Pediatr Blood Cancer 2015;62:1872–1873
LETTER TO THE EDITOR Homozygous Southeast Asian Hereditary Ovalostomatocytosis: Management Dilemma
Southeast Asian Ovalostomatocytosis (SAO) is a red blood cell membrane abnormality that occurs at a high prevalence rate in Malaysia.[1] The molecular defect has been identified as a 27nucleotide deletion in exon 11 of the band 3 protein or anion exchange 1 (AE1) gene located at chromosome 17.[2] The red cell assumes an ovalostomatocyte shape, becomes super-rigid and cannot utilize its deformability characteristics to travel and squeeze through the microvasculature to deliver oxygen. The inheritance pattern is autosomal dominant, where carriers are heterozygotes and devoid of symptoms. The homozygous state is usually lethal. The following case describes a living infant with homozygous SAO and the management dilemma faced. A male fetus showing pericardial effusion and fetal ascites by detailed fetal scan was suspected of haemoglobin (Hb) Barts hydrops fetalis. Cord blood Hb was 3.0 g/dL and intrauterine red cell transfusion was commenced at 25 weeks period of gestation. The child was delivered via caesarean section at 35 weeks with a birth weight of 2 kg. After birth, his first transfusion was at a month old. At 4 months old, the child was severely pale, jaundiced and tachypnoiec, with an enlarged liver, spleen and weighed only 3.6 kg. Hb was 7.4 g/dL. His father, mother, and older female sibling had no prior medical illness. A full blood profile of both parents showed normal Hb level with ovalostomatocytosis on morphology. Hb analysis was not suggestive of either a or b globin gene abnormalities. DNA analysis confirmed both parents were heterozygotes for the Band 3 deletion, while the child was homozygous. At 19 months old, he was small for age and had received red cell transfusions 47 times. Pre-transfusion Hb was around 5–8 g/dL with post-transfusion level of 10–13 g/dL. His ferritin level was 1500 ug/L (30–400 ug/L). He also developed renal tubular acidosis type 1 due to persistent metabolic acidosis with hypokalaemia. His developmental age was between 0 and 3 months. Dietary intake consisted mainly of formula milk. HLA typing with his sibling’s was incompatible. Homozygous SAO is hypothesized to be incompatible with life due to a 50% decrease in anion transport. Some suggest that other cell types that rely on the expression of the Band 3 allele during the embryonal stage may not be capable of chloride-bicarbonate exchange.[3–4] Homozygous SAO may also lead to extensive aggregation of SAO cells during erythropoiesis that preclude its release from the bone marrow. In another observation, when both parents are carriers, a higher frequency of miscarriage is seen.[5] The child failed to thrive despite blood transfusions of 2-weekly interval. Due to his small size, venous access was poor, and limited. He also had massive hepatosplenomegaly from the disease and iron overload from receiving multiple transfusions (Fig. 1). All these factors contribute to high risk of mortality from conditioning with chemotherapy. Emphasis must be placed on the importance of obtaining a diagnosis before embarking on intrauterine transfusion. Other than passive passage of maternal antibodies that are shortlived, the long-term outcome after intrauterine transfusion for other conditions has not always been reported.[6]
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25545 Published online 20 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
Fig. 1. At 19 months of age, the head circumference, weight, and height were all below the third centiles. Abdominal distension with gross hepatosplenomegaly; spleen measured 18 cm (outlined); liver measured 8 cm (Illustration used with permission from guardians).
ACKNOWLEDGEMENT The authors would like to thank the Director General, Ministry of Health Malaysia for granting permission to publish this case.
Abbreviations: AE, anion exchange; cm, centimeter; g/dL, gram per desilitre; Hb, haemoglobin; kg, kilogram; SAO, southeast asian ovalostomatocytosis; ug/L, microgram per liter Conflict of interest: Nothing to declare. Ethics statement: Photograph was used with permission from the patient’s guardian. Correspondence to: Asral Wirda Ahmad Asnawi, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia (USIM), Level 13 Menara B, Persiaran MPAJ, Jalan Pandan Utama, 55100 Kuala Lumpur, Malaysia. E-mail: [email protected]
Received 13 March 2015; Accepted 16 March 2015
Homozygous Southeast Asian Ovalostomatocytosis Asral Wirda Ahmad Asnawi, MD, MPATH* Faculty of Medicine and Health Sciences Universiti Sains Islam Malaysia (USIM) Level 13 Menara B, Persiaran MPAJ, Jalan Pandan Utama 55100 Kuala Lumpur, Malaysia Jameela Sathar, MD, MRCP, FRCPATH Department of Haematology, Hospital Ampang Jalan Mewah Utara, Pandan Mewah 68000 Ampang, Selangor, Malaysia Siti Farah Sophia Mohd Nasir, MBBCH BAO (Ireland) Department of Pathology, Hospital Ampang Jalan Mewah Utara, Pandan Mewah 68000 Ampang, Selangor, Malaysia Rashidah Mohamed, MBBCH BAO (Ireland), MPATH Department of Pathology, Hospital Ampang Jalan Mewah Utara, Pandan Mewah 68000 Ampang, Selangor, Malaysia
Pediatr Blood Cancer DOI 10.1002/pbc
1873
Kerry Vivienne Jayaprakasam, MBBS, MRCPCH (UK) Pantai Hospital Kuala Lumpur 8 Jalan Bukit Pantai 59100 Kuala Lumpur, Malaysia Shamani Thavamalar Vellapandian Department of Paediatrics Hospital Ampang, Jalan Mewah Utara Pandan Mewah, 68000 Ampang, Selangor, Malaysia.
REFERENCES 1. Wrong O, Bruce LJ, Unwin RJ, Tanner MJA. Band 3 mutations, distal renal tubular acidosis and southeast asian ovalostomatocytosis. Kidney Int 2002;62:10–19. 2. Mandal D, Moitra PK, Basu J. Mapiong of a spectrin-binding domain of human erythrocyte membrane protein 4.2. Biochem J 2002 364:841–847. 3. Mohd Yusoff N, Van Rostenberghe H, Shirakawa T, Nishiyama K, Amin N, Darus Z, Isa N, Nozu H, Matsuo M. High prevalence of southeast Asian ovalostomatosytosis is Malays with distal renal tubular acidosis. J Hum Genet 2003;48:650–653. 4. Kay MM. Band 3 and its alterations in health and disease. Cell Mol Biol 2004;50:117–138. 5. Liu SC, Jarolim P, Rubin HL, Palek J, Amato D, Hassan K, Zaik M, Sapak P. The homozygous state for the band 3 protein mutation in southeast Asian ovalostomatocytosis may be lethal. Blood 1994 84:3590–3591. 6. Lindenburg ITM, van Kamp IL, Oepkes D. Intrauterine blood transfusion: Current indications and associated risks. Fetal Diagn Ther 2014;36:263–271.
LETTER TO THE EDITOR Homozygous Southeast Asian Hereditary Ovalostomatocytosis: Management Dilemma
Southeast Asian Ovalostomatocytosis (SAO) is a red blood cell membrane abnormality that occurs at a high prevalence rate in Malaysia.[1] The molecular defect has been identified as a 27nucleotide deletion in exon 11 of the band 3 protein or anion exchange 1 (AE1) gene located at chromosome 17.[2] The red cell assumes an ovalostomatocyte shape, becomes super-rigid and cannot utilize its deformability characteristics to travel and squeeze through the microvasculature to deliver oxygen. The inheritance pattern is autosomal dominant, where carriers are heterozygotes and devoid of symptoms. The homozygous state is usually lethal. The following case describes a living infant with homozygous SAO and the management dilemma faced. A male fetus showing pericardial effusion and fetal ascites by detailed fetal scan was suspected of haemoglobin (Hb) Barts hydrops fetalis. Cord blood Hb was 3.0 g/dL and intrauterine red cell transfusion was commenced at 25 weeks period of gestation. The child was delivered via caesarean section at 35 weeks with a birth weight of 2 kg. After birth, his first transfusion was at a month old. At 4 months old, the child was severely pale, jaundiced and tachypnoiec, with an enlarged liver, spleen and weighed only 3.6 kg. Hb was 7.4 g/dL. His father, mother, and older female sibling had no prior medical illness. A full blood profile of both parents showed normal Hb level with ovalostomatocytosis on morphology. Hb analysis was not suggestive of either a or b globin gene abnormalities. DNA analysis confirmed both parents were heterozygotes for the Band 3 deletion, while the child was homozygous. At 19 months old, he was small for age and had received red cell transfusions 47 times. Pre-transfusion Hb was around 5–8 g/dL with post-transfusion level of 10–13 g/dL. His ferritin level was 1500 ug/L (30–400 ug/L). He also developed renal tubular acidosis type 1 due to persistent metabolic acidosis with hypokalaemia. His developmental age was between 0 and 3 months. Dietary intake consisted mainly of formula milk. HLA typing with his sibling’s was incompatible. Homozygous SAO is hypothesized to be incompatible with life due to a 50% decrease in anion transport. Some suggest that other cell types that rely on the expression of the Band 3 allele during the embryonal stage may not be capable of chloride-bicarbonate exchange.[3–4] Homozygous SAO may also lead to extensive aggregation of SAO cells during erythropoiesis that preclude its release from the bone marrow. In another observation, when both parents are carriers, a higher frequency of miscarriage is seen.[5] The child failed to thrive despite blood transfusions of 2-weekly interval. Due to his small size, venous access was poor, and limited. He also had massive hepatosplenomegaly from the disease and iron overload from receiving multiple transfusions (Fig. 1). All these factors contribute to high risk of mortality from conditioning with chemotherapy. Emphasis must be placed on the importance of obtaining a diagnosis before embarking on intrauterine transfusion. Other than passive passage of maternal antibodies that are shortlived, the long-term outcome after intrauterine transfusion for other conditions has not always been reported.[6]
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25545 Published online 20 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
Fig. 1. At 19 months of age, the head circumference, weight, and height were all below the third centiles. Abdominal distension with gross hepatosplenomegaly; spleen measured 18 cm (outlined); liver measured 8 cm (Illustration used with permission from guardians).
ACKNOWLEDGEMENT The authors would like to thank the Director General, Ministry of Health Malaysia for granting permission to publish this case.
Abbreviations: AE, anion exchange; cm, centimeter; g/dL, gram per desilitre; Hb, haemoglobin; kg, kilogram; SAO, southeast asian ovalostomatocytosis; ug/L, microgram per liter Conflict of interest: Nothing to declare. Ethics statement: Photograph was used with permission from the patient’s guardian. Correspondence to: Asral Wirda Ahmad Asnawi, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia (USIM), Level 13 Menara B, Persiaran MPAJ, Jalan Pandan Utama, 55100 Kuala Lumpur, Malaysia. E-mail: [email protected]
Received 13 March 2015; Accepted 16 March 2015
Homozygous Southeast Asian Ovalostomatocytosis Asral Wirda Ahmad Asnawi, MD, MPATH* Faculty of Medicine and Health Sciences Universiti Sains Islam Malaysia (USIM) Level 13 Menara B, Persiaran MPAJ, Jalan Pandan Utama 55100 Kuala Lumpur, Malaysia Jameela Sathar, MD, MRCP, FRCPATH Department of Haematology, Hospital Ampang Jalan Mewah Utara, Pandan Mewah 68000 Ampang, Selangor, Malaysia Siti Farah Sophia Mohd Nasir, MBBCH BAO (Ireland) Department of Pathology, Hospital Ampang Jalan Mewah Utara, Pandan Mewah 68000 Ampang, Selangor, Malaysia Rashidah Mohamed, MBBCH BAO (Ireland), MPATH Department of Pathology, Hospital Ampang Jalan Mewah Utara, Pandan Mewah 68000 Ampang, Selangor, Malaysia
Pediatr Blood Cancer DOI 10.1002/pbc
1873
Kerry Vivienne Jayaprakasam, MBBS, MRCPCH (UK) Pantai Hospital Kuala Lumpur 8 Jalan Bukit Pantai 59100 Kuala Lumpur, Malaysia Shamani Thavamalar Vellapandian Department of Paediatrics Hospital Ampang, Jalan Mewah Utara Pandan Mewah, 68000 Ampang, Selangor, Malaysia.
REFERENCES 1. Wrong O, Bruce LJ, Unwin RJ, Tanner MJA. Band 3 mutations, distal renal tubular acidosis and southeast asian ovalostomatocytosis. Kidney Int 2002;62:10–19. 2. Mandal D, Moitra PK, Basu J. Mapiong of a spectrin-binding domain of human erythrocyte membrane protein 4.2. Biochem J 2002 364:841–847. 3. Mohd Yusoff N, Van Rostenberghe H, Shirakawa T, Nishiyama K, Amin N, Darus Z, Isa N, Nozu H, Matsuo M. High prevalence of southeast Asian ovalostomatosytosis is Malays with distal renal tubular acidosis. J Hum Genet 2003;48:650–653. 4. Kay MM. Band 3 and its alterations in health and disease. Cell Mol Biol 2004;50:117–138. 5. Liu SC, Jarolim P, Rubin HL, Palek J, Amato D, Hassan K, Zaik M, Sapak P. The homozygous state for the band 3 protein mutation in southeast Asian ovalostomatocytosis may be lethal. Blood 1994 84:3590–3591. 6. Lindenburg ITM, van Kamp IL, Oepkes D. Intrauterine blood transfusion: Current indications and associated risks. Fetal Diagn Ther 2014;36:263–271.
