Novel Insights from Clinical Practice Neonatology 2014;105:1–4 DOI: 10.1159/000354884
Received: April 25, 2013 Accepted after revision: August 6, 2013 Published online: October 31, 2013
Variations in Both α-Spectrin (SPTA1) and β-Spectrin (SPTB) in a Neonate with Prolonged Jaundice in a Family where Nine Individuals Had Hereditary Elliptocytosis Robert D. Christensen a Roberto H. Nussenzveig b N. Scott Reading b Archana M. Agarwal b Josef T. Prchal b, c Hassan M. Yaish d a
Department of Women and Newborns, Intermountain Healthcare, b Department of Pathology, ARUP Laboratories, Division of Hematology and, Departments of Genetics and Pathology, and d Division of Hematology/Oncology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA
c
Established Facts • Hereditary elliptocytosis (HE) is generally a benign autosomal dominant trait caused by a variety of mutations in spectrin.
Novel Insights • A Caucasian male with prolonged neonatal jaundice was born into a family where nine members had HE, but none with problematic neonatal jaundice. His blood film and laboratory studies suggested pyropoikilocytosis. • Gene sequencing revealed two variations in SPTA1 (α-spectrin), plus a novel mutation in SPTB (β-spectrin) and no variations in other potentially relevant genes.
Key Words Jaundice · Neonate · Hemolysis · Elliptocytosis · Pyropoikilocytosis
Abstract We cared for a neonate who had problematic hyperbilirubinemia born into a family where nine first-degree relatives had hereditary elliptocytosis (HE). As neonates, the nine relatives did not have any significant jaundice or anemia that
© 2013 S. Karger AG, Basel 1661–7800/14/1051–0001$39.50/0 E-Mail [email protected] www.karger.com/neo
was recognizable. Blood films on the proband suggested a diagnosis of pyropoikilocytosis. Analysis of the α-spectrin gene (SPTA1) in the proband revealed two previously reported low-frequency heterozygous polymorphisms of unknown clinical significance and the αLELY allele. In addition, a novel heterozygous mutation was identified in exon 2 of the β-spectrin gene SPTB. No mutations were identified in ANK1 (ankyrin-1), SLC4A1 (band 3), EPB41 (band 4.1), or EPB42 (band 4.2). © 2013 S. Karger AG, Basel
Robert D. Christensen, MD Intermountain Healthcare 4401 Harrison Blvd Ogden, UT 84403 (USA) E-Mail Robert.Christensen @ imail.org
Introduction I
II
III
?
IV
Fig. 1. Genetic pedigree chart. Family members known to have hereditary elliptocytosis are shown by a half-filled symbol (indicating autosomal dominant inheritance) and those who do not have this diagnosis are designated by an open symbol. The generations are listed by Roman numerals, beginning with the first recognized case of elliptocytosis in this family. The proband is shown by the solid symbol in generation IV.
Color version available online
Hereditary elliptocytosis (HE) is a group of red blood cell disorders where circulating erythrocytes have an elliptical shape [1–4]. The heterozygous (autosomal dominant) condition occurs in about 1 per 3,000 individuals worldwide and does not usually produce severe neonatal jaundice or anemia. Most individuals with HE are of West African or Asian descent, in keeping with the antimalarial effect of this mutation [5]. Homozygous forms of HE (autosomal recessive) can be so severe as to result in fetal hydrops [1–5]. We cared for a neonate born to a family where nine first-degree relatives had HE, none of whom had a history of severe neonatal jaundice or anemia. He required intensive phototherapy for 1 week and had anemia with a very low mean corpuscular volume (MCV) for age, and a blood film showing not only elliptocytes, but also poikilocytosis and cell fragmentation. Genomic analysis revealed a unique set of variants in both α-(SPTA1) and β-(SPTB) spectrin. The parents consented to have this case published, with no identifying features.
Case The patient was born vaginally after 40 weeks’ gestation to a Caucasian mother with known HE. Nine family members were known to have HE (fig. 1), but none had a history of severe neonatal jaundice or anemia. The original family member found to have HE was discovered at the age of 40 years during hospitalization for a ruptured ovarian cyst. All with HE in this kindred, up to the proband, had the diagnosis of HE made by distinctive red blood cell morphology – not by genetic analysis. The father of the proband and the couple’s 4-year-old daughter were healthy with no history of anemia or jaundice. Jaundice was noted on the day of birth and phototherapy was initiated (total serum bilirubin 14.2 mg/dl). His blood type as well as his mother’s was O positive, but Coombs testing was not performed. Over the next 7 days, phototherapy was stopped and restarted twice due to bilirubin ‘rebound’. The highest recorded total serum bilirubin was 14.2 mg/dl on the day of birth. The hematocrit on the third day of life was 33%. No other laboratory studies were performed before being discharged home on the eighth day of life. He received phototherapy at home for 2 weeks. Because of the family history and the need for prolonged phototherapy, he was referred to the hematology clinic, where on the 36th day of life he appeared well with a heart rate of 166/min. His spleen was palpable 2 cm below the costal margin, but otherwise the examination was normal. Hematocrit was 26.9%, MCHC 37.5 g/dl, MCV 78.4 fl, RDW 14.5, reticulocyte count 14.3%, platelets 790 × 109/l, and serum bilirubin 1.2 mg/dl. His blood film (fig. 2) had elliptocytes, microcytes, schistocytes, and echinocytes with normal leukocyte and platelet morphology. On the 44th day of life he was seen again in the clinic where his hemoglobin was 9.6 g/dl, MCHC 35.0 g/dl, MCV 75.1 fl, reticulo-
2
Neonatology 2014;105:1–4 DOI: 10.1159/000354884
Fig. 2. Wright-stained blood film of the proband with elliptocytes,
microcytes, and schistocytes.
cyte count 3.7%, and platelets 770 × 109/l. The blood film was similar to the first, but with more elliptocytes. A blood film from his mother (hemoglobin 11.4 g/dl) had abundant elliptocytes, but did not have schistocytosis, microcytosis, or other features of pyropoikilocytosis. Blood films from his father and sister were normal. His growth and development were normal and he received no transfusions. When evaluated again at 10 months his hemoglobin was 12.2 g/dl, MCHC 35.3 g/dl, MCV 68.4 fl, RDW 16.3, and reticulocyte count 2.2%. His blood film continued to have elliptocytes, microcytes, schistocytes, and echinocytes, but with less poikilocytosis and more elliptocytosis than on the previous examinations.
Christensen /Nussenzveig /Reading / Agarwal /Prchal /Yaish
Genetic analysis of erythrocyte membrane proteins was performed using HaloPlex (Agilent Technologies, Santa Clara, Calif., USA) for targeted gene capture and sequencing on a HiSeq 2000 system (Illumina, San Diego, Calif., USA). DNA was fragmented using restriction enzymes and then denatured with a probe library hybridized to the fragments. The probe contained a method-specific sequencing motif incorporated during circularization and a barcode sequence. Probes were biotinylated and the fragments retrieved for sequencing using magnetic streptavidin beads. Analysis of the α-spectrin gene SPTA1 (1q22–23) revealed the benign polymorphisms giving rise to αLELY (low-expression allele). In addition, two nonsynonymous, low-frequency polymorphisms were identified in exon 43 leading to amino acid substitutions A1998P and R2016C. Two independent software tools, PolyPhen and Sift [6], predicted both of these mutations would adversely affect the function of the α-spectrin protein. In addition, we identified a novel mutation in exon 2 of the β-spectrin gene SPTB (14q23–24.1). This mutation, a transition G>A at the second codon position of amino acid 52, resulted in a nonsynonymous substitution (R52Q) predicted to adversely affect β-spectrin protein function [6]. No mutations were identified in ANK1 (ankyrin-1), SLC4A1 (band 3), EPB41 (band 4.1), or EPB42 (band 4.2). Likewise, no mutations were identified in G6PD (glucose-6-phosphate dehydrogenase), GPI (glucose-6-phosphate isomerase), HIF1A (hypoxia-inducible factor-1-a), HK1 (hexokinase 1), NTSCB (59-nucleotidase, cytosolic III), PIN1 (peptidylprolyl cis/trans isomerase), PKLR (pyruvate kinase, liver, and red blood cell), or in UGT1A1 (UDP-glucuronosyltransferase) promoter region.
MCHC high even in the neonatal period, much like in hereditary spherocytosis [15]. In addition to these abnormalities, the erythrocyte morphological abnormalities in our patient were more consistent with pyropoikilocytosis than with HE [3, 4, 7–9, 15–18]. We recognize that several elements of this case remain unclear. For instance, we are uncertain how the two lowfrequency variants in the α-spectrin gene and the novel mutation in the β-spectrin gene resulted in this phenotype. Moreover, it is not clear whether one or more of these variants is a de novo mutation or was inherited from the asymptomatic father. Despite these problems, we maintain it is very likely that these spectrin variants were responsible for the phenotype in this patient. We also believe this case has instructive elements for neonatologists due to the fact that HE is a relatively common condition worldwide, involving many races and ethnicities. Specifically, a neonate with hyperbilirubinemia born to a parent known to have HE, even if the parent has always been asymptomatic, should have a careful review of the CBC and blood film for evidence of pyropoikilocytosis. Such neonates should be afforded the benefit of careful bilirubin monitoring, close follow-up, and intensive phototherapy when indicated to avoid bilirubin neurotoxicity [19].
Discussion Acknowledgements
Hereditary pyropoikilocytosis can present as neonatal jaundice with erythrocyte morphological abnormalities including schistocytes, microcytes, spherocytes, and poikilocytes [1, 3, 7–9]. Affected individuals typically have one parent with HE and the other parent with a molecular defect leading to asymptomatic spectrin deficiency; thus, hereditary pyropoikilocytosis is genetically similar to a compound heterozygous autosomal recessive condition. HE, prominent on the proband’s maternal side [10], is generally a clinically mild condition detected when elliptical erythrocytes are seen on a blood film. The most common mutations causing HE involve the α-spectrin heterodimer self-association site [2, 11]. However, variants in the β-spectrin gene (SPTB) have been found, including a mutation in a large German family with autosomal dominant HE [12], a family in Southern Italy with a C-toG substitution at position 6284 of the SPTB gene [13], and two unrelated families from Sardinia [14]. Neonates and children with HE generally have normal erythrocyte indices. In fact, typical cases of HE may not present with elliptocytic morphology in the first few months of life [1]. However in the present case, as in other reports of pyropoikilocytosis, the MCV is low and the Hereditary Pyropoikilocytosis and Neonatal Jaundice
The authors thank Renee Marlette, RN, ARNP, Primary Children’s Medical Center, and Diane K. Lambert, RN, Intermountain Healthcare, for valuable assistance with this case report.
Disclosure Statement The authors have no conflict of interest to disclose relative to this paper.
References
Neonatology 2014;105:1–4 DOI: 10.1159/000354884
1 Gallagher PG, Glader B: Hereditary spherocytosis, hereditary elliptocytosis, and other disorders associated with abnormalities of the erythrocyte membrane; in Greer JP, Forester J, Rodgers GM, Paraskevas F, Glader B, Arber DA, Means RT Jr (eds): Wintrobe’s Clinical Hematology, ed 12. Philadelphia, Lippincott, Williams & Wilkins, 2010, pp 923–924. 2 Coetzer T, Palek J, Lawler J, Liu SC, Jarolim P, Lahav M, et al: Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis. Blood 1990;75:2235–2244.
3
3 Gallagher PG: Red cell membrane disorders. Hematology Am Soc Hematol Educ Program 2005, pp 13–18. 4 Coetzer T, Lawler J, Prchal JT, Palek J: Molecular determinants of clinical expression of hereditary elliptocytosis and pyropoikilocytosis. Blood 1987;70:766–772. 5 Gallagher PG: Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol 2004; 41:142–164. 6 Flanagan SE, Patch AM, Ellard S: Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations. Genet Test Mol Biomarkers 2010;14:533–537. 7 Zarkowsky HS, Mohandas N, Speaker CB, Shohet SR: A congenital haemolytic anemia with thermal sensitivity of the erythrocyte membrane. Br J Haematol 1975;29:537–543. 8 Prchal JT, Castleberry RP, Parmley RT, Crist WM, Malluh A: Hereditary pyropoikilocytosis and elliptocytosis: clinical, laboratory, and ultrastructural features in infants and children. Pediatr Res 1982;16:484–489.
4
9 Ramos MC, Schafernak KT, Peterson LC: Hereditary pyropoikilocytosis: a rare but potentially severe form of congenital hemolytic anemia. J Pediatr Hematol Oncol 2007; 29: 128–129. 10 Greenberg LH, Tanaka KR: Hereditary elliptocytosis with hemolytic anemia – a family study of five affected members. Calif Med 1969;110:389–393. 11 Liu SC, Palek J, Prchal JT: Defective spectrin dimer-dimer association with hereditary elliptocytosis. Proc Natl Acad Sci USA 1982;79: 2072–2076. 12 Yoon SH, Yu H, Eber S, Prchal JT: Molecular defect of truncated beta-spectrin associated with hereditary elliptocytosis. Beta-spectrin Gottingen. J Biol Chem 1991;266:8490–8494. 13 Qualtieri A, Pasqua A, Bisconte MG, Le Pera M, Brancati C: Spectrin Cosenza: a novel beta chain variant associated with Sp-alpha(I/74) hereditary elliptocytosis. Br J Haematol 1997; 97:273–278. 14 Sahr KE, Coetzer TL, Moy LS, Derick LH, Chishti AH, Jarolim P, et al: Spectrin cagliari: an Ala–>Gly substitution in helix 1 of beta spectrin repeat 17 that severely disrupts the structure and self-association of the erythrocyte spectrin heterodimer. J Biol Chem 1993; 268:22656–22662.
Neonatology 2014;105:1–4 DOI: 10.1159/000354884
15 Christensen RD, Yaish HM, Henry E, Baer VL, Bennett ST: A simple method of screening newborn infants for hereditary spherocytosis. J Applied Hematol 2013;4:27–32. 16 Yaish HM, Christensen RD: A neonate with Coombs-negative hemolytic jaundice with spherocytes but normal erythrocyte indices: a rare case of autosomal-recessive hereditary spherocytosis due to alpha-spectrin deficiency. J Perinatol 2013;33:404–406. 17 Niazi GA, Yaish HM, Dery JP, Al Shaalan M: Erythocytic genetic disorders in the newborn population of the Saudi Arabian National Guard. Saudi Med J 1990;11:497–599. 18 Tolpinrud W, Maksimova YD, Forget BG, Gallagher PG: Nonsense mutations of the alpha-spectrin gene in hereditary pyropoikilocytosis. Haematologica 2008;93:1752–1754. 19 Christensen RD, Lambert DK, Henry E, Eggert LD, Yaish HM, Reading NS, Prchal JT: Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system. Blood Cells Mol Dis 2013; 50: 105– 109.
Christensen /Nussenzveig /Reading / Agarwal /Prchal /Yaish
Copyright: S. Karger AG, Basel 2013. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: April 25, 2013 Accepted after revision: August 6, 2013 Published online: October 31, 2013
Variations in Both α-Spectrin (SPTA1) and β-Spectrin (SPTB) in a Neonate with Prolonged Jaundice in a Family where Nine Individuals Had Hereditary Elliptocytosis Robert D. Christensen a Roberto H. Nussenzveig b N. Scott Reading b Archana M. Agarwal b Josef T. Prchal b, c Hassan M. Yaish d a
Department of Women and Newborns, Intermountain Healthcare, b Department of Pathology, ARUP Laboratories, Division of Hematology and, Departments of Genetics and Pathology, and d Division of Hematology/Oncology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA
c
Established Facts • Hereditary elliptocytosis (HE) is generally a benign autosomal dominant trait caused by a variety of mutations in spectrin.
Novel Insights • A Caucasian male with prolonged neonatal jaundice was born into a family where nine members had HE, but none with problematic neonatal jaundice. His blood film and laboratory studies suggested pyropoikilocytosis. • Gene sequencing revealed two variations in SPTA1 (α-spectrin), plus a novel mutation in SPTB (β-spectrin) and no variations in other potentially relevant genes.
Key Words Jaundice · Neonate · Hemolysis · Elliptocytosis · Pyropoikilocytosis
Abstract We cared for a neonate who had problematic hyperbilirubinemia born into a family where nine first-degree relatives had hereditary elliptocytosis (HE). As neonates, the nine relatives did not have any significant jaundice or anemia that
© 2013 S. Karger AG, Basel 1661–7800/14/1051–0001$39.50/0 E-Mail [email protected] www.karger.com/neo
was recognizable. Blood films on the proband suggested a diagnosis of pyropoikilocytosis. Analysis of the α-spectrin gene (SPTA1) in the proband revealed two previously reported low-frequency heterozygous polymorphisms of unknown clinical significance and the αLELY allele. In addition, a novel heterozygous mutation was identified in exon 2 of the β-spectrin gene SPTB. No mutations were identified in ANK1 (ankyrin-1), SLC4A1 (band 3), EPB41 (band 4.1), or EPB42 (band 4.2). © 2013 S. Karger AG, Basel
Robert D. Christensen, MD Intermountain Healthcare 4401 Harrison Blvd Ogden, UT 84403 (USA) E-Mail Robert.Christensen @ imail.org
Introduction I
II
III
?
IV
Fig. 1. Genetic pedigree chart. Family members known to have hereditary elliptocytosis are shown by a half-filled symbol (indicating autosomal dominant inheritance) and those who do not have this diagnosis are designated by an open symbol. The generations are listed by Roman numerals, beginning with the first recognized case of elliptocytosis in this family. The proband is shown by the solid symbol in generation IV.
Color version available online
Hereditary elliptocytosis (HE) is a group of red blood cell disorders where circulating erythrocytes have an elliptical shape [1–4]. The heterozygous (autosomal dominant) condition occurs in about 1 per 3,000 individuals worldwide and does not usually produce severe neonatal jaundice or anemia. Most individuals with HE are of West African or Asian descent, in keeping with the antimalarial effect of this mutation [5]. Homozygous forms of HE (autosomal recessive) can be so severe as to result in fetal hydrops [1–5]. We cared for a neonate born to a family where nine first-degree relatives had HE, none of whom had a history of severe neonatal jaundice or anemia. He required intensive phototherapy for 1 week and had anemia with a very low mean corpuscular volume (MCV) for age, and a blood film showing not only elliptocytes, but also poikilocytosis and cell fragmentation. Genomic analysis revealed a unique set of variants in both α-(SPTA1) and β-(SPTB) spectrin. The parents consented to have this case published, with no identifying features.
Case The patient was born vaginally after 40 weeks’ gestation to a Caucasian mother with known HE. Nine family members were known to have HE (fig. 1), but none had a history of severe neonatal jaundice or anemia. The original family member found to have HE was discovered at the age of 40 years during hospitalization for a ruptured ovarian cyst. All with HE in this kindred, up to the proband, had the diagnosis of HE made by distinctive red blood cell morphology – not by genetic analysis. The father of the proband and the couple’s 4-year-old daughter were healthy with no history of anemia or jaundice. Jaundice was noted on the day of birth and phototherapy was initiated (total serum bilirubin 14.2 mg/dl). His blood type as well as his mother’s was O positive, but Coombs testing was not performed. Over the next 7 days, phototherapy was stopped and restarted twice due to bilirubin ‘rebound’. The highest recorded total serum bilirubin was 14.2 mg/dl on the day of birth. The hematocrit on the third day of life was 33%. No other laboratory studies were performed before being discharged home on the eighth day of life. He received phototherapy at home for 2 weeks. Because of the family history and the need for prolonged phototherapy, he was referred to the hematology clinic, where on the 36th day of life he appeared well with a heart rate of 166/min. His spleen was palpable 2 cm below the costal margin, but otherwise the examination was normal. Hematocrit was 26.9%, MCHC 37.5 g/dl, MCV 78.4 fl, RDW 14.5, reticulocyte count 14.3%, platelets 790 × 109/l, and serum bilirubin 1.2 mg/dl. His blood film (fig. 2) had elliptocytes, microcytes, schistocytes, and echinocytes with normal leukocyte and platelet morphology. On the 44th day of life he was seen again in the clinic where his hemoglobin was 9.6 g/dl, MCHC 35.0 g/dl, MCV 75.1 fl, reticulo-
2
Neonatology 2014;105:1–4 DOI: 10.1159/000354884
Fig. 2. Wright-stained blood film of the proband with elliptocytes,
microcytes, and schistocytes.
cyte count 3.7%, and platelets 770 × 109/l. The blood film was similar to the first, but with more elliptocytes. A blood film from his mother (hemoglobin 11.4 g/dl) had abundant elliptocytes, but did not have schistocytosis, microcytosis, or other features of pyropoikilocytosis. Blood films from his father and sister were normal. His growth and development were normal and he received no transfusions. When evaluated again at 10 months his hemoglobin was 12.2 g/dl, MCHC 35.3 g/dl, MCV 68.4 fl, RDW 16.3, and reticulocyte count 2.2%. His blood film continued to have elliptocytes, microcytes, schistocytes, and echinocytes, but with less poikilocytosis and more elliptocytosis than on the previous examinations.
Christensen /Nussenzveig /Reading / Agarwal /Prchal /Yaish
Genetic analysis of erythrocyte membrane proteins was performed using HaloPlex (Agilent Technologies, Santa Clara, Calif., USA) for targeted gene capture and sequencing on a HiSeq 2000 system (Illumina, San Diego, Calif., USA). DNA was fragmented using restriction enzymes and then denatured with a probe library hybridized to the fragments. The probe contained a method-specific sequencing motif incorporated during circularization and a barcode sequence. Probes were biotinylated and the fragments retrieved for sequencing using magnetic streptavidin beads. Analysis of the α-spectrin gene SPTA1 (1q22–23) revealed the benign polymorphisms giving rise to αLELY (low-expression allele). In addition, two nonsynonymous, low-frequency polymorphisms were identified in exon 43 leading to amino acid substitutions A1998P and R2016C. Two independent software tools, PolyPhen and Sift [6], predicted both of these mutations would adversely affect the function of the α-spectrin protein. In addition, we identified a novel mutation in exon 2 of the β-spectrin gene SPTB (14q23–24.1). This mutation, a transition G>A at the second codon position of amino acid 52, resulted in a nonsynonymous substitution (R52Q) predicted to adversely affect β-spectrin protein function [6]. No mutations were identified in ANK1 (ankyrin-1), SLC4A1 (band 3), EPB41 (band 4.1), or EPB42 (band 4.2). Likewise, no mutations were identified in G6PD (glucose-6-phosphate dehydrogenase), GPI (glucose-6-phosphate isomerase), HIF1A (hypoxia-inducible factor-1-a), HK1 (hexokinase 1), NTSCB (59-nucleotidase, cytosolic III), PIN1 (peptidylprolyl cis/trans isomerase), PKLR (pyruvate kinase, liver, and red blood cell), or in UGT1A1 (UDP-glucuronosyltransferase) promoter region.
MCHC high even in the neonatal period, much like in hereditary spherocytosis [15]. In addition to these abnormalities, the erythrocyte morphological abnormalities in our patient were more consistent with pyropoikilocytosis than with HE [3, 4, 7–9, 15–18]. We recognize that several elements of this case remain unclear. For instance, we are uncertain how the two lowfrequency variants in the α-spectrin gene and the novel mutation in the β-spectrin gene resulted in this phenotype. Moreover, it is not clear whether one or more of these variants is a de novo mutation or was inherited from the asymptomatic father. Despite these problems, we maintain it is very likely that these spectrin variants were responsible for the phenotype in this patient. We also believe this case has instructive elements for neonatologists due to the fact that HE is a relatively common condition worldwide, involving many races and ethnicities. Specifically, a neonate with hyperbilirubinemia born to a parent known to have HE, even if the parent has always been asymptomatic, should have a careful review of the CBC and blood film for evidence of pyropoikilocytosis. Such neonates should be afforded the benefit of careful bilirubin monitoring, close follow-up, and intensive phototherapy when indicated to avoid bilirubin neurotoxicity [19].
Discussion Acknowledgements
Hereditary pyropoikilocytosis can present as neonatal jaundice with erythrocyte morphological abnormalities including schistocytes, microcytes, spherocytes, and poikilocytes [1, 3, 7–9]. Affected individuals typically have one parent with HE and the other parent with a molecular defect leading to asymptomatic spectrin deficiency; thus, hereditary pyropoikilocytosis is genetically similar to a compound heterozygous autosomal recessive condition. HE, prominent on the proband’s maternal side [10], is generally a clinically mild condition detected when elliptical erythrocytes are seen on a blood film. The most common mutations causing HE involve the α-spectrin heterodimer self-association site [2, 11]. However, variants in the β-spectrin gene (SPTB) have been found, including a mutation in a large German family with autosomal dominant HE [12], a family in Southern Italy with a C-toG substitution at position 6284 of the SPTB gene [13], and two unrelated families from Sardinia [14]. Neonates and children with HE generally have normal erythrocyte indices. In fact, typical cases of HE may not present with elliptocytic morphology in the first few months of life [1]. However in the present case, as in other reports of pyropoikilocytosis, the MCV is low and the Hereditary Pyropoikilocytosis and Neonatal Jaundice
The authors thank Renee Marlette, RN, ARNP, Primary Children’s Medical Center, and Diane K. Lambert, RN, Intermountain Healthcare, for valuable assistance with this case report.
Disclosure Statement The authors have no conflict of interest to disclose relative to this paper.
References
Neonatology 2014;105:1–4 DOI: 10.1159/000354884
1 Gallagher PG, Glader B: Hereditary spherocytosis, hereditary elliptocytosis, and other disorders associated with abnormalities of the erythrocyte membrane; in Greer JP, Forester J, Rodgers GM, Paraskevas F, Glader B, Arber DA, Means RT Jr (eds): Wintrobe’s Clinical Hematology, ed 12. Philadelphia, Lippincott, Williams & Wilkins, 2010, pp 923–924. 2 Coetzer T, Palek J, Lawler J, Liu SC, Jarolim P, Lahav M, et al: Structural and functional heterogeneity of alpha spectrin mutations involving the spectrin heterodimer self-association site: relationships to hematologic expression of homozygous hereditary elliptocytosis and hereditary pyropoikilocytosis. Blood 1990;75:2235–2244.
3
3 Gallagher PG: Red cell membrane disorders. Hematology Am Soc Hematol Educ Program 2005, pp 13–18. 4 Coetzer T, Lawler J, Prchal JT, Palek J: Molecular determinants of clinical expression of hereditary elliptocytosis and pyropoikilocytosis. Blood 1987;70:766–772. 5 Gallagher PG: Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol 2004; 41:142–164. 6 Flanagan SE, Patch AM, Ellard S: Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations. Genet Test Mol Biomarkers 2010;14:533–537. 7 Zarkowsky HS, Mohandas N, Speaker CB, Shohet SR: A congenital haemolytic anemia with thermal sensitivity of the erythrocyte membrane. Br J Haematol 1975;29:537–543. 8 Prchal JT, Castleberry RP, Parmley RT, Crist WM, Malluh A: Hereditary pyropoikilocytosis and elliptocytosis: clinical, laboratory, and ultrastructural features in infants and children. Pediatr Res 1982;16:484–489.
4
9 Ramos MC, Schafernak KT, Peterson LC: Hereditary pyropoikilocytosis: a rare but potentially severe form of congenital hemolytic anemia. J Pediatr Hematol Oncol 2007; 29: 128–129. 10 Greenberg LH, Tanaka KR: Hereditary elliptocytosis with hemolytic anemia – a family study of five affected members. Calif Med 1969;110:389–393. 11 Liu SC, Palek J, Prchal JT: Defective spectrin dimer-dimer association with hereditary elliptocytosis. Proc Natl Acad Sci USA 1982;79: 2072–2076. 12 Yoon SH, Yu H, Eber S, Prchal JT: Molecular defect of truncated beta-spectrin associated with hereditary elliptocytosis. Beta-spectrin Gottingen. J Biol Chem 1991;266:8490–8494. 13 Qualtieri A, Pasqua A, Bisconte MG, Le Pera M, Brancati C: Spectrin Cosenza: a novel beta chain variant associated with Sp-alpha(I/74) hereditary elliptocytosis. Br J Haematol 1997; 97:273–278. 14 Sahr KE, Coetzer TL, Moy LS, Derick LH, Chishti AH, Jarolim P, et al: Spectrin cagliari: an Ala–>Gly substitution in helix 1 of beta spectrin repeat 17 that severely disrupts the structure and self-association of the erythrocyte spectrin heterodimer. J Biol Chem 1993; 268:22656–22662.
Neonatology 2014;105:1–4 DOI: 10.1159/000354884
15 Christensen RD, Yaish HM, Henry E, Baer VL, Bennett ST: A simple method of screening newborn infants for hereditary spherocytosis. J Applied Hematol 2013;4:27–32. 16 Yaish HM, Christensen RD: A neonate with Coombs-negative hemolytic jaundice with spherocytes but normal erythrocyte indices: a rare case of autosomal-recessive hereditary spherocytosis due to alpha-spectrin deficiency. J Perinatol 2013;33:404–406. 17 Niazi GA, Yaish HM, Dery JP, Al Shaalan M: Erythocytic genetic disorders in the newborn population of the Saudi Arabian National Guard. Saudi Med J 1990;11:497–599. 18 Tolpinrud W, Maksimova YD, Forget BG, Gallagher PG: Nonsense mutations of the alpha-spectrin gene in hereditary pyropoikilocytosis. Haematologica 2008;93:1752–1754. 19 Christensen RD, Lambert DK, Henry E, Eggert LD, Yaish HM, Reading NS, Prchal JT: Unexplained extreme hyperbilirubinemia among neonates in a multihospital healthcare system. Blood Cells Mol Dis 2013; 50: 105– 109.
Christensen /Nussenzveig /Reading / Agarwal /Prchal /Yaish
Copyright: S. Karger AG, Basel 2013. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
