Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 10-1

Three-Week-Old Boy



The patient was a 3-week-old Caucasian male, born at 38 weeks gestation, who presented to an outpatient clinic for evaluation of anemia. Shortly after birth, he was noted to be pale in the newborn nursery. At that time, his hemoglobin was 12.3 g/dL with a mean corpuscular volume (MCV) of 120 fL. The hemoglobin was repeated at 2 weeks of age and was 8.1 g/dL with a reticulocyte count of 1.2%. He had initial problems with weight gain that improved after his mother started pumping and giving him breast milk via bottle in addition to breastfeeding. His parents thought he was often “sleepy” and were specifically concerned that he frequently fell asleep during feeds. He had no vomiting, diarrhea, fever, or cough. He had normal gold-colored bowel movements. There had been no change in urine color and he had no rash.


The infant was a twin born via vaginal delivery at 38 weeks gestational age following in vitro fertilization. He had transverse lie and was delivered vertex after external manipulation. The mother had anemia during pregnancy and her only medication was prenatal vitamins. Her blood type was O positive. The birth weight was 2470 g; the infant’s twin sibling weighed 2900 g at birth. On his first day of life, the infant was noted to have a swollen right upper leg with significant bruising. The initial radiograph was normal but a subsequent film showed evidence of a healing fracture that was presumably related to birth trauma. There was no history of jaundice in the newborn nursery.

The infant received multivitamin with iron. He did not have any known allergies. He received a diet of breast milk with occasional formula supplementation.

The family history was remarkable for the mother’s anemia, which did not require treatment. The maternal grandmother also had a history of anemia. Both the maternal grandmother and aunt required cholecystectomy for gallstones.


T 36.7°C; HR 166-230 bpm; RR 46-66/min; BP 70/37 mmHg

Weight 3.1 kg (25th percentile); Height 50 cm (50th percentile); Head circumference 36 cm (~75th percentile)

On examination, the infant was remarkably pale appearing, awakened easily, and cried. The anterior fontanel was open and flat. The conjunctivae were pale and the sclerae were anicteric. Mucous membranes were moist. The clavicles were intact. The infant was tachypneic but the lungs were clear to auscultation. On cardiac examination, the patient had a normal S1 and S2 and there was a 3/6 systolic murmur best appreciated at the left upper sternal border but not heard along the back. There were no gallops or rubs. The liver edge was palpable but the spleen was not. On musculoskeletal examination, the site of known extremity fracture had minimal edema but no tenderness and the right distal femur appeared larger than the left. The remainder of the examination was normal.


Complete blood count revealed the following: hemoglobin, 3.9 g/dL; 11 300 WBCs/mm3 (1% metamyelocytes, 43% segmented neutrophils, 34% lymphocytes, and 19% monocytes); 430 000 platelets/mm3; MCV, 117 fL; red cell distribution width, 17; and reticulocyte count, 0.3%. The peripheral blood smear revealed a few small spherocytes but no schistocytes, burr cells, or target cells.


The infant was admitted for supportive care and a diagnostic evaluation begun. What are the likely cause for his anemia?



Table 10-4 lists the differential diagnosis of anemia in an infant. This patient presented with pallor during infancy and no history of jaundice, which lessened the likelihood of hemolysis. There was no concern of a dietary etiology because of the baby’s young age, there was no chronic illness apparent, and no history of blood loss; therefore, the focus shifted to a congenital defect in red cell production. There was a remarkable drop in the hemoglobin along with a very poor bone marrow response as far as production of reticulocyte. The white cells and platelets were normal and the anemia was macrocytic. The sum of these findings indicated a defect of red cell production. There was also the physical examination finding of a possible skeletal anomaly in the distal right femur.

Red cell aplasia may be congenital or acquired. Most of the acquired forms occur during adulthood or adolescence. In childhood the major causes of red cell aplasia are Diamond-Blackfan anemia, transient erythroblastopenia of childhood, and acquired aplasia of red cells associated with chronic hemolysis (as seen in sickle cell disease).

TABLE 10-4. Causes of anemia during infancy.


In this case, there was no evidence of acute or chronic hemolysis and the patient was too young to be considered for transient erythroblastopenia of childhood. Another possible etiology to be considered was Fanconi anemia. Fanconi anemia is an autosomal recessive disorder associated with aplastic anemia, short stature, skeletal defects, pigmentation changes, and other abnormalities. Some cases of Fanconi anemia are diagnosed in the first year of life. The anemia involves all cell lines and the diagnosis is established via bone marrow analysis and genetic studies. However, the patient had anemia without abnormalities in the white blood cell or platelet count, thus Diamond-Blackfan was the most plausible diagnosis.


The infant was admitted with the diagnosis of anemia secondary to a hypoproductive state. The infant was felt to have symptomatic anemia (difficulty feeding); therefore, he was transfused with a total of 15 mL/kg of packed red blood cells administered in three separate aliquots. He underwent bone marrow aspiration, which revealed absence of red cell precursors with normal granulocyte precursors, a finding consistent with Diamond-Blackfan anemia. Following the packed red cell transfusion, the infant’s hemoglobin was 8.7 g/dL. He was more active and was no longer in respiratory distress. The baby received corticosteroids at 2 mg/kg/day, and was given an additional 5 mL/kg of packed red blood cells prior to discharge. The final diagnosis in this case was Diamond-Blackfan anemia.


The precise incidence is unknown; however, it is estimated that there are 300-1000 new cases of red cell aplasia annually in the United States. Diamond-Blackfan occurs primarily in infancy. Studies show that 10% of patients are anemic at birth, 25% by 1 month, 50% by 3 months, and 70% by 1 year. It is seen in all ethnic groups but primarily in Caucasians. There is no gender predominance.


Pallor caused by anemia in the early months of life characterizes this form of anemia. About one-third of patients have at least one associated finding, including characteristic facies, thumb anomalies, short stature, eye abnormalities including glaucoma, renal anomalies, hypogonads, skeletal anomalies, congenital heart disease, and mental retardation. There is a wide range of involvement. Some patients progress to full aplastic anemia and about 5% may develop leukemia or myelodysplasia.


Complete blood count and peripheral blood smear. The mean hemoglobin level for all patients with Diamond-Blackfan anemia is 7 g/dL at diagnosis. Infants diagnosed in the first 4 months of life typically have hemoglobin levels of 4 g/dL at presentation. The reticulocyte count is decreased or zero. The peripheral blood smear reveals macrocytes, anisocytosis, and teardrops. The WBC counts are normal in most patients; though in 20%, WBC counts are less than 5000/mm3.

Bone marrow aspirate. Bone marrow aspirates and biopsies show normal cellularity, myeloid cells, and megakaryocytes. Approximately 90% of patients have erythroid hypoplasia or aplasia. The remaining 10% of patients have either normal erythroblast number and maturation or erythroid hyperplasia with maturation arrest. Despite the variable marrow findings, all patients have reticulocytopenia, indicating some form of ineffective erythropoiesis and delayed precursor maturation.

Other studies. Serum iron, ferritin, folate, vitamin B12, and erythropoietin are all elevated. In most cases, there is an increase in erythrocyte adenosine deaminase (eADA). Among patients with bone marrow failure syndromes, eADA had a sensitivity of 84%, specificity of 95%, and positive and negative predictive values of 91% for the diagnosis of Diamond-Blackfan anemia. Genetic studies have shown one site on chromosome 19 and other gene defects have also been associated.


The treatment includes use of corticosteroids. The current recommended dose is 2 mg/kg/day of prednisone, administered in 3-4 divided doses. Reticulocytes appear within 1-2 weeks but the rise in hemoglobin is delayed for several more weeks. Once the hemoglobin level reaches 10 g/dL, the steroid dose is gradually tapered until the patient receives a single daily dose that adequately maintains appropriate hemoglobin levels. Response followed by steroid dependence is seen in 60% of patients. Approximately one-fifth of the steroid-responsive patients may ultimately be maintained without steroids.

Approximately 30%-40% of patients have poor or no response to steroids and require chronic transfusion therapy to maintain normal hemoglobin. These children require leukocyte-depleted packed red blood cell transfusions every 3-6 weeks with the goal of keeping the hemoglobin level greater than 6 g/dL. Concurrent chelation of iron with subcutaneously administered desferrioxamine may decrease some chronic transfusion-related complications. Complications of chronic transfusion therapy are similar to other conditions that employ this modality (e.g., thalassemia). Bone marrow transplantation has been successful for some patients.

Median survival is 43 years of age but approximately 13% of patients die within the first six years of life. Deaths occur from complications of iron overload, pneumonia, sepsis, and occasionally from transplant-related complications, leukemia, and pulmonary emboli.


1. Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 6th ed. Philadelphia: Saunders; 2003:280-365.

2. Ball SE, McGuckin CP, Jenkins G, et al. Diamond- Blackfan anaemia in the UK: analysis of 80 cases from a 20 year birth cohort. Br J Haematol. 1996;94:645-653.

3. Willing TN, Draptchinskaia N, Dianzani I, et al. Mutations in ribosomal protein S19 gene and Diamond Blackfan anaemia: wide variations in phenotypic expression. Blood. 1999;94:4294-4306.

4. Willing TN, Gazda H, Sieff CA. Diamond Blackfan anaemia. Curr Opin Haematol. 2000;7:85-94.

5. Fargo JH, Kratz CP, Giri N, et al. Erythrocyte adenosine deaminase: diagnostic value for Diamond-Blackfan anemia. Br J Haematol. 2012 [Epub ahead of print, PMID 23252420].