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 Bone and Soft-Tissue Disorders

= common inherited autosomal recessive hemoglobinopathy with 2 abnormal β-globin genes (homozygous / heterozygous in combination with other abnormal hemoglobins) characterized by sickle-shaped RBCs cleared by RES

Normal adult hemoglobin:

Hb A = 2 α globin chains on chromosome 16p13.3 (duplicated on each chromosome = 4 gene loci) + 2 β globin chains on chromosome 11p15.5 (one copy on each chromosome = 2 gene loci)

Genetics: mutation in both alleles of β-globulin gene

Hb S = DNA point mutation at the 6th codon in β-globin gene located on short arm of chromosome 11 → glutamic acid in position 6 on β-chain is substituted with valine (α2βS2)

Hb C = DNA point mutation substitutes glutamic acid in position 6 on β-chain with lysine (α2βC2)

Definition:

Sickle cell anemia = any formation of Hb S in combination with one other abnormal hemoglobin:

  1. homozygous (with another sickle cell chain Hb S)
    1. Hb SS = sickle cell disease
  2. heterozygous (with other abnormal chain, not Hb S)
    • Hb SC disease
    • Hb S-thal

Prevalence: 8–13% of African Americans carry sickling factor (gene for Hb S); 1÷600 African Americans in USA are homozygous (Hb SS) and have sickle cell disease; 1÷40 with sickling trait will manifest sickle cell disease; 1÷120 with sickling trait will manifest Hb SC disease; affects people from Middle East + eastern Mediterranean region

Pathogenesis:

low oxygen tension → deoxygenation of Hb S → aggregation of abnormal Hb molecules into long chains (= polymerization into twisted ropelike Hb molecule strands with binding between chains) →

  1. increase in blood viscosity with stasis in microvasculature (“log jam” occlusion of small blood vessels) → tissue ischemia → infarction, necrosis, superinfection
  2. altered plasticity + distortion of RBCs into sickle shape → intravascular hemolysis → endothelial injury → coagulopathy + vasomotor in stability + proliferative vasculopathy → pulmonary hypertension

Location: damage of intima occurs most frequently in vessels with high flow rates (terminal ICA); sickling occurs in areas of

  1. slow flow (spleen, liver, renal medulla)
  2. rapid metabolism (brain, muscle, placenta)

Cx: high incidence of infections (lung, bone, brain)

Prognosis: death <40 years (decrease of average life expectancy by 25–30 years)

Osseous Manifestation of Sickle Cell Disease  !!navigator!!

  1. DEOSSIFICATION DUE TO MARROW HYPERPLASIA
    Cause: chronic anemia → constant marrow stimulation and medullary expansion → trabecular thickening + cortical thinning → bone softening → pathologic fractures
    Pathogenesis: arrested conversion of red to yellow marrow → persistence of appendicular red marrow in ankles + wrists + shafts of long bones
    • granular appearance of skull ← porous decrease in bone density of skull (25%)
    • widening of diploe with thinning of inner and outer tables (22%)
    • vertical hair-on-end striations projecting from outer skull vault (5%) ← prominent trabeculae + new bone
    • coarse trabeculae of mandible
    • osteopenia with thinning of trabeculae
    • biconcave “fish-mouth” vertebrae = compression fracture of vertebral endplates ← invagination of intervertebral disks ← bone softening (in 70%)
      Cx: kyphosis from vertebral collapse
    • widening of medullary space + thinning of cortices
      Cx: pathologic fracture
    • coarsening of trabecular pattern in long + flat bones
    • rib notching
  2. EXTRAMEDULLARY HEMATOPOIESIS more common in other hemolytic anemias
    Location: liver, spleen, paravertebral region, kidney, adrenal gland, skin, paranasal sinus
    • intermediate signal intensities on T1WI + T2WI
    • uptake by 99mTc-sulfur colloid
  3. THROMBOSIS AND INFARCTION OF BONE
    Cause: abnormal RBCs → vaso-occlusive disease
    1. bone infarcts + avascular necrosis within epiphyses and medullary cavities
    2. infarcts of muscles + soft tissue → myonecrosis and ulcers

    Location: in diaphysis of small tubular bones (children); in metaphysis + subchondrium of long bones (adults)
    • sickle cell dactylitis = hand-foot syndrome (in 50%):
      Age: 6 months – 2 years; rare >6 years ← regression of red marrow
      Cause: cold-induced vasoconstriction
      • tender swollen hand / foot with reduction in movement; fever
      • patchy areas of lucency + periosteal reaction
      • ± bone destruction → deformity
    • osteolysis (in ACUTE infarction)
    • bone sclerosis (= dystrophic medullary calcification) in pelvis, ribs, spine
    • bone-within-bone appearance = periosteal reaction / layered new bone deposits along inner surface of infarcted cortex
    • juxtacortical sclerosis
    • Lincoln log = Reynold sign = H-vertebrae = steplike endplate depression
    • articular disintegration
    • epiphyseal infarction (in 50% by age 35 years)
      = avascular necrosis = frequently bilateral collapse of femoral head (DDx: Legg-Calvé-Perthes disease)
      • joint pain + limited movement

    NUC (bone agent):
    • decreased / normal radiotracer uptake (first few days)
    • increased uptake (with revascularization)
    • return to normal (after a few months in old infarcts with adequate blood supply)
    • photopenic foci (in avascular bone of old infarcts)

    MR:
    • high signal intensity of bone marrow edema on STIR
    • “serpiginous double line” sign on T2WI = hyperintense inner border (← inflammatory response with granulation tissue) + hypointense periphery (← reactive bone interface)
    • heterogeneous rimlike enhancement
    • ± subperiosteal hemorrhage + fluid collection
  4. SECONDARY OSTEOMYELITIS (18%)
    Pathogenesis: hyposplenism → impaired phagocytosis, complement dysfunction → increased susceptibility to osteomyelitis + septic arthritis
    Organism: Salmonella in unusual frequency (S. typhimurium, S. enteritidis, S. choleraesuis, S. paratyphi B) >Staphylococcus aureus (10%) >gram-negative enteric bacilli
    Location: long bones (mostly), vertebrae
    • positive blood culture (50%)
  5. GROWTH EFFECTS ← diminished blood supply
    Location: particularly in metacarpus / phalanx
    • bone shortening = premature fusion of infarcted physis
    • epiphyseal deformity with cupped metaphysis
    • tibiotalar slant
    • protrusio acetabuli (20%)
    • cup / peg-in-hole defect of distal femur
    • diminution in vertebral height (shortening of stature + kyphoscoliosis)
    • H-shaped vertebra with central growth plate infarction
    • tower vertebrae = compensatory lengthening of vertebrae adjacent to H-shaped vertebra

Bone marrow scintigraphy:

  • usually symmetric marked expansion of hematopoietic marrow beyond age 20 involving entire femur, calvarium, small bones of hand + feet (normally only in axial skeleton + proximal femur and humerus)
  • bone marrow defects indicative of acute / old infarction

99mTc-diphosphonate scan:

  • increased overall skeletal uptake (high bone-to-soft tissue ratio)
  • prominent activities at knees, ankles, proximal humerus (delayed epiphyseal closure / increased blood flow to bone marrow)
  • bone marrow expansion (calvarial thickening with relative decrease in activity along falx insertion)
  • decreased / normal uptake on bone scan within 24 hr in acute infarction / posthealing phase following infarction (cyst formation)
  • increased uptake on bone scan after 2–10 days persistent for several weeks in healing infarction
  • increased uptake on bone scan within 24–48 hours in osteomyelitis
  • increased blood-pool activity + normal delayed image on bone scan in cellulitis
  • renal enlargement with marked retention of tracer in renal parenchyma (medullary ischemia + failure of countercurrent system) in 50%
  • persistent splenic uptake ← degeneration, atrophy, fibrosis, calcifications

CNS Manifestations of Sickle Cell Disease  !!navigator!!

Pathophysiology:

chronic anemia produces cerebral hyperemia, hypervolemia, impaired autoregulation

  1. cerebral blood flow cannot be increased leading to infarction in time of crisis
  2. increased cerebral blood flow → produces epithelial hyperplasia of large intracranial vessels (terminal ICA / proximal MCA) resulting in thrombus formation
  • stroke (5–17%): ischemic infarction (70%), ischemia of deep white matter (25%), hemorrhage (20%), embolic infarct
  • arterial tortuosity (= adaptive response to chronic anemia):
    • ectasia of arterial segment
    • abnormal increase in length of an arterial segment → obvious bowing of an arterial segment

Angio (in 87% abnormal):

  • arterial stenosis / occlusion of supraclinoid portion of ICA + proximal segments of ACA and MCA
  • moyamoya syndrome (35%)
  • distal branch occlusion ← thrombosis / embolism
  • aneurysm (rare)

CT:

  • cerebral infarction (mean age of 7.7 years)
  • subarachnoid hemorrhage (mean age of 27 years)

Splenic Manifestations of Sickle Cell Disease  !!navigator!!

  • splenomegaly <age 10 (in patients with heterozygous sickle cell disease)
    Cx: splenic rupture
  • splenic infarction
  • hemosiderosis

Functional Asplenia

= anatomically present nonfunctional spleen

  • Howell-Jolly bodies, siderocytes, anisocytosis, irreversibly sickled cells
  • normal-sized / enlarged spleen on CT
  • absence of tracer uptake on sulfur colloid scan

Autosplenectomy

= autoinfarction of spleen in homozygous sickle cell disease (function lost by age 5)

Histo: extensive perivascular fibrosis with deposition of hemosiderin + calcium

  • small (as small as 5–10 mm) densely calcified spleen

Acute Splenic Sequestration Crisis

= sudden trapping of large amount of blood in spleen

Cause: obstruction of small intrasplenic veins / sinusoids; unknown trigger event

Age:

  1. homozygous: infancy / childhood
  2. heterozygous: any age
  • LUQ pain ← sudden massive splenic enlargement
  • rapid drop in hemoglobin, hematocrit, platelets ← spleen traps large volumes of blood
  • rise in reticulocytes
  • enlarged spleen
  • multiple lesions at periphery of spleen: hypoechoic by US, of low attenuation by CT
  • hyperdense areas ← acute hemorrhage
  • hyperintense areas on T1WI + T2WI ← subacute hemorrhage
  • main splenic vessels patent by Doppler US

Prognosis: in 50% death <2 years of age ← hypovolemic shock

Other Manifestations of Sickle Cell Disease  !!navigator!!

  • Chest
    • cardiomegaly + CHF
  • Gallbladder
    • cholelithiasis
  • Kidney
    • hematuria ← multiple infarctions
    • hyposthenuria
    • nephrotic syndrome
    • renal tubular acidosis (distal)
    • hyperuricemia ← increased cell turnover
    • progressive renal insufficiency
    • normal urogram (70%)
    • papillary necrosis (20%)
    • focal renal scarring (20%)
    • smooth large kidney (4%)

    US:
    • increased cortical echogenicity ← glomerular hypertrophy + interstitial fibrosis
    • increased medullary echogenicity ← vascular congestion (in older child)

    MR:
    • decreased cortical signal on T2-weighted images ← renal cortical iron deposition
  • Fat embolism syndrome
    = rare potentially lethal complication of sickle cell disease with diagnosis based on clinical manifestations
    Cause: bone marrow infarcts + necrosis → embolization of fat to multiple organs
    Pathomechanism:
    • bone marrow necrosis → fat globules enter venous channels + circulation → R-to-L shunt / traversing pulmonary capillary bed → systemic fat emboli
      1. occlusion of end-organ capillaries → local ischemia + inflammation → release of vasoactive amines
      2. hydrolysis of free fatty acids → toxic intermediates → damage of capillary endothelium

    Primary criteria:
    • cutaneous petechiae (= microscopic hemorrhagic infarcts) ← vessel wall rupture from embolus / extravasation of blood surrounding area of necrosis
    • progressive respiratory distress: dyspnea, severe hypoxemia, ARDS
    • cerebral involvement: altered level of consciousness, seizures, focal neurologic deficits, coma

    Secondary criteria:
    • tachycardia
    • fever
    • anemia + thrombocytopenia

    CT: typically negative
    MR:
    Location: diffuse widespread + unusual sites (splenium, internal capsule)
    • starfield pattern = innumerable bright punctate foci on DWI
    • numerous “blooming” black dots of susceptibility artifacts on T2* (= microhemorrhages)
    • diffuse hyperintense foci on FLAIR + T2WI ← edema

Sickle Cell Trait= Sickling Trait  !!navigator!!

= mild disease with few episodes of crisis + infection; sickling provoked only under extreme stress (unpressurized aircraft, anoxia with CHD, prolonged anesthesia, marathon running)

Prevalence: 8–10% of American Blacks

Composition: Hb AS formation (55% Hb A + 45% Hb S)

  • asymptomatic; recurrent gross hematuria
  • may have normal laboratory tests = NO anemia
  • splenic infarction

SC Disease  !!navigator!!

Prevalence: 3% of American Blacks (more common but less severe form than sickle cell disease)

  • less frequent + less severe symptoms of sickle cell disease
  • occasionally normal Hb levels
  • retinal hemorrhages
  • gross hematuria ← multiple infarctions
  • aseptic necrosis of femoral head

Rx: similar to sickle cell disease

Sickle-Thal Disease = β-Thalassemia (rare)  !!navigator!!

[thalassa, Greek = sea]

= underproduction of the β chain ← mutations in the HBB gene on chromosome 11

Composition: Hb SA (65–90% Hb S + 5–25% Hb A + elevated Hb A2 and Hb F)

  • clinically resembling Hb SS patients
  • anemia (no normal adult hemoglobin)
  • persistent splenomegaly

 Outline