Journal of Perinatology (2014) 34, 645–646 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
PERINATAL/NEONATAL CASE PRESENTATION
Monochorionic-monoamniotic twins discordant for VATER association J Quinlan, P Arora, S Rane and M Bajaj We describe a monozygotic twin discordant for VATER association with single dysplastic kidney and cloacal anomaly, who had no pulmonary hypoplasia. This twin probably had little or no urine output in utero, but still had normal lung development due to production of adequate amniotic fluid by the healthy twin preventing pulmonary hypoplasia. The discordance between monozygotic twins for VATER association indicates that factors other than inherited genetic ones may have a role in the causation of this association. Journal of Perinatology (2014) 34, 645–646; doi:10.1038/jp.2014.61
INTRODUCTION VATER association comprises a constellation of congenital malformations, with a reported incidence of 1 in 10 000 to 1 in 40 000 live births.1 Diagnosis is typically made by the presence of at least three of the following malformations—that is, vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula, renal anomalies and limb defects.1 The prognosis depends upon the severity of malformations. Bilateral renal agenesis, if present, causes pulmonary hypoplasia secondary to lack of amniotic fluid and this condition is incompatible with life.2 We describe a monochorionic-monoamniotic twin discordant for VATER association with single dysplastic kidney and cloacal anamoly. This twin probably did not have sufficient urine output in utero, but still managed to survive owing to production of adequate amniotic fluid by the healthy twin preventing pulmonary hypoplasia. Clinical description Two live monochorionic-monoamniotic twin girls were delivered via cesarean section at 32 weeks of gestation. The mother was 36 years old gravida six, para three with history of diabetes requiring insulin during pregnancy. Prenatal ultrasound scans showed an absent left kidney and an abnormal right kidney in twin B. At birth, twin A had normal physical examination. Twin B weighed 1451 g and her Apgar scores were 5 and 8 at 1 and 5 min, respectively. She was noted to have respiratory distress and was intubated in the delivery room. Her physical examination was significant for a single umbilical artery, a large palpable mass in the right flank extending up to suprapubic region, absent anal opening and two labial folds with a single opening consistent with urorectal septum malformation or persistent cloacae. Postnatal ultrasound confirmed the diagnosis of absent left kidney, a dysplastic right kidney with no corticomedullary differentiation and a poorly formed, rudimentary and hydronephrotic collecting system with a dilated ureter. The urinary bladder was distended. A fluid filled structure was appreciated posterior to the urinary bladder and anterior to the spine, which was thought to represent the rectal
pouch. Skeletal radiographs demonstrated a hemivertebra at T9 level, fusion of seventh and eighth thoracic vertebrae, and a levoscoliotic curvature of the spine (Figure 1). Head ultrasound and echocardiogram were normal. The combination of anal atresia, renal dysgenesis, vertebral anomalies and single umbilical artery suggested VATER association. Result of chromosomal microarray was normal and the infant had a normal female karyotype (46 XX). The infant underwent diverting colostomy and cystoscopic catheterization of the common channel on the first day, which resulted in significant decrease in the size of the palpable mass. However, she did not have adequate urine output and the repeat renal ultrasound redemonstrated dilated ureters. Percutaneous nephrostomy tube was placed at first but later peritoneal dialysis had to be performed for persistent elevation in serum creatinine levels, which had increased to 4.4 mg dl − 1. The peritoneal dialysis was discontinued after two months due to catheter malfunction. A suprapubic drain was placed that was later converted to nephrostomy. Her urine output and serum creatinine levels, although elevated, remained stable and she was discharged home with nephrostomy drainage, colostomy and a vaginostomy with the plan of renal transplant and repair of cloacal anomaly in the future. The infant required ventilatory support after birth but was gradually weaned off and went home on room air.
DISCUSSION Pulmonary hypoplasia is frequently encountered in cases with bilateral renal agenesis/dysgenesis. The most important mechanism leading to coexistence of these two conditions is the lack of amniotic fluid in renal agenesis, as urine produced by the fetus contributes to the formation of amniotic fluid, which in turn facilitates fetal breathing movements and provides various factors for adequate growth of lungs.3,4 However, in our case despite absence of kidney on the left side and dysplastic kidney on the right, the lungs were essentially normal. This may be due to the presence of amniotic fluid produced by her monoamniotic twin
Division of Neonatal-Perinatal Medicine, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA. Correspondence: Dr P Arora, Division of Neonatal-Perinatal Medicine, The Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan & Hutzel Women's Hospital, 3901 Beaubien Street, Detroit, MI 48201, USA. E-mail: [email protected] Received 28 November 2013; accepted 13 February 2014
Discordant monochorionic-monoamniotic twins J Quinlan et al
646
differential gene expressions in the twins.12–15 The cause of discordance largely remains undetermined in our case and such cases would require further research. A recently published review to determine the concordance rates of VATER/VACTERAL association among twin pairs showed a concordance rate of 15% (2 out of 13) in monozygotic and 18% (2 out of 11) in dizygotic twins.16 This review suggests that in majority of these cases, inherited genetic factors do not have a major role. In addition to epigenetic events during early embryogenesis, environmental factors and post-zygotic somatic or de novo germline mutations may be implicated in these cases.16 New genomic techniques such as high-resolution copy number variation studies or next-generation exome sequencing may help to delineate the etiology of these cases.16
CONCLUSIONS Discordance among monozygotic twins for VATER association remains poorly understood. Further studies are required to establish the etiology of VATER association, which could possibly involve several factors besides genes alone.
CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES
Figure 1. Spine radiograph showing levoconvex scoliosis of the thoracic spine centered approximately at T8/T9 level, and multiple segmentation anomalies in the upper and mid thoracic spine including T9 hemivertebra.
with normal kidneys that was sufficient to promote adequate growth of lungs in the affected twin. There have been seven published case reports of monamniotic twins discordant for renal agenesis and normal pulmonary function.2,5–10 Four of these cases had other anomalies consistent with the diagnosis of VATER/VACTERL association.1,3,4,6 Our patient also had clinical features suggestive of VATER association that included vertebral anomalies, anal atresia, renal dysplasia and single umbilical artery. Monozygotic twins, by definition, should have concordant anomalies. The presence of discordance, however, poses a question mark to the etiology of anomalies present in the affected twin. Monozygotic twins develop from a single embryo that splits into two. The degree of placental sharing and the frequency of complications are dependent on the embryonic stage at which the embryo splits. Monochorionicmonamnionic twins develop from an embryo that splits relatively late in the postimplantation blastocyst period.11 A true genetic difference between these twins is highly unlikely. It is plausible that discordance may be caused by some epigenetic factor like DNA methylation. DNA methylation patterns could be affected by various cellular and environmental factors and the difference in DNA methylation can result in somatic mutations as well as
Journal of Perinatology (2014), 645 – 646
1 Solomon BD. VACTERL/VATER association. Orphanet J Rare Dis 2011; 6: 56. 2 Klinger G, Merlob P, Aloni D, Maayan A, Sirota L. Normal pulmonary function in a monoamniotic twin discordant for bilateral renal agenesis: report and review. Am J Med Genet 1997; 73(1): 76–79. 3 Potter EL. Bilateral renal agenesis. J Pediatr 1946; 29: 68–76. 4 Perlman M, Levin M. Fetal pulmonary hypoplasia, anuria, and oligohydramnios: clinicopathologic observations and review of the literature. Am J Obstet Gynecol 1974; 118(8): 1119–1123. 5 Mauer SM, Dobrin RS, Vernier RL. Unilateral and bilateral renal agenesis in monoamniotic twins. J Pediatr 1974; 84(2): 236–238. 6 Koffler H, Aase JM, Papile LA, Coen RW. Persistent cloaca with absent penis and anal atresia in one of identical twins. J Pediatr 1978; 93(5): 821–823. 7 Cilento BG Jr., Benacerraf BR, Mandell J. Prenatal and postnatal findings in monochorionic, monoamniotic twins discordant for bilateral renal agenesisdysgenesis (perinatal lethal renal disease). J Urol 1994; 151(4): 1034–1035. 8 McNamara MF, McCurdy CM, Reed KL, Philipps AF, Seeds JW. The relation between pulmonary hypoplasia and amniotic fluid volume: lessons learned from discordant urinary tract anomalies in monoamniotic twins. Obstet Gynecol 1995; 85(5 Pt 2): 867–869. 9 Perez-Brayfield MR, Kirsch AJ, Smith EA. Monoamniotic twin discordant for bilateral renal agenesis with normal pulmonary function. Urology 2004; 64(3): 589. 10 Meyer SR, Smith KM, Ravish IR, Saltzman DA, Shukla AR. Complex cloacal anomaly in discordant monozygotic twins. Urology 2009; 73(3): 532–534. 11 Hall JG. Twinning. Lancet 2003; 362(9385): 735–743. 12 Singh SM, Murphy B, O'Reilly R. Epigenetic contributors to the discordance of monozygotic twins. Clin Genet 2002; 62(2): 97–103. 13 Thompson SL, Konfortova G, Gregory RI, Reik W, Dean W, Feil R. Environmental effects on genomic imprinting in mammals. Toxicol Lett 2001; 120(1–3): 143–150. 14 Esteller M. Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer 2000; 36(18): 2294–2300. 15 Mancini D, Singh S, Ainsworth P, Rodenhiser D. Constitutively methylated CpG dinucleotides as mutation hot spots in the retinoblastoma gene (RB1). Am J Hum Genet 1997; 61(1): 80–87. 16 Bartels E, Schulz AC, Mora NW, Pineda-Alvarez DE, Wijers CH, Marcelis CM et al. VATER/VACTERL association: identification of seven new twin pairs, a systematic review of the literature, and a classical twin analysis. Clin Dysmorphol 2012; 21(4): 191–195.
© 2014 Nature America, Inc.
PERINATAL/NEONATAL CASE PRESENTATION
Monochorionic-monoamniotic twins discordant for VATER association J Quinlan, P Arora, S Rane and M Bajaj We describe a monozygotic twin discordant for VATER association with single dysplastic kidney and cloacal anomaly, who had no pulmonary hypoplasia. This twin probably had little or no urine output in utero, but still had normal lung development due to production of adequate amniotic fluid by the healthy twin preventing pulmonary hypoplasia. The discordance between monozygotic twins for VATER association indicates that factors other than inherited genetic ones may have a role in the causation of this association. Journal of Perinatology (2014) 34, 645–646; doi:10.1038/jp.2014.61
INTRODUCTION VATER association comprises a constellation of congenital malformations, with a reported incidence of 1 in 10 000 to 1 in 40 000 live births.1 Diagnosis is typically made by the presence of at least three of the following malformations—that is, vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula, renal anomalies and limb defects.1 The prognosis depends upon the severity of malformations. Bilateral renal agenesis, if present, causes pulmonary hypoplasia secondary to lack of amniotic fluid and this condition is incompatible with life.2 We describe a monochorionic-monoamniotic twin discordant for VATER association with single dysplastic kidney and cloacal anamoly. This twin probably did not have sufficient urine output in utero, but still managed to survive owing to production of adequate amniotic fluid by the healthy twin preventing pulmonary hypoplasia. Clinical description Two live monochorionic-monoamniotic twin girls were delivered via cesarean section at 32 weeks of gestation. The mother was 36 years old gravida six, para three with history of diabetes requiring insulin during pregnancy. Prenatal ultrasound scans showed an absent left kidney and an abnormal right kidney in twin B. At birth, twin A had normal physical examination. Twin B weighed 1451 g and her Apgar scores were 5 and 8 at 1 and 5 min, respectively. She was noted to have respiratory distress and was intubated in the delivery room. Her physical examination was significant for a single umbilical artery, a large palpable mass in the right flank extending up to suprapubic region, absent anal opening and two labial folds with a single opening consistent with urorectal septum malformation or persistent cloacae. Postnatal ultrasound confirmed the diagnosis of absent left kidney, a dysplastic right kidney with no corticomedullary differentiation and a poorly formed, rudimentary and hydronephrotic collecting system with a dilated ureter. The urinary bladder was distended. A fluid filled structure was appreciated posterior to the urinary bladder and anterior to the spine, which was thought to represent the rectal
pouch. Skeletal radiographs demonstrated a hemivertebra at T9 level, fusion of seventh and eighth thoracic vertebrae, and a levoscoliotic curvature of the spine (Figure 1). Head ultrasound and echocardiogram were normal. The combination of anal atresia, renal dysgenesis, vertebral anomalies and single umbilical artery suggested VATER association. Result of chromosomal microarray was normal and the infant had a normal female karyotype (46 XX). The infant underwent diverting colostomy and cystoscopic catheterization of the common channel on the first day, which resulted in significant decrease in the size of the palpable mass. However, she did not have adequate urine output and the repeat renal ultrasound redemonstrated dilated ureters. Percutaneous nephrostomy tube was placed at first but later peritoneal dialysis had to be performed for persistent elevation in serum creatinine levels, which had increased to 4.4 mg dl − 1. The peritoneal dialysis was discontinued after two months due to catheter malfunction. A suprapubic drain was placed that was later converted to nephrostomy. Her urine output and serum creatinine levels, although elevated, remained stable and she was discharged home with nephrostomy drainage, colostomy and a vaginostomy with the plan of renal transplant and repair of cloacal anomaly in the future. The infant required ventilatory support after birth but was gradually weaned off and went home on room air.
DISCUSSION Pulmonary hypoplasia is frequently encountered in cases with bilateral renal agenesis/dysgenesis. The most important mechanism leading to coexistence of these two conditions is the lack of amniotic fluid in renal agenesis, as urine produced by the fetus contributes to the formation of amniotic fluid, which in turn facilitates fetal breathing movements and provides various factors for adequate growth of lungs.3,4 However, in our case despite absence of kidney on the left side and dysplastic kidney on the right, the lungs were essentially normal. This may be due to the presence of amniotic fluid produced by her monoamniotic twin
Division of Neonatal-Perinatal Medicine, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA. Correspondence: Dr P Arora, Division of Neonatal-Perinatal Medicine, The Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan & Hutzel Women's Hospital, 3901 Beaubien Street, Detroit, MI 48201, USA. E-mail: [email protected] Received 28 November 2013; accepted 13 February 2014
Discordant monochorionic-monoamniotic twins J Quinlan et al
646
differential gene expressions in the twins.12–15 The cause of discordance largely remains undetermined in our case and such cases would require further research. A recently published review to determine the concordance rates of VATER/VACTERAL association among twin pairs showed a concordance rate of 15% (2 out of 13) in monozygotic and 18% (2 out of 11) in dizygotic twins.16 This review suggests that in majority of these cases, inherited genetic factors do not have a major role. In addition to epigenetic events during early embryogenesis, environmental factors and post-zygotic somatic or de novo germline mutations may be implicated in these cases.16 New genomic techniques such as high-resolution copy number variation studies or next-generation exome sequencing may help to delineate the etiology of these cases.16
CONCLUSIONS Discordance among monozygotic twins for VATER association remains poorly understood. Further studies are required to establish the etiology of VATER association, which could possibly involve several factors besides genes alone.
CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES
Figure 1. Spine radiograph showing levoconvex scoliosis of the thoracic spine centered approximately at T8/T9 level, and multiple segmentation anomalies in the upper and mid thoracic spine including T9 hemivertebra.
with normal kidneys that was sufficient to promote adequate growth of lungs in the affected twin. There have been seven published case reports of monamniotic twins discordant for renal agenesis and normal pulmonary function.2,5–10 Four of these cases had other anomalies consistent with the diagnosis of VATER/VACTERL association.1,3,4,6 Our patient also had clinical features suggestive of VATER association that included vertebral anomalies, anal atresia, renal dysplasia and single umbilical artery. Monozygotic twins, by definition, should have concordant anomalies. The presence of discordance, however, poses a question mark to the etiology of anomalies present in the affected twin. Monozygotic twins develop from a single embryo that splits into two. The degree of placental sharing and the frequency of complications are dependent on the embryonic stage at which the embryo splits. Monochorionicmonamnionic twins develop from an embryo that splits relatively late in the postimplantation blastocyst period.11 A true genetic difference between these twins is highly unlikely. It is plausible that discordance may be caused by some epigenetic factor like DNA methylation. DNA methylation patterns could be affected by various cellular and environmental factors and the difference in DNA methylation can result in somatic mutations as well as
Journal of Perinatology (2014), 645 – 646
1 Solomon BD. VACTERL/VATER association. Orphanet J Rare Dis 2011; 6: 56. 2 Klinger G, Merlob P, Aloni D, Maayan A, Sirota L. Normal pulmonary function in a monoamniotic twin discordant for bilateral renal agenesis: report and review. Am J Med Genet 1997; 73(1): 76–79. 3 Potter EL. Bilateral renal agenesis. J Pediatr 1946; 29: 68–76. 4 Perlman M, Levin M. Fetal pulmonary hypoplasia, anuria, and oligohydramnios: clinicopathologic observations and review of the literature. Am J Obstet Gynecol 1974; 118(8): 1119–1123. 5 Mauer SM, Dobrin RS, Vernier RL. Unilateral and bilateral renal agenesis in monoamniotic twins. J Pediatr 1974; 84(2): 236–238. 6 Koffler H, Aase JM, Papile LA, Coen RW. Persistent cloaca with absent penis and anal atresia in one of identical twins. J Pediatr 1978; 93(5): 821–823. 7 Cilento BG Jr., Benacerraf BR, Mandell J. Prenatal and postnatal findings in monochorionic, monoamniotic twins discordant for bilateral renal agenesisdysgenesis (perinatal lethal renal disease). J Urol 1994; 151(4): 1034–1035. 8 McNamara MF, McCurdy CM, Reed KL, Philipps AF, Seeds JW. The relation between pulmonary hypoplasia and amniotic fluid volume: lessons learned from discordant urinary tract anomalies in monoamniotic twins. Obstet Gynecol 1995; 85(5 Pt 2): 867–869. 9 Perez-Brayfield MR, Kirsch AJ, Smith EA. Monoamniotic twin discordant for bilateral renal agenesis with normal pulmonary function. Urology 2004; 64(3): 589. 10 Meyer SR, Smith KM, Ravish IR, Saltzman DA, Shukla AR. Complex cloacal anomaly in discordant monozygotic twins. Urology 2009; 73(3): 532–534. 11 Hall JG. Twinning. Lancet 2003; 362(9385): 735–743. 12 Singh SM, Murphy B, O'Reilly R. Epigenetic contributors to the discordance of monozygotic twins. Clin Genet 2002; 62(2): 97–103. 13 Thompson SL, Konfortova G, Gregory RI, Reik W, Dean W, Feil R. Environmental effects on genomic imprinting in mammals. Toxicol Lett 2001; 120(1–3): 143–150. 14 Esteller M. Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer 2000; 36(18): 2294–2300. 15 Mancini D, Singh S, Ainsworth P, Rodenhiser D. Constitutively methylated CpG dinucleotides as mutation hot spots in the retinoblastoma gene (RB1). Am J Hum Genet 1997; 61(1): 80–87. 16 Bartels E, Schulz AC, Mora NW, Pineda-Alvarez DE, Wijers CH, Marcelis CM et al. VATER/VACTERL association: identification of seven new twin pairs, a systematic review of the literature, and a classical twin analysis. Clin Dysmorphol 2012; 21(4): 191–195.
© 2014 Nature America, Inc.
