Bone and Soft-Tissue Disorders
= inherited disorders of hemoglobin synthesis typically seen in individuals of Mediterranean descent
Physiologic hemoglobins:
- in adulthood:
- Hb A (98% = 2 α- and 2 β-chains);
- Hb A2 (2% = 2 α- and 2 δ-chains)
- in fetal life:
- Hb F (= 2 α- and 2 γ-chains)
- rapidly decreasing up to 3 months of newborn period
- ALPHA-THALASSEMIA
= decreased synthesis of α-chains → excess of β-chains and γ-chains (Hb H = 4 β-chains; Hb Bart = 4 γ-chains)- disease begins in intrauterine life as no fetal hemoglobin is produced
- homozygosity is lethal (lack of oxygen transport)
- BETA-THALASSEMIA
= decreased synthesis of β-chains leading to excess of α-chains + γ-chains (= fetal hemoglobin)- disease manifest in early infancy
- homozygous defect = thalassemia major = Cooley anemia
- heterozygous defect = thalassemia minor
= COOLEY ANEMIA = MEDITERRANEAN ANEMIA = HEREDITARY LEPTOCYTOSIS = β-THALASSEMIA
= most severe form with trait inherited from both parents (= homozygous form)
Prevalence: 1% for American Blacks; 7.4% for Greek population; 10% for certain Italian populations
Age: develops after newborn period within first 2 years of life
- retarded growth
- elevated serum bilirubin
- hyperpigmentation of skin
- hyperuricemia
- secondary sexual characteristics retarded, normal menstruation rare ← primary gonadotropin insufficiency ← iron overload in pituitary gland
- hypochromic microcytic anemia (Hb 2–3 g/dL), nucleated RBC, target cells, reticulocytosis, decrease in RBC survival, leukocytosis
- susceptible to infection ← leukopenia ← splenomegaly
- bleeding diathesis ← thrombocytopenia
- Skull:
- mongoloid facies
- marrow expansion of diploe:
- widening of diploic space with coarsened trabeculations and displacement ← marrow hyperplasia (= extramedullary hematopoiesis)
- thinning of outer table
- frontal bossing
- severe hair-on-end appearance (frontal bone, NOT inferior to internal occipital protuberance)
- marrow expansion in paranasal sinuses:
- impaired pneumatization of maxillary antra + mastoid sinuses
- narrowing of nasal cavity
- rodent facies = ventral displacement of incisors ← marrow overgrowth in maxillary bone with dental malocclusion
- lateral displacement of orbits
- Peripheral skeleton:
- earliest changes in small bones of hands + feet (>6 months of age)
- diffuse osteopenia:
- atrophy + coarsening of trabeculae ← marrow hyperplasia
- prominence of nutrient foramina
- widened medullary spaces with thinning of cortices
- Erlenmeyer flask deformity = bulging of normally concave outline of metaphyses
- premature fusion of epiphyses (10%), usually at proximal humerus + distal femur
- arthropathy ← hemochromatosis + CPPD + acute gouty arthritis
- regression of peripheral skeletal changes (as red marrow becomes yellow)
- Chest:
- cardiac enlargement + congestive heart failure ← anemia
- paravertebral masses (= extramedullary hematopoiesis)
- Ribs
- costal osteomas = bulbous widening of posterior aspect of ribs with thinned cortices
- undertubulated broad ribs
- heterogeneous rib ossification:
- localized lucencies
- cortical erosion
- rib-within-rib appearance
- Abdomen:
- hepatosplenomegaly
- gallstones
Cx:
- Pathologic fractures
- Iron overload + hemosiderosis ← frequent blood transfusion therapy (absent puberty, diabetes mellitus, adrenal insufficiency, myocardial insufficiency)
Prognosis: usually death within 1st decade
Rx: systematic transfusion has lessened the severity of skeletal abnormalities
DDx: chronic anemia, storage diseases, fibrous dysplasia
= subgroup of homozygous form
- milder clinical presentation
- not requiring hypertransfusion to maintain an adequate hematocrit
Prognosis: longer life expectancy
= beta-thalassemia trait inherited from one parent (heterozygous)
- usually asymptomatic except for periods of stress (pregnancy, infection)
- microcytic hypochromic anemia (Hb 9–11 g/dL)
- occasionally jaundice + splenomegaly