Musculoskeletal Pathology

EMBRYOLOGY

From what embryologic tissue type are muscle, bone, and connective tissue derived?

Mesoderm

What are the two embryologic processes by which bone may be formed?

1. Endochondral ossification—bones are formed by ossification of a cartilaginous matrix
   
2. Membranous ossification—bones are formed from connective tissues (eg, the skull)

Describe the process of endochondral ossification:

Primitive mesenchyme differentiates into chondrocytes which create a cartilaginous matrix at what will be the base of an articular surface. Osteoclasts remodel and mineralize this matrix creating bone tissue. Osteoblasts and blood vessels migrate into the newly forming bone.

Which stage of bone formation present in endochondral ossification is missing in membranous ossification?

Cartilaginous stage—in membranous ossification, mesenchyme differentiates directly into fibrous tissue containing osteoblasts.

ANATOMY

What are the three general types of bones in the human body?

1. Long bones
   
2. Flat bones
   
3. Short, tubular bones

The skeleton can also be classified as axial (central) or appendicular (appendage related).

What are the anatomic portions of long bones?

Epiphysis, metaphysis, diaphysis, and physis (the growth plate)

What are the four tendons that comprise the rotator cuff?

1. Supraspinatus
   
2. Subscapularis
   
3. Infraspinatus
   
4. Teres minor

What are the four major ligaments of the knee?

1. Anterior cruciate ligament
   
2. Posterior cruciate ligament
   
3. Medial collateral ligament
   
4. Lateral collateral ligament

What is the functional difference between a ligament and a tendon?

Ligaments connect bone to bone while tendons connect muscle to bone.

What system innervates smooth muscle?

Autonomic nervous system

HISTOLOGY

In cross-section of the diaphysis, what are the layers observed in bone?

From external to internal: periosteum, cortex, and medullary space

Name the two types of vascular channels found in compact bone:

1. Haversian (longitudinal) canals
   
2. Volkmann (transverse) canals

What are the main cell types found in bone?

Osteoblasts, osteoclasts, osteocytes, progenitor cells

What are osteoblasts?

Cells derived from osteoprogenitor cells that produce osteoid, hormones for local activity, alkaline phosphatase, and many other matrix proteins

What is osteoid?

A protein material produced by osteoblasts which will mineralize to become bone

What are osteocytes?

Mature osteoblasts that line areas of mineralized bone

What are osteoclasts?

Cells derived from monocytes that are responsible for bone resorption and remodeling

What cell type is responsible for creating calcified columns into which osteoblasts will migrate?

Chondrocytes

What is found in the medullary cavity of long bones?

Trabecular bone, bone marrow, blood vessels

What is the histologic composition of tendons?

Fibroblasts arranged in parallel rows, proteoglycan matrix, and type I collagen fibrils

What are the histologic differences between ligaments and tendons?

These structures are very similar histologically except that ligaments have slightly less collagen and more proteoglycan matrix.

Describe the histologic appearance of smooth muscle tissue:

Smooth muscle consists of spindle shaped cells of variable size each with one centrally placed nucleus.

Describe the histologic appearance of skeletal muscle tissue:

Skeletal muscle consists of tubular shaped cells (myocytes) with abundant red striated cytoplasm and peripherally located nuclei.

What is a sarcomere?

The smallest contractile unit in skeletal muscle. Regions of the sarcomere that are visible histologically, include I-band, A-band, H-band, Z-line, and M-line.

What is the “I-band” in a sarcomere?

A region of only actin filaments—this region becomes smaller during contraction.

What is the “H-band” in a sarcomere?

A region of only myosin filaments within the A-band—this region becomes smaller during contraction

What is the “A-band” in a sarcomere?

Represents the length of the myosin filaments, both ends of which overlap with actin filaments. The A-band stays the same length during contraction.

What molecular events occur during contraction of skeletal muscle?

Calcium enters the myocyte which binds troponin C causing a conformational change that results in release of tropomyosin from the myosin binding region on the actin filaments. In an ATP-dependent reaction, myosin binds the now exposed binding region on the actin filament. Contraction occurs when myosin relaxes back to its resting conformation causing movement of the actin and myosin filaments relative to each other.

How is the smooth muscle contractile apparatus different from the skeletal muscle contractile apparatus?

The smooth muscle apparatus utilizes calmodulin instead of troponins.

PATHOLOGY

Congenital

What is the condition in which patients experience failure of longitudinal bone growth resulting in short limbs but normal skull, facial bones, and axial skeleton development?

Achondroplasia

What is the condition associated with a genetic abnormality of type I collagen and susceptibility to bone fractures?

Osteogenesis imperfecta

What is the inheritance pattern of osteogenesis imperfecta (OI)?

Autosomal dominant—but sporadic cases are also possible

What are the abnormalities of type I collagen in OI?

There are eight types of OI, each with different clinical and genetic features. In all cases, there is either a qualitative (abnormal function) or quantitative (abnormal production) defect of type I collagen.

What eye abnormality is classically associated with OI?

Blue-colored sclera—sclera is thinner in OI patients due to collagen defect

What is Ehlers-Danlos syndrome (EDS)?

EDS is actually a group of inherited connective tissue disorders caused by a defect in type III collagen function or production. There are six types of EDS, each with different clinical and genetic features.

What are the usual major signs and symptoms of EDS?

Highly flexible joints which are prone to injury, hyperextension of joints, easy bruising and fragile blood vessels, “stretchy” skin, and abnormal wound healing and scar formation

What is muscular dystrophy?

A group of many inherited muscle disorders that are characterized by progressive skeletal muscle weakness, defective muscle proteins, and ultimately death of myocytes and muscle tissue

What is the most common form of childhood muscular dystrophy?

Duchenne muscular dystrophy

What gene is affected in Duchenne muscular dystrophy (DMD)?

Dystrophin gene—which normally encodes for a protein that is part of a complex which anchors myocytes to the surrounding connective tissue framework. In DMD, this protein is nonfunctional.

What is the inheritance pattern of DMD?

X-linked recessive—predominately affects males, while carrier females have a milder phenotype; sporadic mutations account for one-third of cases

What is Becker muscular dystrophy (BMD)?

Clinically, BMD is a less severe form of DMD. Whereas patients with DMD usually die in the twenties or thirties, patients with BMD may survive much longer.

What gene is affected in BMD?

Dystrophin gene—unlike DMD, in BMD the dystrophin protein is truncated but partially functional. Inheritance is also X-linked recessive.

Anatomic

What is osteopetrosis?

A condition resulting from the failure of normal bone resorption which results in thickened, dense bones

What cell type is defective in osteopetrosis?

Osteoclasts

With what other clinical features may patients with osteopetrosis present?

Anemia, thrombocytopenia, leukopenia—due to decreased marrow space

What is osteitis fibrosa cystica?

Associated with hyperparathyroidism, this condition is characterized by cystic spaces lined by osteoclasts that are filled with fibrous stroma and sometimes blood.

What pattern of serum calcium, phosphorous, and alkaline phosphatase is expected in osteitis fibrosa cystic patients?

Elevated serum calcium, low serum phosphorous, and high alkaline phosphatase

What is osteomalacia? How is this different from rickets?

Defective bone mineralization due to vitamin D deficiency and subsequent decreased serum calcium. This process is called osteomalacia when it occurs in adults and called rickets when it occurs in children.

What is thoracic outlet syndrome?

A syndrome of clinical features resulting from compression of the subclavian artery, subclavian vein, or structures in the brachial plexus as they pass through the superior thoracic outlet

What are some common causes of thoracic outlet syndrome?

Fibrous bands; cervical ribs; hypertrophied muscles

Traumatic

What name is given to a fracture of the distal radius caused by falling onto an outstretched hand?

Colles fracture

What is the most common carpal bone fracture?

Scaphoid fracture

Where is the pain located in scaphoid fractures?

Anatomical snuffbox

What is the injury that results in jersey finger?

Avulsion of flexor digitorum profundus

What causes de Quervain tenosynovitis?

Repetitive movements (like washing, hammering, or skiing) causing inflammation in the tendons of abductor pollicis longus and extensor pollicis brevis which control thumb movements

What nerve is entrapped in carpal tunnel syndrome?

The median nerve as it passes through the carpal tunnel at the wrist

What are some clinical conditions commonly associated with carpal tunnel syndrome?

Diabetes; hypothyroidism; renal failure; heart failure; pregnancy; amyloidosis

Degenerative

What disease is characterized by pain in weight-bearing joints, is worse after use, has crepitation with motion, no signs of inflammation, and is seen in the middle-aged population?

Osteoarthritis, aka degenerative joint disease (DJD)

What are the signs of DJD on x-ray?

Joint space narrowing, osteophytes

What are Heberden nodules?

Palpable distal interphalangeal (DIP) joints with osteophytes

What are Bouchard nodules?

Palpable proximal interphalangeal (PIP) joints with osteophytes

What are some treatments of DJD?

Nonsteroidal anti-inflammatory drugs (NSAIDs) and weight reduction to reduce strain on joints

What is osteoporosis?

Most often, an age-related reduction in bone density and mass

What are the two dominate clinical patterns of osteoporosis?

1. Postmenopausal
   
2. Senile

Name two fractures that are common among osteoporotic patients:

1. Vertebral crush fractures
   
2. Distal radius fractures

Inflammatory/Autoimmune

What is podagra?

Gout of the metatarsophalangeal (MTP) joint of the big toe

What is gout?

A condition in which monosodium urate crystals precipitate in joint spaces due to hyperuricemia

What other findings should be looked for in a patient with gout?

Tophi, subcutaneous deposits of uric acid crystals

How do tophi appear on x-ray?

As “punched out” lesions

What lab tests help to diagnose gout?

Uric acid level; joint fluid aspiration of needle-shaped crystals with negative birefringence

What other historical findings are associated with gout?

Thiazide diuretic use; Lesch-Nyhan syndrome; diets with high protein and alcohol

What is the treatment for gout?

Acute—colchicine, NSAIDs; maintenance—allopurinol

What are the notable differences between gout and pseudogout?

Pseudogout is clinically similar to gout except that it affects predominately large joints (eg, knee), is the result of deposition of calcium pyrophosphate crystals, and has no effective treatment options.

What other conditions are associated with pseudogout?

Hyperparathyroidism; hemochromatosis

How are the crystals of pseudogout different from the crystals of gout?

Calcium pyrophosphate (pseudogout) instead of monosodium urate (gout) and weakly positively birefringent (pseudogout) instead of negatively birefringent (gout)

Which joints are most commonly involved in rheumatoid arthritis (RA)?

Wrists, PIP, and metacarpophalangeal (MCP)—generally presenting with morning stiffness, symmetric distribution, and other systemic symptoms

What are some other findings with RA?

Fever; malaise; pericarditis; pleural effusions; uveitis; subcutaneous nodules

Which lab test should you order when you suspect RA?

Rheumatoid factor (RF)

What is rheumatoid factor (RF)?

An immunoglobin M (IgM) antibody to the Fc (fragment crystallizable) portion of IgG

What is the name given to the chronically inflamed cartilage found in RA?

Pannus

What disease would be expected in a young woman that suffers with RA-like symptoms (polyarthritis), leukopenia, leg ulcers, and splenomegaly?

Felty syndrome

What disease is similar to RA (bilateral joint pain, fever) but is seen in children, along with rash and hepatosplenomegaly?

Still disease (juvenile RA)

What is different about juvenile RA compared to adult RA?

It is often RF negative.

A 5-year-old child with juvenile RA presents with complaints in only two joints. Which subtype of juvenile RA is this?

Pauciarticular juvenile RA

What is a child with pauciarticular RA at risk for?

Iritis (requires slit lamp examination to diagnose)

What is Reiter syndrome?

Considered a seronegative spondyloarthropathy, Reiter syndrome is a form of arthritis associated with anterior uveitis or conjunctivitis and urethritis. There is a strong association with HLA-B27 and a male predominance.

What does “seronegative” refer to when discussing spondyloarthropathy?

Patients are seronegative for rheumatoid factor.

Previous exposure to which bacteria can precipitate Reiter syndrome?

Chlamydia trachomatis; GI infections including: Shigella, Salmonella, Campylobacter, or Yersinia species

Name two other types of seronegative spondyloarthropathy:

1. Ankylosing spondylitis
   
2. Psoriatic arthritis

What is ankylosing spondylitis?

A seronegative spondyloarthropathy involving chronic inflammation of the spine and sacroiliac joints and is also associated with uveitis, aortic regurgitation, and HLA-B27.

What clinical test should be performed in the office if considering a diagnosis of ankylosing spondylitis?

Schober test—decreased angle of anterior flexion of the back, eliciting pain

What is the classic sign on radiograph for ankylosing spondylitis?

Bamboo spine

What is the most common distribution of psoriatic arthritis?

Asymmetric arthritis in fingers or toes

What other symptoms are common with psoriasis?

Nail pitting; psoriatic arthritis with sausage digits

What is the phenomenon that describes the development of a psoriatic plaque in an area of previous trauma?

Koebner phenomenon

What is the name of the sign that occurs when a small amount of scale is removed from a psoriatic plaque, leaving small bleeding points behind?

Auspitz sign

What HLA type is associated with psoriatic arthritis?

HLA-B27

What are the official criteria for the diagnosis of SLE?

Oral ulcers; Renal disorder; Photosensitivity; Hematologic (anemias, cytopenias); Arthritis (nonerosive synovitis); Neurologic (seizures, psychosis); Serositis; Malar rash; Antinuclear antibody; Immunologic (anti-DNA, anti-Smith [anti-Sm], false positive rapid plasma reagin/Venereal Disease Research Laboratory (RPR/VDRL); Discoid rash

*The ORPHANS’ MAID has lupus

* 4 of 11 criteria are needed for diagnosis

In which sex and race is SLE most common and severe?

African American females

What cardiac lesion is associated with SLE in the adult and consists of nonbacterial verrucous valvular vegetations?

Libman-Sacks endocarditis

What are some other causes for chest pain in a patient with SLE?

Pleuritis; pericarditis

Which antibody system is associated with drug-induced lupus?

Antihistone antibodies

What are wire-loop lesions in the kidney and what do they represent?

Thickening of the capillary wall found in diffuse proliferative glomerulonephritis (GN); indicate a poor prognosis with SLE

Which neoplasm is associated with SLE and myasthenia gravis?

Thymoma

Which antibody is sensitive but not specific for the diagnosis of SLE?

Antinuclear antibody

Which two antibodies are very specific for SLE?

1. Anti-Smith antibody
   
2. Anti-double-stranded DNA antibody

Which two HLA types is SLE linked to?

1. HLA-DR2
   
2. HLA-DR3

What is sarcoidosis?

A multisystem inflammatory disease characterized by the presence of noncaseating granulomas often found in the lungs and lymph nodes but can be present in any organ system. Presenting symptoms are often vague but may include arthralgias, muscle pains, and skin rash.

What electrolyte abnormality is common with sarcoidosis?

Hypercalcemia

On biopsy of affected tissue, what is the classic finding?

Noncaseating granulomas

What skin findings are associated with sarcoidosis?

Erythema nodosum; lupus pernio (chronic, indurated, often violaceous skin lesion which may appear on the face, fingers, and ears)

What is scleroderma (systemic sclerosis)?

A condition of excessive fibrosis and collagen deposition throughout the body usually involving the skin and also heart, GI tract, and kidneys

What is the autoantibody that is most closely associated with this disease?

Anti-DNA topoisomerase I (anti-Scl-70) antibody

What are the two types of scleroderma?

1. Diffuse scleroderma
   
2. CREST syndrome

What are the characteristics of CREST syndrome?

Calcinosis (subcutaneous); Raynaud phenomenon; esophageal dysfunction; sclerodactyly; telangiectasia

What antibodies are most closely associated with CREST syndrome?

Anti-centromere antibody

What is the difference in clinical behavior between diffuse scleroderma and CREST syndrome?

Diffuse scleroderma has widespread skin involvement and rapid progression to involvement of visceral organs. CREST syndrome has a more benign clinical course with skin involvement often limited to the face and fingers.

What are the classic symptoms of Sjögren disease?

Xerostomia (dry mouth) and xerophthalmia (dry eyes)—(this combination is known as Sicca symptoms), secondary to autoimmune destruction of exocrine glands

What other symptoms are commonly associated with Sjögren disease?

Constipation, pancreatic insufficiency, parotid gland enlargement, vaginal dryness

How is Sjögren disease diagnosed?

Lip biopsy—looking for fibrosis and collagen deposition; Schirmer test (showing decreased lacrimation)

What autoantibodies are associated with Sjögren disease?

Anti-nuclear antibody (ANA) (nonspecific) and antinucleoprotein antibodies (SS-A [Ro] and SS-B)

What are patients with Sjögren disease at risk for developing?

Lymphoma

What is polymyositis?

A chronic inflammatory myopathy which may present with proximal muscle weakness. The etiology is not clearly known.

What lab findings support the diagnosis of polymyositis?

Increased ESR; increased creatine phosphokinase (CPK); increased aldolase; increased lactate dehydrogenase (LDH); antinuclear antibody (ANA) may be positive; abnormal electromyography

What is the only specific test that provides a definitive diagnosis of polymyositis?

Muscle biopsy showing lymphoid inflammation

What disease is characterized by symptoms and lab values similar to polymyositis, but also has a lilac edematous rash on the eyelids?

Dermatomyositis

What is the name of the rash on the eyelids found in dermatomyositis?

Heliotrope rash

What is the treatment for dermatomyositis and polymyositis?

High-dose steroids

What is polymyalgia rheumatic?

A syndrome associated with aching and stiffness in the neck, shoulders, and pelvic girdle of older adults. The etiology is not known.

What lab value would be abnormal in polymyalgia rheumatica?

Elevated ESR

With what other disease is polymyalgia rheumatica associated?

Temporal arteritis

What is fibromyalgia?

A chronic syndrome involving diffuse pains affecting the entire body and areas of tenderness in joints, muscles, and other soft tissues

What lab values should be evaluated in fibromyalgia?

CBC—normal; ESR—normal

How should a patient with fibromyalgia be treated?

Nonsteroidal anti-inflammatory drugs (NSAIDs) and antidepressants

Vascular

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