October 2024 NeoQuest: Term Neonate With Failure to Thrive and Anemia

A 1-month old term infant, who is exclusively breastfeeding, is evaluated for failure to thrive. She has a 2-week history of 6–8 non-bloody, bulky stools per day and has gained less than 5 grams/day. Her family history is notable for early childhood deaths of three siblings who all had poor growth and global developmental delay. Her physical examination is notable for pallor and a systolic murmur. Her hemoglobin is 8 mg/dL with a mean corpuscular volume (MCV) of 75 fl and mean corpuscular hemoglobin (MCH) of 25 pg. Her white blood cell and platelet counts are within normal limits.  Her peripheral smear is shown in Figure 1. Stool microscopy demonstrates fat globules.

Figure 1: Peripheral smear findings of the female infant in the vignette. Abnormal red blood cells (RBCs) are shown in black and green arrows. Image from More T, Nair S, Mhatre S, Ranya Raghavendra P, Haribalakrishna A. A neonate with anemia and diarrhea. Neoreviews. 2024;25(10):e648–e651.¹

Which of the following peripheral smear findings are most consistent with this infant’s likely disorder?

1. Macrocytic, normochromic anemia, neutropenia, and normal RBC morphology
2. Microcytic, hypochromic, anemia, “star-shaped” RBCs, and RBCs with small horny projections
3. Microcytic anemia, polychromasia, spherical RBCs with loss of central pallor
4. Normocytic, normochromic anemia with fragmented, and oval-shaped RBC cells
5. Normocytic/macrocytic anemia, polychromasia, and presence of RBCs with small horny projections

Answer: B.  Microcytic, hypochromic, anemia, “star-shaped” RBCs, and RBCs with small horny projections

Explanation:

The infant in this vignette has anemia, failure to thrive, and bulky stools that are positive for fat globules, which is consistent with the fat malabsorption disorder abetalipoproteinemia (ABL).^1,2 ABL is an autosomal recessive condition that occurs due to the mutation of the gene encoding microsomal triglyceride transfer protein (MTTP) leading to its deficiency.¹ This mutation results in the termination of the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver.¹ The anemia in ABL is typically described as microcytic and hypochromic due to the low MCV (normal 90–112 fl) and low MCH (normal 31–37 pg), consistent with the infant’s laboratory findings (Option B).¹ In addition, patients with ABL can have abnormally shaped RBCs including star-shaped RBCs, called acanthocytes or “spur cells” (Figure 2) and RBCs with small horny projections, called echinocytes or “burr cells” (Figures 1 and 2) (Option B).^1,2 The cause of abnormally shaped RBCs is due to an increase in membrane sphingomyelin-to-lecithin ratio, causing decreased membrane fluidity. ¹ As a result of abnormal fat malabsorption, affected patients can also have absent or extremely low-density lipoprotein (LDL) cholesterol, triglycerides, and apoprotein B levels, which are diagnostic of ABL.^1,2 Molecular testing to detect the genetic mutation can establish the diagnosis. Affected patients are managed with a low-fat diet (ie, a specialized low-fat nutritional formula for infants) as well as iron and fat-soluble vitamin supplementation.^1,2

Figure 2: Schematic demonstrating normal and abnormal RBC shapes.

Infants with growth failure, exocrine pancreatic insufficiency, fat malabsorption, and bone marrow suppression should be evaluated for Schwachman-Diamond syndrome (SDS).³ SDS is an autosomal recessive congenital disorder due to heterozygous mutations in the SBDS gene.^2,3 Affected patients most typically present with neutropenia, but can eventually develop aplastic, macrocytic anemia (Option A). Patients with SDS have normal RBC morphology (Figure 2).^2,3 They can present with severe bacterial and fungal infections due to neutropenia. Molecular diagnosis can help detect associated mutations. Affected patients require monitoring of blood counts to assess for leukemic transformation and are treated with recombinant-granulocyte colony forming units (rh-GCF), pancreatic enzymes, and fat-soluble vitamins.^2,3 The patient in this vignette does not have specific concerns for bone marrow suppression (eg, neutropenia, thrombocytopenia), which makes the diagnosis of SDS less likely.

In patients with anemia and abnormal RBC shape, RBC membrane defects such as hereditary spherocytosis (HS) and hereditary elliptocytosis (HE) may be considered. Abnormal RBC shape in these conditions occurs due to changes in the unique composition of lipids and proteins that help achieve the normal biconcave shape of the RBC (Figure 2). HS is caused by alterations in genes encoding RBC membrane proteins such as ankyrin, ɑ-spectrin, ß-spectrin, band-3, and protein 4.2, which lead to abnormal connections between the inner cytoskeleton and outer lipid layer of the RBC membrane.^2,4 As such, these RBCs appear spherical with a decrease in MCH (microcytic), an increase in MCHC (due to cellular dehydration), and an absence of central pallor (Figure 2 and Figure 3) (Option C).^2,4 Patients with HS present with hemolytic anemia, reticulocytosis, splenomegaly, unconjugated hyperbilirubinemia, and cholelithiasis. Due to an abnormal RBC membrane, these cells have increased osmotic fragility.^2,4 Diagnosis of HE is confirmed using flow cytometry. Initial management includes treatment of hyperbilirubinemia and anemia.^2,4 These patients would require iron and folic acid supplementation, hydration, and PRBC transfusions for the management of anemia.^2,4 Long-term management also includes partial or complete splenectomy to decrease infection risk, and post-splenectomy prophylactic antibiotics and vaccinations against encapsulated organisms such as Hemophilus influenza, Pneumococcus, and Meningococcal.^2,4

Figure 3: Peripheral smear of a patient with hereditary spherocytosis with polychromasia and spherical RBCs with loss of central pallor. Image from Tise CG, Joshi NS, Erice-Taganas AD, Blecharczyk EM. Rapidly rising bilirubin level in a 3-day-old term infant. Neoreviews. 2020;21(10):e687–e690.⁴

HE is due to a defect in protein 4.1, band-3 protein, ɑ-spectrin, and ß-spectrin.^2,5 Due to commonly affected proteins, HE and HS have several overlapping clinical features as noted previously. The RBCs seen in HE are typically oval-shaped on peripheral smears (Figure 2 and Figure 4) (Option D).^2,5 Diagnosis is confirmed using molecular genetic testing detecting specific mutations associated with HE. The patient in this vignette also has signs of fat malabsorption, which is not typically seen in HS or HE.^2,5

Figure 4: Peripheral smear of a patient with hereditary elliptocytosis with oval-shaped RBCs (black arrows). Image from Alallah J, Elfarra A, Ahmed A, Alyamani A. Jaundice in a preterm infant twelve hours after birth. Neoreviews. 2021;22(11):e770-e773.⁵

Another diagnosis to consider in a newborn presenting with anemia is an RBC enzyme defect such as pyruvate kinase deficiency (PKD). PKD is an autosomal recessive disorder of the PKLR gene that affects the pyruvate kinase enzyme, resulting in decreased cell ATP production.^2,6 This deficit in ATP leads to challenges in maintaining cell structure and integrity, predisposing to RBC hemolysis.^2,6 The peripheral smear can demonstrate normochromic and polychromatic anemia with RBCs showing small horny projections (eg, echinocytes/ “burr cells”), (Figure 2 and Figure 5) (Option E).^2,6 Symptoms in affected patients depend on the degree of enzyme deficiency and can range in severity from anemia and subsequent hyperbilirubinemia to fetal hydrops secondary to fetal anemia. The diagnosis of PKD is made by measuring low PK activity levels using a spectrophotometric assay. Infants with PKD do not present with fat malabsorption, as seen in the patient in this vignette, making the diagnosis of PKD in this infant less likely.^2,6

Figure 5: Peripheral smear of a patient with pyruvate kinase deficiency, with abnormal RBCs that have small horny projections (eg, echinocytes or “burr cells”), shown in black arrows. Image from Sharma M, Marques M. Index of suspicion in the nursery. Neoreviews. 2013;14(12):e613-e617.⁶

Did you know?

• Sites of erythropoiesis vary with gestation: yolk sac (3–8 weeks’ gestation), liver (6–30 weeks’ gestation), and spleen (9–28 weeks’ gestation).²
• The bone marrow becomes the primary site for erythropoiesis at 28 weeks’ gestation.²

What are some of the causes of protracted diarrhea in a newborn? For a detailed differential diagnosis of protracted diarrhea in a newborn, please refer to Table 2 in Rajbhandari P, Mandelia C, Janjua HS, Selvakumar PKC, Krishna S. A 9-day-old with weight loss and diarrhea. Pediatrics. 2017;139(5):e20162953

NeoQuest October 2024 Authors
Srirupa Hari Gopal, MBBS, FAAP, Baylor College of Medicine
Faith Kim, MD, Columbia University Medical Center

References:

1. More T, Nair S, Mhatre S, Ranya Raghavendra P, Haribalakrishna A. A neonate with anemia and diarrhea. Neoreviews. 2024;25(10):e648–e651
2. Joshi R, Myers E, Kokhanov A. Congenital disorders of red blood cells. Neoreviews. 2022;23(12):e813–e828
3. Dipak NK, Jain P, Shagufta N, Sharma S, Garg S. Tripathi P. A febrile neonate with hyperferritinemia. Neoreviews. 2024;25(7):e452–e456
4. Tise CG, Joshi NS, Erice-Taganas AD, Blecharczyk EM. Rapidly rising bilirubin level in a 3-day-old term infant. Neoreviews. 2020;21(10):e687–e690
5. Alallah J, Elfarra A, Ahmed A, Alyamani A. Jaundice in a preterm infant twelve hours after birth. Neoreviews. 2021;22(11):e770–e773
6. Sharma M, Marques M. Index of suspicion in the nursery. Neoreviews. 2013;14(12):e613-e617
7. Rajbhandari P, Mandelia C, Janjua HS, Selvakumar PKC, Krishna S. A 9-day-old with weight loss and diarrhea. Pediatrics. 2017;139(5):e20162953