Pyruvate Kinase Deficiency Cases Mimicking Congenital Dyserythropoietic Anemia

Introduction

Pyruvate kinase (PK) deficiency is the most common glycolytic pathway defect that leads to hereditary hemolytic anemia with autosomal recessive inheritance pattern, which may present with severe hemolysis in the neonatal period, frequent blood transfusion requirement during infancy or with milder course of anemia. The prevalence reported among the Caucasians is 51 per million. Herein we present two cases of PK deficiency who were clinically and morphologically mimicking congenital dyserythropoietic anemia (CDA) at presentation and were diagnosed molecularly.

Case 1

A three-year-old male patient was admitted with jaundice. Personal history revealed that he was born prematurely from a non-consanguineous family, and he did not need phototherapy at neonatal period. By the third month, he received first erythrocyte transfusion; then he needed transfusions every month. Strikingly, transfusion requirements increased in febrile episodes. Physical examination at admission revealed jaundice and splenomegaly. Complete blood count showed hemoglobin (Hb) 7.2 g/dL, mean corpuscular volume (MCV) 86.1 fL, mean corpuscular hemoglobin (MCH) 27.3 pg, mean corpuscular hemoglobin concentration (MCHC) 31.7 pg, and reticulocytes 12.3%. A blood film examination showed macrocytosis, hypochromia, anisocytosis, and rare spherocytes. Hemoglobin electrophoresis was normal, and direct Coombs' test was negative. The PK enzyme level was ignored since the patient was regularly transfused. Bone marrow aspiration showed erythroid hyperactivity and severe megaloblastic changes with double and multi-nucleated erythroid precursors suggestive for CDA. However, no genetic mutation detected concerning CDA (C15orf41, F8, F9, KLF1, CDAN1, VWF, SEC23B, GATA1, G6IBA genes). After negative molecular testing for CDA, sequencing of the PK-LR gene revealed the presence of a homozygous c.1151C> T mutation.

Case 2

A three-month-old male patient presented with pallor and jaundice. Personal history revealed that he was born at term from a non-consanguineous family, and he required phototherapy and exchange transfusion due to icterus and anemia at the neonatal period. He needed erythrocyte transfusions during follow-up. Hemogram revealed Hb 6.7 g/dL, MCV 81.2 fL, MCH 25.2 pg, MCHC 31.1 pg, and reticulocytes 2.6%. Blood film examination showed polychromasia, rare spherocytes, and acanthocytes. Direct Coombs' test and Parvovirus B19 PCR analysis were negative. Bone marrow aspiration showed erythroid hyperactivity along with double and multi-nucleated erythroid precursors, which suggested CDA. However, no genetic mutation detected concerning CDA (SEC23B, CDAN1). The PK enzyme level was normal, which was 2 ½ months after the last transfusion. Finally, the molecular analysis of the PK-LR gene revealed the presence of a novel homozygous c.880G>A mutation. The mutation predicted as possibly damaging by in Silico analysis.

Discussion

The diagnostic approach to transfusion-dependent hereditary hemolytic anemia could be challenging related to false normal erythrocyte enzyme studies and osmotic fragility tests in previously transfused patients. It was reported that PK deficiency cases with inappropriately low reticulocytes might mimic CDA, which was discerned in cases where NGS performed for CDA but revealed PK-LR mutation. PK deficiency may lead to ineffective erythropoiesis due to erythrocyte ATP depletion, as well as CDA-like morphological findings (Cases 1 and 2) and low reticulocyte counts (Case 2). We suggest that in cases where CDA is suspected, PK deficiency should be considered in the differential diagnosis. Furthermore, instead of the PK enzyme level in patients with regular transfusions, PK-LR genetic analysis would be appropriate.