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Defect in the gene encoding activin receptor type IA/activin-like kinase 2(ACVR1/ALK2), a bone morphogenetic protein type 1 (BMP-1) receptor

Also linked to overproduction of BMP-4

Clinical features

Congenital malformation of the great toe (short, valgus position with an abnormally shaped proximal phalanx)

Progressive heterotopic ossification of tendons, ligaments, fascia, and skeletal muscle, which ultimately eliminates motion of the jaw, neck, spine, shoulders, hips, and more distal joints

Any form of trauma may precipitate new ossification.

Also called myositis ossificans progressiva or stone man syndrome


No clearly effective medical treatment

Goal to minimize the risk of injury without compromising the patient’s functional level and independence

Surgical excision not indicated; may precipitate new ossification


Rett Syndrome

Family of deletion mutations of the X-linked gene encoding a protein called methyl-CpG-binding protein 2 (MECP2)

Clinical features

Progressive impairment and stereotaxic abnormal hand movements (like those in autism)

Manifests in girls at 6–18 months of age

Loss of developmental milestones that is rapid and then stabilizes

Scoliosis with a C-shaped curve that is unresponsive to bracing


Spinal instrumentation must include all of the kyphosis and the scoliosis.

Spasticity results in joint contractures, which are treated as they are in cerebral palsy.


Beckwith-Wiedemann Syndrome

Mutation of chromosome 11 near IGF gene

Clinical features

Organomegaly, omphalocele, and a large tongue

Orthopaedic manifestations include hemihypertrophy with spasticity

Spasticity is thought to be the result of infantile hypoglycemic episodes secondary to pancreatic islet cell hypertrophy

Growth arrest may be necessary in large limb

Predisposition to Wilms tumor (patient must be screened regularly with kidney ultrasonography)


Nail Patella Syndrome

Autosomal dominant

The gene for nail-patella syndrome is LMX1B, located on chromosome 9

Clinical features

Nail deformity (present in 98% of patients) is greatest in the thumbnails and becomes less severe in the more ulnar digits.

Absence or hypoplasia of patella, hypoplastic lateral femoral condyle, and genu valgum may all contribute to patellar instability.

Hypoplasia of the lateral side of the elbow, cubitus valgus

Iliac horns (conical bony projections on posterior ilia)

Nephropathy present in up to 40% of patients


There is no specific treatment for the disorder.

The iliac horns do not affect gait and should not be resected.

Recurrent dislocation of the patella is treated by proximal or distal realignment.


Gaucher's Disease

Autosomal recessive lysosomal storage disease

Deficiency of the enzyme β-glucocerebrosidase

Results in accumulation of cerebroside in the reticuloendothelial system

Clinical features


Bone pain (Gaucher crisis) and bleeding abnormalities

Hepatosplenomegaly (characteristic finding)


Type I: most commonly in persons of Ashkenazi Jewish descent

Type II: infantile

Type III: chronic neuropathic

Radiographic findings

Metaphyseal enlargement (failure of remodeling)

Femoral head necrosis (may be confused with Perthes disease or MED)

Moth-eaten trabeculae, patchy sclerosis, and Erlenmeyer flask deformity of the distal femora (70% of cases)

Treatment is supportive; enzyme replacement and bone marrow transplant are options


Niemann-Pick Disease

Autosomal recessive disorder

lipid storage disorge

Accumulation of sphingomyelin in reticuloendothelial system cells

Occurs commonly in Jews of eastern European descent

Marrow expansion and cortical thinning common in long bones; coxa valga also seen


Sickle-Cell Anemia

Mutation in the β-globin gene, resulting in sickle hemoglobin (HbS)

When the cell becomes deoxygenated, HbS molecules assemble into fibers that produce a sickle-shaped red blood cell.

Sickle cell trait: one abnormal HbS allele

More common but less severe than sickle cell anemia (8% prevalence)

Patient at risk for exertional sickling; treated with oxygen and hydration

Patient also at risk for sudden death

Clinical features

Sickle cell disease affects 1% of African Americans

Sickle cell crises usually begin at ages 2 to 3 years

Caused by substance P

May lead to bone infarctions

Hydroxyurea has produced dramatic relief of bone in crises


Salmonella infection more commonly seen than in normal population but S. aureus still most common etiology

Differentiation of bone infarction and osteomyelitis

Sequential radionuclide bone marrow and bone scans (crises show decreased bone marrow uptake)

Aspiration and culture may be necessary

Avascular necrosis of the femoral and humeral head

Acetabular protrusion



Similar to sickle cell anemia in manifestation

Most commonly observed in people of Mediterranean descent

Common symptoms include bone pain and leg ulceration.

Radiographic findings

Long-bone thinning, metaphyseal expansion, osteopenia, and premature physeal closure



X-linked recessive disorder

Hemophilia A: decreased amounts of factor VIII

Hemophilia B: decreased amounts of factor IX

Can be mild (5%–25% of normal amounts of factor present), moderate (1%–5% present), or severe (<1% present)

Clinical features

Hemarthrosis manifests as painful swelling and decreased ROM of affected joints

Knee most commonly affected

Deep intramuscular bleeding is also common and can lead to formation of a pseudotumor (blood cyst).

Intramuscular hematomas can cause compression of adjacent nerves (iliacus hematoma that compresses femoral nerve).

Radiographic findings

Squaring of patellae and condyles, epiphyseal overgrowth with LLD

Generalized osteopenia with resulting fractures

Cartilage atrophy resulting from enzymatic matrix degeneration and chondrocyte death


Factor VIII should be administered in the following situations (target increase shown in parentheses)

Vigorous PT (20%)

Treatment of hematoma (30%)

Acute hemarthrosis or soft tissue surgery (>50%)

Skeletal surgery (approaching 100% preoperatively and maintained at >50% for 10 days postoperatively)

Acute treatment of hemarthrosis is crucial and should begin immediately with administration of factor VIII or factor IX

Administration should continue for 3 to 7 days after cessation of bleeding and should be followed by PT.

Home transfusion therapy, with the advantage of immediate treatment when bleeding occurs, has reduced the severity of the arthropathy

Aspiration of a hemarthrosis is controversial.


Indicated for hemarthroses that recur despite optimal medical management

Arthroscopy has better results with motion and duration of hospitalization than does open synovectomy.

Radiation synovectomy: useful in patients with antibody inhibitors and poor medical management

Contracture release and osteotomies

Total joint arthroplasty for hemophilic arthropathy




Vitamin D deficiency

Clinical features

Short stature

Limb angulation (usually varus)

Bone pain


Deficiency of calcium (and sometimes phosphorus), which affects mineralization at the epiphyses of long bones

X-linked hypophosphatemic (vitamin D–resistant) rickets: defect in cellular endopeptidase (phosphate-regulating neutral endopeptidase)

Histologic findings: widened osteoid seams and Swiss cheese trabeculae are characteristic in bone.

Growth plate abnormalities include an enlarged and distorted maturation zone (zone of hypertrophy) and a poorly defined zone of provisional calcification.

Radiographic findings

Brittle bones with physeal cupping/widening, bowing of long bones, transverse radiolucent Looser lines, ligamentous laxity, flattening of the skull, enlargement of costal cartilages (rachitic rosary), and dorsal kyphosis (cat back) (Fig. 3.44)


Based on the underlying abnormality (e.g., kidney, diet, gastrointestinal, and organ); see Chapter 1, Section 1


Osteogeneis Imperfecta

Defect in type I collagen (COL1A1 and COL1A2 genes) that causes abnormal cross-linking and leads to decreased collagen secretion

Histologic findings: increased diameters of haversian canals and osteocyte lacunae, increased numbers of cells, and replicated cement lines, which result in the thin cortices seen on radiographs


Multiple types have been identified.

Sillence originally described four types; now at least eight forms recognized

Disorder probably best considered a continuum with different inheritance patterns and severity (Table 3.19).

Clinical features

Bone fragility (brittle wormian bone), short stature


Tooth defects (dentinogenesis imperfecta)

Hearing defects

Blue sclerae in types I and II

Ligamentous laxity

Basilar invagination is common in more severe clinical phenotypes.

Fractures are common.

Healing is normal, but bone typically does not remodel

Fractures occur less frequently with advancing age (usually cease at puberty)

Compression fractures (codfish vertebrae) are also common.

Olecranon apophyseal fractures more commonly seen in OI than in the general population

Bowing results from multiple transverse fractures of the long bones and muscle contraction across the weakened diaphysis.

Typically an anterolateral bow or proximal varus deformity of the femur develops.

An anterior or anteromedial bow of the tibia may develop.


Bracing of extremities early to prevent deformity and minimize fractures

Sofield osteotomies—“shish kebab” osteotomies; multiple long-bone osteotomies with either fixed-length Rush rods or telescoping (Bailey-Dubow or Fassier-Duval) intramedullary rods—are sometimes required for progressive bowing of long bones.


Treatment in children younger than 2 years similar to that in children without osteogenesis imperfecta

After age 2 years, telescoping intramedullary rods can be considered.

Bisphosphonates have been shown to decrease the number of fractures in these patients.

Characteristic dense parallel metaphyseal bands may be seen on x-ray. Distance between bands corresponds to time between treatments.

Iatrogenic osteopetrosis can occur with high-dose, long-term use of bisphosphonates.


Bracing generally ineffective

Fusion associated with large blood loss


Juvenile Idiopathic arthritis

Clinical features

Persistent noninfectious arthritis lasting 6 weeks to 3 months and diagnosed after other possible causes have been ruled out

Affects girls more than boys and typically manifests before age 4 years

Can be polyarticular, pauciarticular, or systemic

Commonly involves the knee, wrist (flexed and ulnar deviated), and hand (fingers extended, swollen, radially deviated)

To confirm diagnosis, one of the following must be present: presence of rheumatoid factor, iridocyclitis, cervical spine involvement, pericarditis, tenosynovitis, rash, intermittent fever, or morning stiffness.

Ophthalmology consultation with slit-lamp examination is required twice yearly because progressive iridocyclitis can lead to rapid loss of vision if left untreated.

In 50% of affected patients, symptoms resolve without sequelae; 25% of patients are slightly disabled, and 20%–25% have crippling arthritis, blindness, or both.

Cervical spine involvement can lead to kyphosis, facet ankylosis, and atlantoaxial subluxation.

Lower extremity problems include flexion contractures (hip and knee flexed, ankle dorsiflexed), subluxation, and other deformities (hip protrusion, valgus knees, equinovarus feet)


NSAIDS or steroids

Disease modifying antirheumatic drugs (DMARDs)


TNF blockers (etanercept, infliximab)

Rituximab (chimeric anti-CD20 monoclonal antibody)

Surgical interventions

Joint injections and (rarely) synovectomy for chronic swelling refractory to medical management

Arthrodesis and arthroplasty may be required for severe juvenile idiopathic arthritis

Systemic-onset JIA (Still disease): approximately 10%–20% of patients

Systemic involvement: can be fatal

Diurnal fevers (rabbit-ear graph)

Nonpruritic salmon-pink macular evanescent rash

Lymphadenopathy, hepatosplenomegaly, serositis

Macrophage activation syndrome (MAS)

Cytokine storm caused by T-cell activation

Disseminated intravascular coagulation (DIC) causes bruising and mucosal bleeding

Causes elevated ferritin value but decreased ESR


Ankylosing Spondylitis

Systemic autoimmune spondyloarthropathy

HLA-B27 present in 90%–95% of patients

The antigen is also present in 4%–8% of all white Americans; thus its usefulness as a screening tool is limited.

Clinical features

Typically affects adolescent boys

Asymmetric, lower-extremity, large-joint arthritis

Heel pain

Hip and back pain (cardinal symptoms) may develop later.

Progressive kyphosis

Limitation of chest wall expansion is a more specific finding than is a positive result of HLA-B27 test.

Uveitis and iritis

Radiographic findings

Bilateral symmetric sacroiliac erosion followed by joint space narrowing, subsequent ankylosis, and late vertebral scalloping (bamboo spine). Radiographs typically lack sensitivity in early stages of the condition.

Early sacroiliitis evident on MRI may allow for diagnosis far earlier than was previously possible.


NSAIDs and PT mainstays of treatment

TNF antagonists such as etanercept, infliximab, and adalimumab are used if NSAIDs are ineffective.

Management of spinal deformity is discussed in Chapter 8, Spine.