Erythrocytes in circulating blood carry oxygen to tissues. Hemoglobin carries the oxygen in erythrocytes. Mutations in the genes that encode for protein synthesis can cause abnormal hemoglobin molecules that affect the form and function of erythrocytes. Iron deficiency and chronic inflammation can also diminish production of hemoglobin, resulting in anemia. Disorders in number, form, or function of erythrocytes can cause significant musculoskeletal pathology, and can complicate the treatment of other musculoskeletal conditions.
Sickle Cell Disease.
Sickle cell disease (SCD) is an inherited disorder of hemoglobin synthesis. The protein component of hemoglobin is composed of four globin chains: two α-globin chains and two β-globin chains. Hemoglobin S refers to hemoglobin containing abnormal β-globin produced by a single base change mutation (GAT to GTT) in the sixth codon of exon 1 in the β-globin gene on chromosome 11 (36
). As a result, the molecule polymerizes upon (37
) deoxygenation, causing distortion or “sickling” of the erythrocytes that contain the abnormal hemoglobin. Hemoglobin C contains β-globin chains with a glutamic acid-to-lysine substitution at the same position.
Four major types of SCD are recognized, according to the genotype of the β-globin gene and the resulting proportion of hemoglobin S. (a) SS disease results from homozygous inheritance of the hemoglobin S mutation. All hemoglobin is hemoglobin S and the sickling is severe. (b) SC disease results from inheritance of one hemoglobin S allele and one hemoglobin C allele. None of the hemoglobin is normal, but the tendency to sickle is tempered by the presence of hemoglobin C. (c) Sβ+ disease results from inheritance of one hemoglobin S allele and an allele with a β-thalassemia mutation that causes slightly reduced β-globin synthesis. Some normal β-globin is produced, and sickling is less severe. (d) Sβ0 disease results from inheritance of one hemoglobin S allele and an allele with a β-thalassemia mutation that causes greatly reduced β-globin synthesis. Very little normal β-globin is produced, leading to a preponderance of hemoglobin S and severe sickling.
Marrow hyperplasia can lead to osteopenia, biconcave vertebrae, and medullary expansion and cortical thinning due to marrow (38
) (Fig. 10-2
Vascular occlusion causes most of the clinical manifestations of SCD. Several factors cause sickle cells to occlude the microvasculature, including abnormal cell shape, cellular dehydration, and increased cellular adhesion to vascular endothelium. Sickling of erythrocytes is thought to confer resistance to infection by Plasmodium falciparum
malaria, contributing to the high prevalence in populations where malaria is common. In the United States, SCD affects 1 in 300 to 1 in 600 African Americans (39
). Screening facilitates early diagnosis and treatment, which can improve the clinical course (41
Vaso-occlusive pain events, or pain crises involving the extremities and the back, are common manifestations of SCD (42
). Pain crises are commonly associated with infarcts in the humerus, tibia, and femur (43
), although infarcts can occur in any bone in the body. Patients presenting with pain crises rarely have striking findings on physical examination. Swelling and decreased range of motion are usually not present. Fever is variably present. Peripheral leukocytosis and erythrocyte morphology on peripheral blood smears have no diagnostic use in a pain crisis (44
). Analgesia is the cornerstone of treatment for
a pain crisis. Hydration is an important adjunct to analgesics. Oxygen supplementation has no proven benefit in a patient who is not hypoxic (45
FIGURE 10-2. Oblique radiograph of the spine in a patient with SCD. Note biconcave vertebral bodies.
Dactylitis, a painful swelling of fingers or toes, occurs in early childhood and is often the first clinical manifestation of SCD and is typically seen in children under the age of 6 years. Onset of dactylitis before the age of 1 year has been suggested to predict a more severe case of SCD (46
). The rarity of dactylitis in older children is thought to result from a shift in hematopoiesis from distal sites such as fingers and toes in infants to more central sites in older children (45
). Radiographs are initially normal, but may progress to demonstrate periosteal elevation and osteolysis, mimicking osteomyelitis. Cultures of bone aspirates can help in making a diagnosis by differentiating between the two disorders. The pain associated with dactylitis is often mild and is relieved by nonsteroidal anti-inflammatory drugs (NSAIDs) in infants, but can be severe in older children.
Osteomyelitis occurs in patients with SCD and can be difficult to differentiate from a pain crisis. Osteomyelitis is much less common than pain crises; in one study, only 1.6% of patients admitted to the hospital for severe musculoskeletal pain had osteomyelitis (47
). Although patients with SCD experience higher rates of Salmonella
osteomyelitis than patients without SCD, Staphylococcus aureus
is still the most common bacterial pathogen (48
). As microvascular occlusion in the spleen causes repeated splenic infarcts, patients become functionally asplenic and susceptible to infections with encapsulated bacteria such as Streptococcus pneumoniae, Salmonella,
). Intestinal infarcts with translocation of gut bacteria are thought to be responsible for the high rate of infection from Salmonella
and other enteric bacteria. Prompt recognition and treatment of osteomyelitis is important. However, it is difficult to differentiate between painful bone infarcts and osteomyelitis, and, therefore, the diagnosis of osteomyelitis is often delayed (54
). The history and physical examination findings are similar in the two conditions. Also laboratory values such as white blood cell count, erythrocyte sedimentation rate, and C-reactive protein are also similar. Imaging is often inconclusive. Plain films are rarely diagnostic. Ultrasound is occasionally effective in detecting subperiosteal fluid collections. Technetium-99m sulfur colloid bone marrow scan followed by technetium-99m methylene diphosphonate bone scan has been reported to differentiate between the two conditions (58
), but without proven consistency. Magnetic resonance imaging (MRI) cannot reliably differentiate between sickle infarct and osteomyelitis. The bone marrow manifestations of SCD are primarily related to the hematopoietic marrow hyperplasia, infarction, and perivascular fibrosis. Findings of acute marrow infarction are present in only one-third of cases. Conversely, similar findings on MIR often occur in the absence of clinical symptoms, probably as a result of subclinical (59
) infarcts. Gadolinium-enhanced MRI can be useful in distinguishing vascularized inflammatory tissue from abscess, thus guiding aspiration for fluid collection.
The clinical response is important for differentiating between painful crisis and osteomyelitis in patients with SCD. In a painful crisis, symptoms should abate within 24 to 48 hours with hydration and analgesics. If the patient fails to improve, MRI is typically the next step. MRI evidence of intraosseous, subperiosteal, or soft-tissue fluid collection warrants aspiration or surgical drainage.
Septic arthritis is less common than osteomyelitis (57
). As opposed to osteomyelitis, septic arthritis is not caused by unusual organisms such as Salmonella
). The treatment of septic arthritis in patients with SCD follows the principles outlined elsewhere in this text.
Osteonecrosis (ON) of the femoral and the humeral heads is common in patients with SCD (Fig. 10-3
). ON of the femoral head is slightly more common than that of the humeral head. The development of ON is related to age and genotype (61
). By age 45, nearly one-third of patients have femoral head ON, and nearly one-fourth have humeral head ON. Femoral head ON is bilateral in 54% of the patients, and humeral head ON is bilateral in 67% of the patients. Concomitant femoral and humeral head ON occurs in three-fourths of the patients. The genotype affects the prevalence of ON. As with other manifestations of the disease, patients with SS or Sβ0
disease have a higher incidence of ON than do those with SC or Sβ+
ON may be asymptomatic in the hips and shoulders of children. Abnormalities may show up on radiographs several
years before symptoms appear, and the prognosis is worse in SCD than other causes of femoral head necrosis (61
). The age at onset of ON of the femoral head has been reported to correlate with outcome (65
), and there may be an impairment of the fibrinolytic pathway in some individuals predisposing them to a worse outcome (66
). Plain radiographs and MRI are used for evaluating ON. MRI can delineate the extent and stages of involvement (67
). Improving the prognosis and outcomes of ON of the femoral head in patients with SCD is difficult, so the treatment is controversial (69
). It roughly parallels that in patients without SCD, as covered elsewhere in this text. Containment and physical therapy may be sufficient in young children with limited involvement of the femoral head. Non-weight-bearing therapy, core decompression, femoral osteotomies, total joint replacement all become options in older and more severely involved hips (71
FIGURE 10-3. A 17-year-old boy with SCD presented with symptoms of a painful crisis in his leg. Plain radiographs of his tibia revealed no abnormalities. Failure to respond to hydration after 2 days, along with elevated peripheral white blood cell count and C-reactive protein, prompted investigation with MRI. Sagittal T1-weighted images before (A) and after (B) gadolinium injection demonstrate heterogeneous enhancement throughout a large area of abnormal signal intensity in the marrow of the tibia. An intraosseous fluid collection can be seen (arrow). Axial T1-weighted (C) and T2-weighted (D) images without gadolinium demonstrate an extraosseous fluid collection (arrows) with surrounding edema. Operative corticotomy yielded purulent material.
Any surgery in patients with SCD should be accompanied by adequate hydration, maintenance of blood volume and oxygenation, and prevention of hypothermia. The use of a tourniquet is allowed, as it does not induce sickling (77
). Transfusions are typically given perioperatively to keep the total hemoglobin around 10 g/dL (78
Pathologic fractures occur in approximately 10% of patients with SCD, usually complicating osteomyelitis (55
One series (79
) found that delayed union, malunion, and joint stiffness complicate 10% to 15% of fractures. However, fractures are not a prominent feature of SCD.
Many other organ systems are affected by SCD. Anemia in SCD is related to erythrocyte fragility and hemolysis. The chronic baseline anemia is generally mild and well tolerated in childhood. However, anemia can be worsened acutely by splenic sequestration, a sudden increase in splenic hemolysis that can be fatal, and by aplastic anemia, a temporary marrow suppression often triggered by parvovirus B19 infection.
Acute chest syndrome (ACS) refers to any new pulmonary infiltrate seen on a chest radiograph in conjunction with fever and chest pain or respiratory symptoms and can be fatal (81
). ACS can result from a wide variety of infectious or noninfectious causes, including rib infarcts (82
SCD also causes genitourinary problems, including enuresis and priapism. Cholelithiasis is common in patients with SCD because of ongoing hemolysis and buildup of bilirubin. Stroke is a common and potentially devastating result of cerebral vasoocclusion or hemorrhage. Infections are a significant risk in infancy and early childhood. Sepsis used to be a major cause of mortality in this age group. The widespread use of penicillin prophylaxis and pneumococcal vaccination in children younger than 5 years reduces the incidence of pneumococcal bacteremia by 84% (83
Medical treatment of SCD has advanced considerably in recent decades. Hydroxyurea, a chemotherapeutic agent, causes increased formation of hemoglobin F and has been found to reduce the incidence of painful crises and ACS, as well as to reduce the requirement for transfusion in adults (84
). Several studies have proven similar efficacy of this drug in children as young as 2 years, although the U.S. Food and Drug Administration (FDA) has not yet approved this drug for use in children. Many other drugs are currently under investigation. Most children now receive pneumococcal vaccine, and it should be highly considered in children with SCD. Bone marrow transplantation has been used in approximately 150 children with severe SCD worldwide, with 92% to 94% survival and 75% to 84% event-free survival (85
The thalassemias are a heterogeneous group of autosomal recessive inherited disorders of hemoglobin synthesis. Together, they represent the most common inherited diseases worldwide (86
). The diseases and their treatments can cause an array of alterations in skeletal dynamics that the orthopaedist should be able to recognize.
The many kinds of mutations that are responsible for thalassemia cause deficient or nil production of either α- or β-globin chains. Alpha thalassemia results from mutations in one or more of the four copies of the α-globin gene. One mutation results in a silent carrier state. Mutation of two genes causes a thalassemia trait, characterized by mild normocytic or microcytic anemia. Mutation of three genes causes substantially diminished α-globin production and hemoglobin H disease (named for the stable tetramer formed by the remaining β chains) with moderate hemolytic anemia. Mutation of all four α-globin genes causes hydrops fetalis, which is usually fatal in utero. Beta thalassemia results from mutations in the β-globin gene and is classified as (a) β+ thalassemia, with reduced synthesis of β-globin or (b) β0 thalassemia, with absent β-globin synthesis. An alternate classification of thalassemia is based entirely on clinical severity. Thalassemia major refers to severe disease, thalassemia intermedia refers to moderate disease, and thalassemia minor refers to mild disease.
Among the α thalassemias, hemoglobin H disease is the most often seen clinically. Children generally present with moderately severe anemia, splenomegaly, and cholelithiasis, which may occur in response to oxidative stress caused by infections, fever, or certain medications (87
). Patients with thalassemia major (homozygous β thalassemia) develop severe anemia, with hemoglobin in the 3 to 4 g/dL range within the first 6 months of life, as fetal hemoglobin production wanes. Thalassemia major requires frequent transfusions in order to maintain health and prolong life expectancy beyond 5 years of age. Transfusions are generally started when the anemia becomes clinically detrimental and are aimed at keeping hemoglobin levels more than 9.5 to 10.5 g/dL. Thalassemia intermedia typically presents in the second year of life with a less profound anemia (86
The skeletal manifestations of the thalassemias, which may occur as a result of both the anemia and its treatments, include marrow hyperplasia, short stature, skeletal dysplasia, and osteopenia. Without transfusions to correct the severe anemia in thalassemia major, erythropoietin secretion increases. The resulting marrow hyperplasia causes widening of the medullary cavities and thinning of the cortices of long bones (Fig. 10-4
). This process is initially apparent in the hands and feet, where the tubular bones become rectangular and then convex. Premature closure of physes, especially in the proximal humerus, can also occur (88
). Marrow hyperplasia can cause dramatic expansion of calvarial bones (89
). Marrow hyperplasia in the spine is associated with back pain in adults with thalassemia who started transfusions after 3 years of age (90
). Extramedullary hematopoiesis commonly occurs in the liver, spleen, and chest. Extramedullary hematopoiesis in the paravertebral space can cause spinal cord compression (91
). MRI is helpful in detecting and evaluating this process in the spine. Surgical decompression, radiation therapy, and transfusions are treatment options. Marrow hyperplasia from severe anemia is not often seen today, because of the use of maintenance transfusions.
Growth disturbance can result from the effects of transfusion-induced iron overload on the anterior pituitary gland and hypothalamus. Endocrinopathies resulting from iron overload include decreased growth hormone (GH) release or GH resistance (95
), delayed puberty and hypogonadism (96
), and hypoparathyroidism. In one series of transfusion-dependent patients with thalassemia major (97
), 8% of boys aged 7 to 8 years had short stature (less than third percentile), as well as 12% and 15% of older boys and girls, respectively. The short stature tends to be disproportionate, with a relatively short trunk (98
). The correction of GH deficiency and the
induction of puberty with gonadotropins partially correct this growth disturbance (96
FIGURE 10-4. A: Lateral radiograph of the skull in a 11-year-old boy with thalassemia major. Note radial striations in the calvarium. B: Radiograph of the hand of the same patient. Note widened marrow cavities, thinned cortices, and osteoporosis.
The skeletal dysplasia of thalassemia is related to iron chelation treatment. Iron chelation with desferrioxamine or oral deferasirox to prevent iron overload has dramatically impacted the health status of patients who require transfusions for thalassemia major (99
). Desferrioxamine, although essential in prolonging survival among transfusion-dependent patients, causes significant skeletal dysplasia in approximately 50% of cases (102
). The findings include a slowing of spinal growth, biconcave vertebrae that progress to platyspondyly in some cases, and physeal widening at the wrist and knee that, in some patients, were severe enough to resemble rickets. Biopsies from patients with desferrioxamine-induced dysplasia show reduced and irregular bone mineralization as well as significant alterations in cartilage histology (103
). The spinal deformities are typically progressive, but metaphyseal lesions may heal with reduction of the desferrioxamine dose or following a switch to other iron chelators (105
). Skeletal dysplasias have not been reported with the newer oral iron chelator deferasirox (99
Osteopenia is a major skeletal manifestation of thalassemia major, occurring in more than 90% of patients despite optimal transfusion and chelation (108
). Bone mineral density is lower in patients who have delayed puberty or amenorrhea (109
), indicating a possible role for endocrinopathy in the pathogenesis of osteopenia. Decreased bone density in patients with thalassemia is predominantly trabecular and associated with iron deposition (111
). Consistent biochemical alterations in bone turnover have not been found (112
). In patients with impaired sexual maturation, bone mineral density increases in response to hormone replacement therapy (113
). In GH-deficient patients, GH administration can normalize markers of bone turnover but does not increase bone density (114
). Bisphosphonates were ineffective in increasing bone mineral density in two placebo-controlled trials (115
Fractures are common in patients with thalassemia major, although they occur less often since the widespread use of young-onset transfusions began. The 40% to 50% incidence of fractures reported in some early series (117
) has decreased to 13% to 21% in recent series (120
). However, a multicenter review (121
) found fractures to be often multiple or recurrent. The orthopaedist treating a fracture in a child with thalassemia should consider the problems of multiple fractures, weakened bone, high refracture risk, and clinically significant anemia.
The problems associated with transfusions and chelation have led to a search for alternative medical treatments for the thalassemias. Hydroxyurea, which stimulates hemoglobin F production, may prove effective (123
), although at the time of writing this chapter, it has not been approved by the U.S. FDA for children with thalassemia. Bone marrow transplantation
has been used successfully in several centers for the treatment of severe thalassemia (124
), but it has not been shown to prevent osteopenia (109
). Stem cell transplantation from umbilical cord blood of related donors has also been used with some success (127
). Despite success in a mouse model (128
), gene therapy for thalassemia is not yet a clinical reality.