• Impaired cartilage proliferation in the growth plate
• Common cause of dwarfism
• Due to an activating mutation in fibroblast growth factor receptor 3 (FGFR3)
• AD
• Over expression of FGFR3 inhibits growth
• Most mutations are sporadic and related to increasing paternal age
• Short extremities with normal sized head and chest due to poor endochondral bone formation
• Intramembranous bone formation is not affected
• Endochondral bone formation is characterized by formation of a cartilage which is then replaced by bone. It is the mechanism by which long bones grow.
• Intramembranous bone formation is characterized by formation of bone without preexisting cartilage matrix.  It is the mechanism by which fiat bones (skull and rib cage) develop
• Mental function, life span, and fertility are not affected  

• Inherited defect of bone resorption resulting in abnormally thick, heavy bones that fractures easily
• Due to poor osteoclast function
• Multiple genetic variants exist: carbonic anhydrase II mutation leads to loss of the acidic environment required for bone resorption
• Bone Fractures
• Anemia, thrombocytopenia, and leukopenia with extramedullary hematopoiesis due to bone replacement of the marrow  (myelophthisic process)
• Vision and hearing impairment: due to impingement on cranial nerves
• Hydrocephalus: Due to narrowing of the foramen magnum
• Renal Tubular acidosis: seen wiht carbonic anhydrase II mutation
• Lack of carbonic anhydrase results in decreased tubular reabsorption of bicarb leading to metabolic acidosis
• Treatment is bone marrow transplant, osteoclasts are derived from monocytes

• Destructive mineralization of osteoid
• Osteoblasts normally produce osteoid which is then mineralized with calcium and phosphate to form bone
• Due to low levels of vitamin D which results in low serum calcium and phosphate
• Vitamin D is normally derived from the skin upon exposure to sunlight and from the diet
• Activation requires 25-hydroxylation by the liver followed by 1-α-hydroxylation by the proximal tubules cells of the kidney
• Active vitamin D reaises serum calcium and phosphate by:
• Intestine: increases absorption of calcium and phosphate
• Kidney: Increases reabsorption of calcium and phosphate
• Bone: Increases resorption of calcium and phosphate
• Vitamin D deficiency is seen with decreased sun exposure, poor diet, malabsorption, liver failure, and renal failure
• Rickets is die to low vitamin D in children resulting in abnormal bone mineralization
• MC < 1 yr of age
• Pigeon-breast deformity-inward bending of the ribs with anterior protrusion of the sternum
• Frontal bossing (enlarged forehead)- due to osteoid deposition on the skull
• Rachitic Rosary- Due to osteoid deposition at the costochondral junction
• Bowing of the legs may be seen in ambulating children
• Osteomalacia is due to low vitamin D in adults
• Inadequate mineralization results in weak bone with an increased risk for fracture
• Decreased Calcium
• Decreased phosphate
• Increased PTH
• Increased alkaline phosphatase

• Reduction in trabecular bone mass
• Results in porous bone with an increased risk for fracture
• Risk of osteoprosis is based on peak bone mass (attained in early adulthood) and rate of bone loss that follows thereafte
• Peak bone mass is achived by 30 yrs of age and is based on genetics, diet, and exercise
• Thereafter slightly less than 1% of bone mass is lost each year
• Bone mass is lost more quickly with lack of weight-bearing exercises, poor diet, or decreased estrogen (menopause)
• Senile and postmenopausal are most common forms
• Bone pain and fractures in weight-bearing areas such as the vertebrea (leads to loss of height and kyphosis), hip, and distal radius
• Bone density is measured using a DEXA scan
•  Serum calcium, phosphate, PTH, and alkaline phosphatase are normal
• Labs help to exclude osteomalacia which has a similar presentation
• Treatment includes:
• Exercis, Vit D, Calcium → Limits bone loss
• Bisphosphonates - induce apoptosis of osteoclasts
• Estrogen replacement therapy is debated (currently not recommeneded)
• Glucocorticoids are contraindicated (worsen osteoporosis)

• Imbalance between osteoclast and osteoblast function
• Avg age > 60 yrs
• Etiology is unknown: possibly viral
• Localized process involving one or more bones: does not invovle the entire skeleton
• Three distinct stages:
• Osteoclastic
• Mixed osteoblastic-osteoclastic
• Osteoblastic
• End result is thick sclerotic bone that fracture easily
• Biopsy reveals a mosaic pattern of lamellar bone
• Bone pain-due to microfractures
• Increasing hat size- skull is commonly affected
• Hearing loss- impingement on cranial nerve
• Lion-like facies- involvement of craniofacial bones
• Isolated elevated alkaline phosphatase- MCC of isolated elevated alkaline phosphatase in patients > 40 yrs
• Treatment includes:
• Calcitonin: inhibits osteoclastic function
• Bisphosphonates: induces apoptosis of osteoclasts
• Complications include:
• High output cardiac failure- due to formation of AV shunts in bone
• Osteosarcoma

• Infection of marrow and bone
• Usually occurs in children
• MC bacterial: arises via hematogenous spread
• Transient bacteremia (children) seeds metaphysis
• Open-wound bactermia (adults) seeds epiphysis
• Causes inculde:
• S. aureus: MCC (90%)
• N. gonorrheae: sexually active young adults
• Salmonella: sickle cell disease
• Pseudomonas: Diabetics or IV drug abuseres
• Pasteurella: Associated with cat or dog bite/scratches
• Mycobacterium tuberculosis: Usually involves vertebrea (Potts disease)
• Bone pain with systemic signs of infections
• Lytic focus (abscess) surrounded by sclerosis of bone on x-ray
• Lytic focus is called sequestrum and sclerosis is called involucrum
• Diagnosis is made by blood culture  

• Ischemic necrosis of bone and bone marrow
• Causes inculde trauma or fracture (MC), steroids, sickle cell anemia, and caisson disease/decompression sickness
• Osteoarthritis and fracture are major complications

• Benign tumor of bone
• MC arises on surface of facial bones
• Associated with Gardner syndrome aka familial colorectal polyposis 

• Benign tumor of osteoblasts that produce osteoid surrounded by a rim of reactive bone
• Occurs in young adults < 25 yrs of age
• M>W
• Arises in cortex of long bone (femur)
• Presents as bone pain that resolves with aspirin
• Imaging reveals a bony mass (<2cm) with a radiolucent core (osteoid)
• Osteoblastoma is similar to osteoid osteoma but is larger > 2cm arises in vertebrae and presents as bone pain that does not respond to aspirin 

• Tumor of bone with an overlying cartilage cap
• MC benign tumor of bone
• Arises from a lateral projection of the growth plate, bone is continuous with the marrow space
• Overlying cartilage can transform rarely to chondrosarcoma  

• Malignant proliferation of osteoblasts
• Peak incidence is seen in teenagers
• Less commonly seen in elderly
• Risk factors include familial retinoblastoma, pagets disease, and radiation exposure
• Arises in the metaphysis of long bones, usually the distal femur or proximal tibia (region of the knee)
• Presents as a pathologic fracture or bone pain with swelling
• Imaging reveals mass with a sunburst appearance and lifting of the periosteum (Codmans triangle)
• Biopsy reveals pleomorphic celsl that produce osteoid

• Tumor comprised of multinucleated giant cells and stromal cells
• Occurs in young adults
• Arises in the epiphysis of long bones, usually the distal femur or proximal tibia (knee region)
• Soap-bubble appearance on x-ray
• Locally agressive tumor
• May recur  

• Malignant proliferation of poorly-differentiated cells derived from neuroectoderm
• Arises in the diaphysis of long bones
• Usually in male children < 15 yrs
• Onion skin appearance on x-ray
• Biopsy reveals small round blue cells that resemble lymphocytes
• Can be confused with lymphoma or chronic osteomyelitis
• (11;22) translocation is characterisitc
• Often presents with metastasis
• Responds to chemotherapy

• Benign tumor of cartilage
• Usually arises in the medulla of small bones of the hands and feet 

• Malignant cartilage forming tumor
• Arises in medulla of the pelvis or central skeleton  

• More common than primary tumors
• Usually result in osteolytic (punchd out) lesions
• Prostate carcinoma classically produces osteoblastic lesions  

• Connection between two bones
• Solid joints are tightly connected to provide structural strength (cranial sutures)
• Synovial Joints have a joint space to allow for motion
• Articular surface of adjoining bones is made of hyaline cartilage (type II collagen) that is surrounded by a joint capsule
• Synovium lining the joint capsule secretes fluid rich in hyaluronic acid to lubricate the joint and facilitate smooth muscle

Osteoarthritis

Degenerative Joint Disease

• Progressive degeneration of articular cartilage
• MC type of arthritis
• Most often due to "wear and tear"
• Major risk factor is age (common after 60 people), additional risk factors include obesity and trauma
• Affects a limited number of joints (oligoarticular): hips, lower lumbar spine, knees, and distal interphalangeal joints (DIPs) and proximal interphalangeal joints (PIPs) of fingers are common sites
• Classic presentation is joint stiffness in the morning that worsens during the day
• Pathologic features include:
• Disruption of the cartilage that lines the articular surface
• Fragments of cartilage floating in the joint space are called "joint mice"
• Eburnation of the subchondral bone
• Osteophyte formation (reactive bony outgrowths) classically arise in DIPs (Heberden nodes) and PIP (Bouchard nodes) of the fingers

• Chronic, systemic autoimmune disease
• Classically arises in women of late childbearing age
• Associated with HLA-DR3/DR4
• Characterized by involvement of joints
• Hallmark is synovitis leading to formation of a pannua (inflamed granulation tissue)
• Leads to destruction of cartilage and ankylosis (fusion of the joint)
• Arthritis with morning stiffness that improves with activity
• Symmetric involvement of PIP (swan neck deformity), wrists (ulnar deviation), elbows, ankles, and knees in characterisitc
• DIP not involved
• Joint space narrowing, loss of cartilage, and osteopenia are seen on x-ray
• Fever, malaise, weight loss, and myalgias
• Rheumatoid nodules: central zone of necrosis surrounded by epitheloid histiocytes: arise in skin and visceral organs
• Vasculitis: multiple organs may be invovled
• Baker Cyst: swelling of the bursa behind the knee
• Pleural effusions: Lymphadenopathy, and interstitil lung fibrosis
• IgM auto antibody against Fc portion of the IgG rheumatoid factor
• Marker of tissue damage and disease activity
• Neutrophils and high protein in synovial fluid
• Compliations include anemia of chronic disease and secondary amyloidosis

• Group of joint disorders characterized by
• Lack of rheumatoid factor
• Axial skeleton involvement
• HLA-B27 association
• Involves the sacroiliac joint and spine
• Arises in young adults, most often male
• Presents with low back pain, involvement of the vertebral bodies eventually arises leading to fusion of the vertebrae (bamboo spine)
• Extra-articular manifestations include uveitis, and aortitis (leading to aortic regurgitation)
• Reiter syndrome is characterized by the triad of arthritis, urethritis and conjunctivitis
• Arises in young adults (usually males) weeks after GI or C. trachomatis infection
• Psoriatic arthritis is seen in 10% of cases of psoriasis
• Involves axial and peripheral joints: DIP joints of the hands and feet are most commonly affected
• Leading to sausage fingers or toes  

• Arthritis due to an infectious agent usually bacterial
• N. Gonorrhea: young adults MCC
• S. aureus: older children and adults: 2nd MCC
• Classically involves a single joint, usually the knee
• Presents as a warm joint with limited range of motion, fever, increased WBC, and elevated ESR are often present

• Deposition of monosodium urate (MSU) crystals in tissue, especially the joints (big toe)
• Due to hyperuricemia: related to overproduction or decreased excretion of uric acid
• Uric acid is derived from purine metabolism and is excreted by the kidney
• Primary gout is the MC form: etiology is unknown
• Secondary gout is seen with:
• Leukemia and myeloproliferative disorders- increased cell turnover leads to hyperuricemia
• Lesch-Nyhan syndrome- X-linked deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) presents with mental retardation and self-mutialtion
• Renal insufficiency-decreased renal excretion
• Presents as exquisitely painful arthritis of the big toe
• Monosodium urate crystals deposit in the joint tiggering an acute inflammatory reaction
• Alcohol or consumption of meat may precipitate arthritis
• Chronic Gout leads to:
• Development of tophi-white, chalky aggregates of uric acid crystals with fibrosis and giant cell reaction in the soft tissue and joints
• Renal failure-urate crystals may deposit in kidney tubules (urate nephropathy)
• Lab findings:
• Hyperuricemia
• Synovial fluid shows needle shaped crystals wiht negative birefrigence under polarized light (yellow when parallel) 

• Resembles gout clinically
• Due to the deposition of calcium pyrophosphate dihydrate
• Synovial fluid shows rhomboid-shaped crystals with weakly positive birefringence under polarized light (blue when parallel) 

• Inflammatory disorder of the skin and skeletal muscle
• Unknown etiology
• Some cases are associated with carcinoma (gastric carcinoma)
• Bilateral proximal muscle weakness, distal involvement can develop rapidly
• Rash of the upper eyelids (heliotropic rash) or malar rash may be seen
• Grotton lesion: red papules on the elbows, knuckles, and knees
• Increased CK
• Positive ANA and anti-jo antibody
• Perimysial inflammation (CD4 Tcells) with perifascicular atrophy on biopsy
• Treatment is corticosteroids
• "Can't stand from a chair can't bursh your hair" 

• Inflammatory disorder of the skin and skeletal muscle
• Resembles dermatomyositis clinically but skin is not invovled
• Endomysial inflammation (CD4 T cells) with necrotic muscle fibers is seen on biopsy
• "Can't stand from a chair can't bursh your hair" 

• Degenerative disorder characterized by muscle wasting and replacement of skeletal muscle by adipose tissue
• Due to mutations in dystrophin  which is important for anchoring the muscle ctyoskeleton to the extracellular matrix
• Mutations are often spontaneous
• Large gene size predisposes to high rate of mutation
• Duchene muscular dystrophy is due to a deletion of dystrophin
• Presents as proximal muscle weakness at 1 year of age
• Progresses to involve distal muscles
• Calf pseudohypertrophy is a characteristic finding
• Serum CK is elevated
• Death results from cardiac or respiratory failure, myocardium is commonly involved
•  Becker muscular dystrophy is due to mutated dystrophin. Clinically results in milder disease

• Autoantibodies against the postsynaptic acetylcholine receptor at NMJ
• W>M
• Muscle weakness that worsens with use and improves with rest
• Classically involves the eye leading to ptosis and diplopia
• Symptoms improve with anticholinesterase agents
• Associated with thymic hyperplasia or thymoma, thymectomy improves symptoms 

• Antibodies against presynaptic calcium channel of the NMJ
• Arises as a paraneoplastic syndrome MC due to small cell lung cancer
• Leads to impaired aceylcholine release
• Firing of presynaptic calcium channels is required for acetylcholine release
• Proximal muscle weakness that improves with use
• The eye are usually spared
• Anticholinesterase agents do not improve symptoms
• Resolves with resection of the cancer

• Benign tumor of adipose tissue
• MC benign soft tissue tumor in adults 

• Malignant tumor of adipose tissue
• MC malignant soft tissue tumor in adults
• Lipoblast is the characteristic cell  

• Benign tumor of skeletal muscle
• Cardiac rhabdomyoma is associated with tuberous sclerosis 

• Malignant tumor of skeletal muscle
• MC malignant soft tissue tumor in children
• Rhabdomyoblast is the characterisitc cell
• Desmin (+)
• MC site is at the head, neck and vagina is the classic site in young girls