Pediatr Blood Cancer 2014;61:1463–1465

BRIEF REPORTDyserythropoiesis in a Child With Pyruvate Kinase Deficiency and Coexistent

Unilateral Multicystic Dysplastic Kidney

Marwa Abu El Haija, MD,1 You-Wen Qian, MD,2 and Akila Muthukumar, MD1*

INTRODUCTION

Pyruvate kinase (PK) deficiency is the commonest enzyme

abnormality in the glycolytic pathway [1] which leads to hereditary

hemolytic anemia secondary to decreased ATP synthesis. PK

deficiency in red blood cells occurs due to mutation in the PKLR

1q21 [2] gene and leads to highly variable clinical presentation

ranging from severe fetal anemia leading to hydrops fetalis [3,4] to

well compensated hemolytic anemia in adults. We describe here the

evidence of dyserythropoiesis in the bone marrow of a 3-month-old

child who has PK deficiency and coexistent Unilateral Multicystic

Dysplastic Kidney (MCDK). Dyserythropoiesis raised concerns of

Congenital Dyserythropoietic Anemia type I (CDA type I) but

persistently low erythrocyte PK levels and PKLR gene sequencing

results consistent with double heterozygous mutations in the PKLR

gene confirmed the diagnosis of PK deficiency.

CASE REPORT

The patient was born full term as the first child to an 18-year-old

primigravida mother. Ancestry of mother is mixed Hispanic and

European while father is Hispanic with no history of consanguinity

among parents. Mother had anemia during her third trimester of

pregnancywhichwas thought to be secondary to iron deficiency and

she required packed red blood cell (pRBC) transfusion once in the

immediate postpartum period. The patient was diagnosed during

intra-uterine period with left sided multicystic kidney, oligohy-

dramnios, and mild pericardial effusion by prenatal ultrasonogram.

At birth the patient was pale, required basic stimulation, and

resuscitation as well as administration of oxygen. His Apgar scores

were 6 and 9 at 1 and 5minutes, respectively. He was treated in the

neonatal intensive care unit due to further oxygen requirement. On

physical examination, no abnormal facial features, skeletal

abnormalities, or hepatosplenomegaly were noted except for 2/6

soft systolic heart murmur and a palpable left kidney on

examination of abdomen. His complete blood count at birth

revealed very low hemoglobin of 7.8 gm/dl and a high reticulocyte

count of 36.8%. He received pRBC transfusion immediately after

birth. Echocardiogram done after birth revealed ostium secundum

Atrial Septal Defect (ASD). Renal Ultrasonogram done postnatally

showed a small cystic structure measuring 7.2 cm� 3 cm� 3.6 cm in

diameter in the left renal fossa with no identifiable solid parenchyma

consistent with left sided Muticystic Dysplastic Kidney (MCDK).

Mild pelviectasis of right kidney was also seen. MRI abdomen

confirmed the diagnosis of MCDK and ruled out any hemorrhage.

The patient had transient thrombocytopenia with platelets

ranging from 60,000 to 80,000/ml in the first week of life which

improved spontaneously.

Peripheral smear at birth showed macrocytic red cells with a

moderate increase in poikilocytes, including schistocytes, and

spherocytes. Increased polychromasia and nucleated red cells were

suggestive of a hemolytic process either immune mediated or

secondary to intrinsic red cell defects. His renal function tests were

in the normal range. Fetomaternal bleeding was ruled out by

maternal blood testing for fetal hemoglobin. There was no ABO or

Rh incompatibility present to suggest immune hemolysis andDirect

Antibody testing of the patient was negative. Infections like

Parvovirus B19, Cytomegalovirus, and syphilis were ruled out by

clinical evaluations and lab tests.

Serum folate, ferritin, vitamin B12, and Glucose-6-phosphate

Dehydrogenase enzyme levels werewithin normal limits. His blood

tests revealed a low erythrocyte PK enzyme activity of 5.1U/gHb

(normal range 9.0–22.0U/gHb). His peripheral smear showed a few

spiculated red cells but no spheroechinocytes seen. At week 7 of

age, his hemoglobin and reticulocyte count were 5.6 gm/dl and

2.58%, respectively. He underwent bone marrow aspiration at

3 months of age since his reticulocyte response was thought to be

inadequate. Bone marrow showed increased erythropoiesis with

cytoplasmic bridging between many erythroblasts and infrequent

dyserythropoiesis which raised the concern of CDA type I (Fig. 1).

Pyruvate kinase (PK) deficiency is the commonest enzymedeficiency in the glycolytic pathway leading to hemolytic anemiasecondary to decreased Adenosine Triphosphate (ATP) synthesis inthe red cells. synthesis. PK deficiency due to mutations in the PKLR(1q21) gene leads to highly variable clinical presentation rangingfrom severe fetal anemia to well compensated anemia in adults. Wedescribe dyserythropoiesis in the bone marrow of a child with

transfusion dependent anemia and unilateral multicystic dysplastickidney (MCDK) mimicking Congenital Dyserythropoietic Anemiatype I (CDA type I). Persistently low erythrocyte PK levels and doubleheterozygous mutations present in the PKLR gene confirmed thediagnosis of PK deficiency. Pediatr Blood Cancer 2014;61:1463–1465. # 2014 Wiley Periodicals, Inc.

Key words: dyserythropoiesis; hemolytic anemia; multicystic dysplastic kidney; pyruvate kinase deficiency

1Department of Pediatric Hematology and Oncology, University of

Texas Medical Branch at Galveston, Galveston, Texas; 2Department of

Pathology, University of Texas Medical Branch at Galveston,

Galveston, Texas

Conflict of interest: Nothing to declare.

�Correspondence to: Akila Muthukumar, Assistant Professor of

Pediatrics, Division of Pediatric Hematology/Oncology, University

of TexasMedical Branch at Galveston, 301 University Blvd, TX 77555-

0371. E-mail: akmuthuk@utmb.edu

Received 27 September 2013; Accepted 30 December 2013

�C 2014 Wiley Periodicals, Inc.DOI 10.1002/pbc.24953Published online 30 January 2014 in Wiley Online Library(wileyonlinelibrary.com).

By electron microscopy, some nucleated red cell precursors in the

bone marrow aspirate showing nuclear chromatin changes that

mimic “Swiss Cheese” morphology as described in CDA type I

were seen (Fig. 2). Cytogenomic microarray analysis showed no

significant DNA copy number changes.

PK levels were repeated twice prior to subsequent pRBC

transfusions and they were 4.7 and 4.8 U/gHb done at ARUP

Laboratories (Salt Lake City, UT). Since there was presence of

dyserythropoiesis, sequencing of PKLR gene at 1q21 [2] which

codes for PK in red cells was sent to confirm the diagnosis of PK

deficiency. PKLR gene testing done at Centogene, Germany was

positive with two heterozygous mutations c.1378G>A p.Val460-

Met, and c.341T>C p.Ile114Thr. One of the mutations has been

described earlier [5]. A previously unreported heterozygous

variant in exon 3 of the gene (c.341T>C p.Ile114Thr) was

also found.

The patient received a total of three pRBC transfusions for low

hemoglobin during first month of life and every 3–4 weeks in the

first few months of life. At present he is clinically doing well with

normal growth and development and continues to be pRBC

transfusion dependent at 1 year of age.

DISCUSSION

Since PK deficiency is usually associated with reticulocytosis,

the disproportionately low reticulocyte count seen in the patient

described above raised concerns about other causes of neonatal

anemia. But, low reticulocyte count seen here could be explained by

sequestration and destruction of the reticulocytes by the reticulo-

endothelial system in PK deficiency [6]. PK levels seen here were

higher than a typical patient with homozygous mutation and

could be explained by previous pRBC transfusions, presence of

compound heterozygous mutation and higher values usually seen in

children than in adults.

Dyserythropoiesis seen in the bonemarrowwas initially thought

to be secondary to CDA type I. Incomplete division of the nuclei

leading to nuclear bridging as a characteristic feature of CDA type I

has been described in studies of DNA content of erythroblasts [7].

Since PK deficiency is confirmed by the compound heterozygous

mutation of the PKLR gene (1q21) as evidenced by gene

sequencing, we think that dyserythropoieisis is likely secondary

to ineffective erythropoiesis which has been described earlier.

Evidence of extramedullary erythropoieis and ineffective erythro-

poiesis has been demonstrated in the spleen of a child with PK

deficiency [8] and also in mutant mice with PK deficiency [9].

Higher levels of iron seen in patients with PK deficiency could be

secondary to ineffective erythropoiesis in addition to other factors

such as hemolysis [10].

MCDK is one of the commonest abnormalities detected by

antenatal ultrasound and has been found to be associated with other

urogenital abnormalities [11,12] and nonurogenital findings. Long-

term follow-up studies show that majority of multicystic kidneys

involute during first decade of life [13]. Interestingly, the MUC1

gene involved in Medullary Cystic Kidney Disease type I, which

usually manifests in adults, is also located in the chromosome 1q21.

Multicystic kidney is known to be associated with Diamond

Blackfan Anemia, but its association with PK deficiency is not

reported earlier. Since the gene coding forM2-PK, the isoenzyme of

PK specific for kidneys is located in a different chromosome at

15q22 [14], we think that PK deficiency and MCDK are coexistent

in this patient.

Acquired erythrocyte PK deficiency has been reported earlier in

some conditions with dyserythropoiesis [15,16]. This case report of

dyserythropoiesis in a child with congenital PK deficiency supports

earlier theories that ineffective erythropoiesis also contributes to

anemia in PK deficiency along with ATP depletion.

ACKNOWLEDGMENTS

The authors thank Ketan N. Patel, MD, Department of

Pediatrics, Division of Nephrology, UTMB Galveston for his

helpful comments and assistance in preparation of the case

report.

Fig. 1. Bone marrow aspirate slide shows inter-cytoplasmic bridging

(Wright–Giemsa staining, �500).

Fig. 2. Electron microscopy examination of the bone marrow aspirate

shows the red blood cell nuclear chromatin changes that mimic “Swiss

Cheese” morphology as described in congenital dyserythropoietic

anemia (�25,000).

Pediatr Blood Cancer DOI 10.1002/pbc

1464 Haija et al.

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