Pediatric Examination and Board Review (152 page)

11.
(C)
Beta-thalassemia patients are subdivided based on clinical severity into thalassemia carriers and those with thalassemia trait, thalassemia intermedia, or thalassemia major. Beta-thalassemia carriers are asymptomatic, with only mild microcytosis; patients with thalassemia trait have a mild microcytic anemia but generally are otherwise well. Patients with thalassemia intermedia and thalassemia major both have moderate to severe anemia and require transfusion therapy. Red blood cells produced by the bone marrow in patients with more severe thalassemia are poorly functional, stimulating further red blood cell production. This ineffective erythropoiesis eventually results in bone marrow hyperplasia and extramedullary hematopoiesis, which cause the clinical features of thalassemia major (also called Cooley anemia) that occur in the absence of regular transfusions. These features of thalassemia major include severe anemia with massive hepatosplenomegaly and growth failure. Bone marrow hyperplasia results in frontal bossing, maxillary prominence, a “hair-on-end” appearance of the skull on radiograph, and long bone changes including severe osteoporosis and cortical thinning from medullary expansion. The thin bony cortices leave the bones susceptible both to bowing and to fractures. Scleral icterus and jaundice are not features of thalassemia.

Laboratory features of beta-thalassemia include an increased concentration of hemoglobin A2, although hemoglobin F, or fetal hemoglobin, is usually normal. The red blood cells in patients with thalassemia are microcytic, with hypochromia and basophilic stippling. The presence of target cells and ovalocytes is also consistent with thalassemia.

12.
(D)
The alpha-globin chains in hemoglobin are produced by 4 separate alpha-globin gene alleles. A single allele deletion results in an asymptomatic carrier state, with microcytosis but no anemia. Two alpha-globin allele deletions cause alpha-thalassemia trait with mild anemia but marked hypochromia and microcytosis. Deletion of 3 alleles results in more severe hemoglobin H disease, characterized by moderate anemia, with hemoglobin levels of 7-10 g/dL, associated with jaundice and hepatosplenomegaly. Hemoglobin H is composed of 4 beta-globin chains and comprises 5-30% of the total hemoglobin in hemoglobin H disease patients. Hemoglobin H unfortunately has no oxygendelivering capacity and precipitates within the red blood cell, forming Heinz bodies and inducing splenic sequestration and destruction.

Deletion of all 4 alpha-globin alleles results in hydrops fetalis with severe intrauterine microcytic anemia and hepatosplenomegaly. The hemoglobin present is exclusively Bart hemoglobin, or gamma4, which is composed of 4 fetal gamma-globin chains. Bart hemoglobin, like hemoglobin H, has no oxygen-delivering capacity, and so hydrops fetalis is invariably fatal (either in utero or perinatally) in the absence of transfusion therapy.

13.
(C)
Transfusion therapy for patients with thalassemia frequently results in hemochromatosis, or “iron overload.” Although many organs are affected by iron overload, the kidneys are relatively spared. Iron overload is associated with dilated cardiomyopathy because of excessive iron deposition in cardiac myocytes, diabetes mellitus because of pancreatic iron deposition, and hypogonadism from pituitary failure secondary to iron deposition. Other complications of iron overload include growth failure, hypothyroidism, hypoparathyroidism, and hepatic fibrosis with an increased risk of hepatocellular carcinoma.

Treatment of iron overload in cases of hereditary hemochromatosis consists of regular phlebotomy to withdraw iron and reduce the body’s iron stores. In cases of transfusion-induced iron overload, iron reduction is accomplished with desferrioxamine chelation. Desferrioxamine, which must be given either intravenously or subcutaneously, binds to iron in the bloodstream and is then excreted in the urine. The success of chelation can be measured by serum ferritin levels or by liver biopsy, the most sensitive measure of total body iron stores.

14.
(A)
Normal red blood cells have a mixture of predominantly hemoglobin A (α2β2), with small amounts of hemoglobins A2 (α2δ2) and F (α2γ2). Normally hemoglobin A comprises at least 95% of the total hemoglobin, with hemoglobin A2 ranging from 2% to 4% and hemoglobin F from 0.5% to 1%. Increasing amounts of hemoglobin F relative to hemoglobin A are found in fetuses and neonates, before the conversion of the erythrocyte precursors to adult hemoglobin A production. Increased levels of hemoglobin F can be found in cases of hereditary persistence of fetal hemoglobin; increased levels of hemoglobin A2 are found in patients with beta-thalassemia.

15.
(A)
Diamond-Blackfan anemia (DBA) is one of a rare group of genetic disorders known as the “inherited bone marrow failure syndromes.” These disorders have in common proapoptotic hematopoietic, bone marrow failure, birth defects, and in most, a predisposition to cancer. The diagnostic criteria for DBA published in 1976 consist of presentation of anemia before the first birthday with near normal or slightly decreased neutrophil counts, variable platelet counts, reticulocytopenia, macrocytosis, and normal marrow cellularity with a paucity of red cell precursors. The incidence of DBA is approximately 5 in 1 million births. Ninety percent of the cases initially present in the first 6 months of life. DBA does not have any race or sex predilection. Several ribosomal protein genes are mutated in patients with DBA, and mutations in these genes account for approximately 50% of DBA cases. With the discovery of these mutated genes in DBA, it became evident that the penetrance of autosomaldominant DBA is quite variable with regard to both hematologic and nonhematologic manifestations. It is estimated that the incidence of familial autosomal-dominant DBA is 15-45%. Physical examination findings of DBA occur in approximately a third of cases and include craniofacial abnormalities such as microcephaly, microphthalmia, hypertelorism, micrognathia, growth failure (either intrauterine or postnatal), and abnormal thumbs, which can be bifid, duplicated, subluxed, hypoplastic, absent, or triphalangeal. The laboratory features include macrocytic anemia, decreased or absent reticulocytes, and an otherwise normal blood count. DBA is also characterized by an increase in hemoglobin F and the presence of the i antigen on red blood cells, which is normally only found on fetal red blood cells. Treatment of DBA involves blood transfusions as needed, but approximately 25% of patients respond to steroid treatment with an increased hemoglobin level. A bone marrow transplant is often required, particularly in cases that do not respond to steroid therapy, and is the only currently available curative therapy.

16.
(C)
TEC, or transient erythroblastopenia of childhood, is most frequently confused with other forms of congenital anemia such as DBA. The features most consistent with TEC include a normocytic anemia in a patient older than 2 years, often with a history of a preceding viral upper respiratory infection. Reticulocytes are also decreased in patients with TEC, as are the red blood cell precursors in the bone marrow. Features that would suggest DBA include age of onset younger than 1 year, abnormal physical features (particularly abnormal thumbs) or growth failure, and elevations in MCV, adenosine deaminase levels, fetal hemoglobin, and i antigen (a red blood cell antigen normally only found on fetal red blood cells). The most significant characteristic feature of TEC is spontaneous recovery in the absence of treatment, whereas anemias because of DBA or other congenital red cell aplasias will not resolve without other therapy.

17.
(D)
Lead toxicity is a cause of microcytic anemia in children that must be ruled out with initial screening because of potentially severe and irreversible complications. Sources of lead poisoning include leaded gasoline, lead smelters, paint chips from houses with lead-based paint, old batteries, magazine color pages, and lead-glazed pottery. Lead toxicity is associated with abdominal pain, emesis, constipation, peripheral neuropathy, renal disease, and can eventually result in encephalopathy with decreased IQ, altered behavior, ataxia, and seizures. Decreased hemoglobin levels from lead toxicity are a product of inhibition of heme synthesis, resulting in accumulation of heme precursors and causing an elevation in the serum-free erythrocyte protoporphyrin levels.

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CASE 89: A 16-YEAR-OLD WITH SICKLE CELL DISEASE AND RESPIRATORY DISTRESS

A mother brings her 16-year-old son, who is known to have sickle cell disease, to the emergency department with “difficulty breathing.” He was well until approximately 1 week ago when he began having bilateral leg and arm pain, which are his usual sites for sickle cell pain. He was taking ibuprofen and codeine at home with some relief. The past evening the pain worsened, and he also began having fevers to 101.6°F (38.6°C). This morning he also began having some chest pain and difficulty taking deep breaths, and so his mother brought him to the emergency department. The patient has had several past admissions for his sickle cell disease for vaso-occlusive crisis pain management. He has never received a blood transfusion.

On physical examination, the patient is awake and alert but clearly in pain. His sclerae are icteric bilaterally. He has a 3/6 systolic ejection murmur, and he has decreased breath sounds in his right lung base. The remainder of his examination is noncontributory.