is the pathogenesis of Duchenne Muscular Dystrophy?
This is an X-linked recessive disorder that is associated with deletions or frameshift mutations that result in total absence of dystrophin. Dystrophin is a proetin anchors the cytoskeleton of a muscular cell to the extracellular matrix by connecting cytoskeletal actin filaments to membrane-bound dystroglycan that is, in turn, connected to extracellular laminin. Mutations and subsequent alterations of the dystrophin protein → partial (BMD) or almost complete impairment (DMD) of the protein → disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells and subsequent replacement with connective and fat tissue → muscle appears larger ("pseudohypertrophy")
Explain the etiology, pathology, presentation, diagnositcs and treatments for Myasthenia Gravis
This is an autoimmune disease involving an autoantibody directd against post-synaptic Ach receptors There is a strong association with thymic abnormalities -30% thymic hyperplasia -10% thymoma Presents as fluctuating weakness, aka it worsens with exertion, as the day progresses. Patients may experience diplopia (double vision) and ptosis (dropping eyelid) Diagnostic tests include muscle electrophysiologic studies that measure a decrement in muscle response with repeated stimuli and identification of anti-Ach receptor autoantibodies Tx: Acetylcholinesterase inhibitors Plasmapheresis Immunosupression Thymectopmy (in patients w thymoma) *resistant to succinylcholine*
Describe Lambert-Eaton Myasthenia Syndrome
This is an autoimmune disorder with antibodies that block Ach release by inhibiting pre-synaptic calcium channels Strong association with neuroendocrine carcinoma of the lung (small cell carcinoma) Manifests as weakness of extremities Muscle strength is increased upon repeated stimulation of the muscle Diagnostic Studies: -Electrophysiological studies to ensure there is a positive muscle response as stimuli increases Treatment: - Succinylcholine sensitive
Explain achondroplasia
This is an autosomal dominant disorder caused by a point mutation that leads to the substitution of arginine in the place of Glycine in the 380 position of gene for Fibroblast growth factor receptor 3 (FGFR3) on chromosome 4 There is impaired proliferation of cartilage at the growth plate. *mutation increases w paternal age*
Explain Osteogenesis imperfecta
This is an autosomal dominant mutation in the genes that encode the alpha 1 (COL1A1) and alpha 2 (COL1A2) chains of type 1 collagen. (results in substitution where glycine is replaced with various other amino acids) This leads to effective assembly of higher order collagen polypeptides. Tissues affected: Bone, Joints, Eyes, Ears, Skin, and Teeth Bones become extremely fragile Sclerae become blue: this is caused by decrease collagen content, making the sclera translucent and allowing partial visualization of the underlying choroid veins Hearing loss: sensorineural and conduction loss due to abnormalities of the bones of the middle and inner ears Dental imperfections: Small, misshapen and blue/yellow teeth (secondary to deficiency in dentin)
What is Osgood-Schlatter disease (traction apophysitis)?
This is an overuse injury caused by repetitive strain. Painful swelling of the tibial tuberosity caused by inflammation of the patellar tendon at the site of its insertion. Occurs in physically active boys (11-15 years) and girls (8-13 years) *Running jumping and quick changes of direction* Enlarged tibial tubercle, pain on anterior aspect of knee, pain with flexing on resistance. Tx: NSAIDs rest, ice,
What is patellofemoral syndrome?
This is an overuse injury found commonly in young female athletes that presents as anterior knee pain Exacerbated by prolonged sitting or weight bearing on a flexed knee. Tx: NSAIDs, think muscle strengthening
What is Osteitis Deformans?
This is another name for paget disease. This is a disorder of increased, but disordered and unstructurally sound bone mass. There are three phases: 1. Initial osteolytic phase 2. Mixed osteoclastic, osteoblastic stage, which ends with a predominance of osteoblastic activity and evolves ultimately into.... 3. Final, burned-out quiescent osteosclerotic stage Pathogenesis: - Most common is mutations in the SQSTM1 gene (50% familial 10% sporadic) which increases that activity of NF-Kb which then increase osteoclastic activity. - Other mutations are activating mutations in RANK genes and inactivating mutation in Osteoprotegerin genes
Why do those with achondroplasia have normal head and vertebrae?
This is because they have an issue of impaired proliferation of cartilage at the growth plates. Endochondral ossification involves growth plates, while inter membranous ossification, the way calvarium and spinal bones form, are not dependent on growth plates.
What is botulism?
This is caused by a neurotoxin produce by C. botulinum MOA blocks the release of acetylcholine from presynaptic neurons (SNRPS)
What is polymyalgia rheumatica?
This is muscle pain and stiffness in the neck, shoulder, and pelvic girdle area, and facial pain, headache, jaw claudication. It is worse in the mornings and worsens with activity. Can have vision changes from diplopia to complete vision loss Process is unknown, idiopathic. Increase ESR up to 100mm/1st hour - Normal: ♀ 0-20 mm/h and ♂ 0-15 mm/h The creatine kinase is normal Associated with giant cell (temporal) arteritis - Temporal, vertebral, and ophthalmic arteries affected Most common in older adults (50+) Histological findings: Medial granulomatous inflammation centered on the internal elastic lamina that produce elastic lamina fragmentation.
How does a vitamin c deficiency affect bone formation?
This is scurvy Interestingly, hydroxylation of collagen is where scurvy comes into play. Collagen is hydroxylated by Prolyl Hydroxylase, which adds Hydroxy groups to the proline and lysine residues of collagen. - In order to do this, it requires molecular oxygen and vitamin C If there is a deficiency of vitamin C, this step is hampered, which leads to very weak collagen because hydroxylation is important to give collagen its strength. The patient has an inability to form the triple helix of collagen Woven bone is not formed Damage to capillary basement membrane = bleeding Subperiosteal hemorrhages Join hematoma
What is myositis ossificans?
This is the formation of reactive bone in muscle. Common after trauma, burns, or surgeries secondary to a circulating factor which activates mesenchymal stem cells residing within muscle to form extra-osseous bone Histological findings: Peripheral neovascularization and fibrosis at the site of damaged tissue, associated hemorrhage, eventually these are calcified and become boney spicule formation. Radiology: Peripheral bone formation with central lucent area - 2 to 6 weeks: calcification becomes apparent - 2 months: well circumscribed peripherally calcified appearance - 4 months and after: smaller and denser *Closest differential osteosarcoma*
What is the T-score in a DXA scan? What are the different measures of T-scores and what they mean?
This is the standard deviation by which the BMD of the patient differs from that of a young-adult reference point from the same ethnicity and sex T-score higher than -1 is considered normal T-score between -2.5 and -1 = osteopenia T-score of -2.5 and lower = osteoporosis
What is a Z-score in a DXA scan?
This is the standard deviation by which the BMD of the patient differs from that of an age-matched reference point of the same ethnic background and sex.
What is neurogenic injury? What changes are associated with it?
This is when damage to skeletal muscle caused by disruption of muscle innervation Two changes: Group Atrophy (B in image) - When all the muscle cells innervated by one nerve atrophy Fiber type grouping (C in image) - When there is ongoing axonal damage, residual motor axons may innervate increasingly larger numbers of myofibers, leading to enlargement of motor units, each compromised of a single type of muscle fiber
What is allelic heterogeneity?
This is when there is a different mutation in a gene locus that produces a similar (can be less can be worse) presentation of a different gene mutation in the same locus. This is brought up a lot when it comes to the differences between becker's muscular dystrophy and Duchenne's MD
What is the manifestation of someone with Carbonic Anhydrase 2 Deficiency Syndrome?
This mutation results in the It is a classic Triad 1. Osteopetrosis 2. Renal Tubular Acidosis 3. Cerebral Calcification
How does hyperparathyroidism play a role in bone pathology?
Unabated secretion of PTH results in large levels of osteoclastic activity. Can lead to: - Osteoporosis - Brown Tumor - Osteitis fibrosa cystica
What are the characteristics of Type 2 muscle fibers?
Used for very fast movement, anaerobic exercise Low resistance to fatigue Low lipid content High glycogen content High glycolytic capacity, Low oxidative capacity Low mitochondrial density Enzymes: -NADH-TR, light staining -ATPase at pH 4.3, light staining -ATPase at pH 9.4, dark staining Genes Expressed: -myosin heavy chain genes 1, 2, and 4 Pale red/tan color due to low myoglobin
What other associated disorders often accompany Lambert-Eaton Myasthenia?
Vitaligo Thyroid disease Strongly associated with neuroendocrine carcinoma of the lung (small cell carcinoma)
How can osteitis deformans (paget disease) be diagnosed?
X-ray: Bone is typically enlarged with thick, coarsened cortices and cancellous bone Elevated serum alkaline phosphatase levels Normal serum calcium and phosphorus
What are the layers of an epiphyseal growth plate?
Zone of Reserve Cartilage: a reserve of normal hyaline cartilage Zone of Proliferation: Cartilage with proliferating chondroblasts aligned as axial aggregates in lacunae Zone of Hypertrophy: Zone of Calcified Cartiliage: Cartilage in which the aligned cells are hypertrophic and the matrix is condensed Zone of Ossification: zone in which blood vessels and osteoblasts invade the lacunae of the old cartilage, producing marrow cavities and osteoid for new bone.
What is anti-Jo-1 ?
anti-histidyl-tRNA synthetase autoantibody Found in dermatomyositis and polymyositis
What are Sharpey's fibers?
collagen fibers that anchor and secure periosteum to underlying bone
What is thanatophoric dysplasia?
most common form of lethal dwarfism. Micromelic shortening (small and short limbs) Frontal bossing Macrocephaly Small chest cavity Bell Shaped Dwarfism Platyspondyly: condition denoted by the decrease of the distance between upper and lower plates of the vertebral body (see image)
