Musculoskeletal, Skin, and Connective Tissue - Pathology (1)

Question 1

Achondroplasia

Answer 1

• Failure of longitudinal bone growth (endochondral ossification) –>Ž short limbs.
• Membranous ossification is not affected –>ŽŽ large head relative to limbs.
• Constitutive activation of fibroblast growth factor receptor (FGFR3) actually inhibits chondrocyte proliferation.
• > 85% of mutations occur sporadically and are associated with advanced paternal age, but the condition also demonstrates autosomal dominant inheritance.
• Common cause of dwarfism.
• Normal life span and fertility.

Question 2

Osteoporosis

• Definition
• Type I
• Type II
  
  • Senile osteoporosis
  • Prophylaxis
  • Treatment

Answer 2

• Definition
  
  • Trabecular (spongy) bone loses mass and interconnections despite normal bone mineralization and lab values (serum Ca2+ and PO₄^3-).
  • Diagnosis by a bone mineral density test (DEXA) with a T-score of ≤ -2.5.
  • Can be caused by long-term exogenous steroid use.
  • Can lead to vertebral crush fractures—acute back pain, loss of height, kyphosis.
• Type I
  
  • Postmenopausal
    
    • Increased bone resorption due to decreased estrogen levels.
  • Femoral neck fracture, distal radius (Colles) fracture.
• Type II
  
  • Senile osteoporosis
    
    • Affects men and women > 70 years old.
  • Prophylaxis
    
    • Regular weight-bearing exercise and adequate calcium and vitamin D intake throughout adulthood.
  • Treatment
    
    • Bisphosphonates, PTH, SERMs, rarely calcitonin
    • Denosumab (monoclonal antibody against RANKL).

Question 3

Osteopetrosis (marble bone disease)

• Definition
• Findings
• Treatment

Answer 3

• Definition
  
  • Failure of normal bone resorption due to defective osteoclasts Ž–> thickened, dense bones that are prone to fracture.
  • Mutations (e.g., carbonic anhydrase II) impair ability of osteoclast to generate acidic environment necessary for bone resorption.
• Findings
  
  • Bone fills marrow space –>Ž pancytopenia, extramedullary hematopoiesis.
  • X-rays show bone-inbone appearance [A].
  • Can result in cranial nerve impingement and palsies as a result of narrowed foramina.
• Treatment
  
  • Bone marrow transplant is potentially curative as osteoclasts are derived from monocytes.

Question 4

Osteomalacia/rickets

• Definition
• Caused by…
• Causes…

Answer 4

• Definition
  
  • Decreased vitamin D Ž–> decreased serum calcium –> increased PTH secretion –> decreased serum PO₄^3-.
• Caused by…
  
  • Vitamin D deficiency.
  • Defective mineralization / calcification of osteoid Ž–> soft bones that bow out.
• Causes…
  
  • Osteomalacia in adults
  • Rickets in children.
  • Hyperactivity of osteoblasts Ž–> increased ALP (osteoblasts require alkaline environment).

Question 5

Paget disease of bone (osteitis deformans) (420)

• Definition
• Findings
• Stages of Paget disease:

Answer 5

• Definition
  
  • Common, localized disorder of bone remodeling caused by increases in both osteoblastic and osteoclastic activity.
  • Increased blood flow from increased arteriovenous shunts may cause high-output heart failure.
  • Increased risk of osteogenic sarcoma.
• Findings
  
  • Serum Ca2+, phosphorus, and PTH levels are normal. 
  • Increased ALP.
  • Mosaic pattern of woven and lamellar bone [A]
    
    • Long bone chalk-stick fractures. 
  • Hat size can be increased [B]
    
    • Hearing loss is common due to auditory foramen narrowing.
• Stages of Paget disease:
  
  • Lytic—osteoclasts
  • ƒƒMixed—osteoclasts + osteoblasts
  • Sclerotic—osteoblasts
  • ƒƒQuiescent—minimal osteoclast/osteoblast activity

Question 6

Osteonecrosis (avascular necrosis)

Answer 6

• Infarction of bone and marrow, usually very painful.
  
  • Most common site is femoral head (due to insufficiency of medial circumflex femoral artery).
• Caused by trauma, high-dose corticosteroids, alcoholism, sickle cell.

Question 7

Lab values in bone disorders

• For each (increased/decreased)
  
  • Serum Ca2+
  • PO₄^3-
  • ALP
  • PTH
  • Comments
• Osteoporosis
• Osteopetrosis
• Paget disease
• Osteomalacia/rickets

Answer 7

• Osteoporosis
  
  • Serum Ca2+: —
  • PO₄^3-: —
  • ALP: —
  • PTH: — 
  • Comments: Decreased bone mass
• Osteopetrosis
  
  • Serum Ca2+: — / decreased
  • PO₄^3-: —
  • ALP: —
  • PTH: —
  • Comments: Dense, brittle bones.
    
    • Ca2+ decreased in severe, malignant disease
• Paget disease
  
  • Serum Ca2+: —
  • PO₄^3-: — 
  • ALP: Increased
  • PTH: —
  • Comments: Abnormal “mosaic” bone architecture
• Osteomalacia/rickets    
  
  • Serum Ca2+: Decreased
  • PO₄^3-: Decreased
  • ALP: Increased
  • PTH: Increased
  • Comments: Soft bones

Question 8

Lab values in bone disorders

• For each (increased/decreased)
  
  • Serum Ca2+
  • PO₄^3-
  • ALP
  • PTH
  • Comments
• Hypervitaminosis D
• Osteitis fibrosa cystica
  
  • 1° hyperparathyroidism
  • 2° hyperparathyroidism
  • General comments

Answer 8

• Hypervitaminosis D  
  
  • Serum Ca2+: Increased
  • PO₄^3-: Increased
  • ALP: — 
  • PTH: Decreased
  • Comments: Caused by over-supplementation or granulomatous disease (e.g., sarcoidosis)
• Osteitis fibrosa cystica
  
  • 1° hyperparathyroidism
    
    • Serum Ca2+: Increased
    • PO₄^3-: Decreased
    • ALP: Increased
    • PTH: Increased
    • Comments: Idiopathic or parathyroid hyperplasia, adenoma, carcinoma
  • 2° hyperparathyroidism
    
    • Serum Ca2+: Decreased
    • PO₄^3-: Increased
    • ALP: Increased
    • PTH: Increased
    • Comments: Often as compensation for ESRD (decreased PO43- excretion and production of activated vitamin D)
  • General comments
    
    • “Brown tumors” due to fibrous replacement of bone, subperiosteal thinning

Question 9

Giant cell tumor

• Type of tumor
• Epidemiology / location
• Characteristics

Answer 9

• Type of tumor
  
  • Benign primary bone tumor
• Epidemiology / location
  
  • 20–40 years old.
  • Epiphyseal end of long bones.
• Characteristics
  
  • Locally aggressive benign tumor often around knee.
  • “Soap bubble” appearance on x-ray [A]
  • Multinucleated giant cells.

Question 10

Osteochondroma (exostosis)

• Type of tumor
• Epidemiology / location
• Characteristics

Answer 10

• Type of tumor
  
  • Benign primary bone tumor
• Epidemiology / location
  
  • Most common benign tumor.
  • Males < 25 years old.
• Characteristics
  
  • Mature bone with cartilaginous cap.
  • Rarely transforms to chondrosarcoma.

Question 11

Osteosarcoma (osteogenic sarcoma)

• Type of tumor
• Epidemiology / location
• Characteristics

Answer 11

• Type of tumor
  
  • Malignant primary bone tumor
• Epidemiology / location
  
  • 2nd most common 1° malignant bone tumor (after multiple myeloma).
  • Bimodal distribution: 10–20 years old (1°), > 65 (2°).
  • Predisposing factors: Paget disease of bone, bone infarcts, radiation, familial retinoblastoma, Li-Fraumeni syndrome (germline P53 mutation).
  • Metaphysis of long bones, often around knee [B] [C].
• Characteristics
  
  • Codman triangle (from elevation of periosteum) or sunburst pattern on x-ray.
  • Aggressive.
  • Treat with surgical en bloc resection (with limb salvage) and chemotherapy.

Question 12

Ewing sarcoma

• Type of tumor
• Epidemiology / location
• Characteristics

Answer 12

• Type of tumor
  
  • Malignant primary bone tumor
• Epidemiology / location
  
  • Boys < 15 years old.
  • Commonly appears in diaphysis of long bones, pelvis, scapula, and ribs.
• Characteristics
  
  • Anaplastic small blue cell malignant tumor [D].
  • Extremely aggressive with early metastases, but responsive to chemotherapy.
  • “Onion skin” appearance in bone.
  • Associated with t(11;22) translocation.
    
    • 11 + 22 = 33 (Patrick Ewing’s jersey number).

Question 13

Chondrosarcoma (423)

• Type of tumor
• Epidemiology / location
• Characteristics

Answer 13

• Type of tumor
  
  • Malignant primary bone tumor
• Epidemiology / location
  
  • Rare, malignant, cartilaginous tumor.
  • Men 30–60 years old.
  • Usually located in pelvis, spine, scapula, humerus, tibia, or femur.
• Characteristics
  
  • Malignant cartilaginous tumor.
  • May be of 1° origin or from osteochondroma.
  • Expansile glistening mass within the medullary cavity.

Question 14

Osteoarthritis

• Etiology
• Joint findings
• Predisposing factors
• Classic presentation
• Treatment

Answer 14

• Etiology
  
  • Mechanical—joint wear and tear destroys articular cartilage.
• Joint findings
  
  • Subchondral cysts, sclerosis [A], osteophytes (bone spurs), eburnation (polished, ivory-like appearance of bone), Heberden nodes (DIP), and Bouchard nodes (PIP).
  • No MCP involvement.
• Predisposing factors
  
  • Age, obesity, joint deformity, trauma.
• Classic presentation
  
  • Pain in weight-bearing joints after use (e.g., at the end of the day), improving with rest.
  • Knee cartilage loss begins medially (“bowlegged”).
  • Noninflammatory.
  • No systemic symptoms.
• Treatment
  
  • NSAIDs, intra-articular glucocorticoids.

Question 15

Rheumatoid arthritis

• Etiology
• Joint findings
• Predisposing factors
• Classic presentation
• Treatment

Answer 15

• Etiology
  
  • Autoimmune—inflammatory destruction of synovial joints.
  • Mediated by cytokines and type III and type IV hypersensitivity reactions.
• Joint findings
  
  • Pannus formation in joints (MCP, PIP), subcutaneous rheumatoid nodules (fibrinoid necrosis), ulnar deviation of fingers, subluxation [B], Baker cyst (in popliteal fossa).
  • No DIP involvement.
• Predisposing factors
  
  • Females > males.
  • 80% have (+) rheumatoid factor (anti-IgG antibody)
  • Anti–cyclic citrullinated peptide antibody is more specific.
  • Strong association with HLA-DR4.
• Classic presentation
  
  • Morning stiffness lasting > 30 minutes and improving with use, symmetric joint involvement, systemic symptoms (fever, fatigue, pleuritis, pericarditis).
• Treatment
  
  • NSAIDs, glucocorticoids, disease-modifying agents (methotrexate, sulfasalazine, TNF-α inhibitors).

Question 16

Sjögren syndrome

• Definition
• Findings
• Complications

Answer 16

• Definition
  
  • Autoimmune disorder characterized by destruction of exocrine glands (especially lacrimal and salivary).
  • Can be a 1° disorder or a 2° syndrome associated with other autoimmune disorders (e.g., rheumatoid arthritis).
  • Predominantly affects old.
• Findings
  
  • Xerophthalmia (decreased tear production and subsequent corneal damage)
  • Xerostomia (decreased saliva production)
  • Presence of antinuclear antibodies: SS-A (anti-Ro) and/or SS-B (anti-La)
  • Bilateral parotid enlargement
• Complications
  
  • Dental caries
  • Mucosa-associated lymphoid tissue (MALT) lymphoma (may present as unilateral parotid enlargement).

Question 17

Gout

• Definition
• Findings
• Symptoms
• Treatment
  
  • Acute
  • Chronic (preventive)

Answer 17

• Definition
  
  • Acute inflammatory monoarthritis caused by precipitation of monosodium urate crystals in joints [A].
• Findings
  
  • Associated with hyperuricemia, which can be caused by:
    
    • Underexcretion of uric acid (90% of patients)
      
      • Largely idiopathic
      • Can be exacerbated by certain medications (e.g., thiazide diuretics).
    • ƒƒOverproduction of uric acid (10% of patients)
      
      • Lesch-Nyhan syndrome, PRPP excess, increased cell turnover (e.g., tumor lysis syndrome), von Gierke disease.
  • Crystals are needle shaped and (-) birefringent
    
    • Yellow under parallel light, blue under perpendicular light).
    • More common in males.
• Symptoms
  
  • Asymmetric joint distribution.
    
    • Joint is swollen, red, and painful [B].
  • Classic manifestation is painful MTP joint of the big toe (podagra).
  • Tophus formation (often on external ear, olecranon bursa, or Achilles tendon).
  • Acute attack tends to occur after a large meal or alcohol consumption (alcohol metabolites compete for same excretion sites in kidney as uric acid, causing decreased uric acid secretion and subsequent buildup in blood).
• Treatment
  
  • Acute: NSAIDs (e.g., indomethacin), glucocorticoids, colchicine.
  • Chronic (preventive): xanthine oxidase inhibitors (e.g., allopurinol, febuxostat).

Question 18

Pseudogout

• Findings
• Diseases that may be associated with pseudogout
• Treatment
• Gout vs. pseudogout

Answer 18

• Findings
  
  • Presents with pain and effusion in a joint, caused by deposition of calcium pyrophosphate crystals within the joint space (chondrocalcinosis on x-ray).
  • Forms basophilic, rhomboid crystals that are weakly positively birefringent [A].
  • Usually affects large joints (classically the knee).
  • > 50 years old; both sexes affected equally.
• Diseases that may be associated with pseudogout
  
  • Hemochromatosis, hyperparathyroidism, and hypoparathyroidism.
• Treatment
  
  • NSAIDs for sudden, severe attacks; steroids; and colchicine.
• Gout vs. pseudogout
  
  • Gout—crystals are yellow when parallel (||) to the light.
  • Pseudogout—crystals are blue when parallel (||) to the light.

Question 19

Infectious arthritis

• Definition
• Common causes
• Gonococcal arthritis

Answer 19

• Definition
  
  • Affected joint is swollen, red, and painful.
• Common causes
  
  • S. aureus, Streptococcus, and Neisseria gonorrhoeae
• Gonococcal arthritis
  
  • An STD that presents as a migratory arthritis with an asymmetric pattern.
  • STD = Synovitis (e.g., knee), Tenosynovitis (e.g., hand), and Dermatitis (e.g., pustules).

Question 20

Seronegative spondyloarthropathies

• Definition
• Conditions

Answer 20

• Definition
  
  • Arthritis without rheumatoid factor (no anti-IgG antibody).
  • Strong association with HLA-B27 (gene that codes for HLA MHC class I).
  • Occurs more often in males.
• Conditions (PAIR)
  
  • ​Psoriatic arthritis
  • Ankylosing spondylitis
  • Inflammatory bowel disease
  • Reactive arthritis (Reiter syndrome)

Question 21

Psoriatic arthritis

Answer 21

• Seronegative spondyloarthropathy
• Joint pain and stiffness associated with psoriasis.
• Asymmetric and patchy involvement.
• Dactylitis (“sausage fingers” [A]), “pencil-incup” [B] deformity on x-ray.
• Seen in fewer than 1 ⁄3 of patients with psoriasis.

Question 22

Ankylosing spondylitis

Answer 22

• Seronegative spondyloarthropathy
• Chronic inflammatory disease of spine and sacroiliac joints –>Ž ankylosis (stiff spine due to fusion of joints), uveitis, and aortic regurgitation.
• Bamboo spine (vertebral fusion) [C].

Question 23

Inflammatory bowel disease

Answer 23

• Seronegative spondyloarthropathy
• Crohn disease and ulcerative colitis are often accompanied by ankylosing spondylitis or peripheral arthritis.
• Bamboo spine (vertebral fusion) [C].

Question 24

Reactive arthritis (Reiter syndrome)

Answer 24

• Seronegative spondyloarthropathies
• Post-GI (Shigella, Salmonella, Yersinia, Campylobacter) or Chlamydia infections.
• Classic triad:
  
  • ƒƒConjunctivitis and anterior uveitis
  • ƒƒUrethritis
  • Arthritis
  • “Can’t see, can’t pee, can’t climb a tree.”

Question 25

Systemic lupus erythematosus:
Symptoms

• Classic presentation
• Libman-Sacks endocarditis
• Lupus nephritis
  
  • Nephritic
  • Nephrotic
• Common causes of death in SLE:
• Symptoms

Answer 25

• Classic presentation
  
  • Rash, joint pain, and fever, most commonly in a female of reproductive age and African descent.
• Libman-Sacks endocarditis
  
  • Wart-like vegetations on both sides of valve.
• Lupus nephritis (type III hypersensitivity reaction):
  
  • ƒƒNephritic—diffuse proliferative glomerulonephritis.
  • ƒƒNephrotic—membranous glomerulonephritis.
• Common causes of death in SLE:
  
  • Cardiovascular disease
  • Infections
  • Renal disease
• Symptoms (RASH OR PAIN)
  
  • Rash (malar [A] or discoid)
  • Arthritis
  • Soft tissues/serositis
  • Hematologic disorders (e.g., cytopenias)
  • Oral/nasopharyngeal ulcers
  • Renal disease, Raynaud phenomenon
  • Photosensitivity, Positive VDRL/RPR
  • Antinuclear antibodies
  • Immunosuppressants
  • Neurologic disorders (e.g. seizures, psychosis)

Question 26

Systemic lupus erythematosus

• Findings
• Treatment

Answer 26

• Findings
  
  • Antinuclear antibodies (ANA)—sensitive, not specific.
  • Anti-dsDNA antibodies—specific, poor prognosis (renal disease).
  • Anti-Smith antibodies—specific, not prognostic (directed against snRNPs).
  • Antihistone antibodies—sensitive for drug-induced lupus.
  • Anticardiolipin antibodies—false positive on tests for syphilis, prolonged PTT (paradoxically, increased risk of arteriovenous thromboembolism).
  • Decreased C3, C4, and CH50 due to immune complex formation.
• Treatment
  
  • NSAIDs, steroids, immunosuppressants, hydroxychloroquine.

Question 27

Sarcoidosis

• Definition
• Findings
• Associated with/
• Treatment

Answer 27

• Definition
  
  • Characterized by immune-mediated, widespread noncaseating granulomas [A] and elevated serum ACE levels.
  • Common in black females.
• Findings
  
  • Often asymptomatic except for enlarged lymph nodes.
  • Incidental findings on CXR of bilateral hilar adenopathy and/or reticular opacities [B].
• Associated with restrictive lung disease (interstitial fibrosis), erythema nodosum, lupus pernio, Bell palsy, epithelioid granulomas containing microscopic Schaumann and asteroid bodies, uveitis, and hypercalcemia (due to increased 1α-hydroxylase–mediated vitamin D activation in macrophages).
• Treatment: steroids.

Question 28

Polymyalgia rheumatica

• Symptoms
• Findings
• Treatment

Answer 28

• Symptoms
  
  • Pain and stiffness in shoulders and hips, often with fever, malaise, and weight loss.
  • Does not cause muscular weakness.
  • More common in women > 50 years old
  • Associated with temporal (giant cell) arteritis.
• Findings
  
  • Increased ESR, increased C-reactive protein, normal CK.
• Treatment
  
  • Rapid response to low-dose corticosteroids.

Question 29

Fibromyalgia

• Findings
• Treatment

Answer 29

• Findings
  
  • Most commonly seen in females 20–50 years old.
  • Chronic, widespread musculoskeletal pain associated with stiffness, paresthesias, poor sleep, and fatigue.
• Treatment
  
  • Treat with regular exercise, antidepressants (TCAs, SNRIs), and anticonvulsants.

Question 30

Polymyositis/dermatomyositis

• Symptoms
  
  • Polymyositis
  • Dermatomyositis
• Findings
• Treatment

Answer 30

• Symptoms
  
  • Polymyositis
    
    • Progressive symmetric proximal muscle weakness
    • Characterized by endomysial inflammation with CD8+ T cells.
    • Most often involves shoulders.
  • Dermatomyositis
    
    • Similar to polymyositis, but also involves malar rash (similar to SLE), Gottron papules [A], heliotrope (erythematous periorbital) rash, “shawl and face” rash [B], “mechanic’s hands.” 
    • Increased risk of occult malignancy.
    • Perimysial inflammation and atrophy with CD4+ T cells.
• Findings
  
  • Increased CK, (+) ANA, (+) anti-Jo-1, (+) anti-SRP, (+) anti-Mi-2 antibodies.
• Treatment
  
  • Steroids.

Question 31

Myasthenia gravis

• Type of disease
• Frequency
• Pathophysiology
• Clinical
• Associated with…
• AChE inhibitor administrator

Answer 31

• Type of disease
  
  • Neuromuscular junction disease
• Frequency
  
  • Most common NMJ disorder
• Pathophysiology
  
  • Autoantibodies to postsynaptic ACh receptor
• Clinical
  
  • Ptosis, diplopia, weakness
  • Worsens with muscle use
• Associated with…
  
  • Thymoma, thymic hyperplasia
• AChE inhibitor administrator
  
  • Reversal of symptoms

Question 32

Lambert-Eaton myasthenic syndrome

• Type of disease
• Frequency
• Pathophysiology
• Clinical
• Associated with…
• AChE inhibitor administrator

Answer 32

• Type of disease
  
  • Neuromuscular junction disease
• Frequency
  
  • Uncommon
• Pathophysiology
  
  • Autoantibodies to presynaptic Ca2+ channel –> decreased ACh release
• Clinical
  
  • Proximal muscle weakness, autonomic symptoms (dry mouth, impotence)
  • Improves with muscle use
• Associated with…
  
  • Small cell lung cancer
• AChE inhibitor administrator
  
  • Minimal effect

Question 33

Myositis ossificans

Answer 33

• Metaplasia of skeletal muscle to bone following muscular trauma [A].
• Most often seen in upper or lower extremity.
• May present as suspicious “mass” at site of known trauma or as incidental finding on radiography.