Ultrasound Obstet Gynecol 2014; 43: 475–476 Published online 3 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13238
Unexplained right atrial enlargement may be a sign of Holt–Oram syndrome in the fetus D. PALADINI*, M. TIESI*, D. BUFFI*, G. TUO† and M. MARASINI† *Fetal Medicine and Surgery Unit - G.Gaslini Institute, Genoa, Italy; †Pediatric Cardiology - G.Gaslini Institute, Genoa, Italy
K E Y W O R D S: atriodigital dysplasia; fetal echocardiography; fetus; right atrium; skeletal anomaly
ABSTRACT Two cases of ultrasound diagnosis of Holt–Oram syndrome are described. Both were characterized by significant right atrial enlargement that was not due to concurrent tricuspid regurgitation or other cardiac anomalies. In both cases the associated skeletal anomaly was subtle and barely visible using ultrasound. Interestingly, despite the fact that Holt–Oram syndrome is also called atriodigital dysplasia, unexplained right atrial enlargement has not been described in this context in the fetus before. When such a finding is detected, we believe a thorough search for upper limb abnormalities should be carried out and genetic testing for Holt–Oram syndrome should be discussed with the parents. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
CASE REPORTS Case 1 In this case, the couple had been referred to our center for prenatal diagnosis because the mother was affected by Holt–Oram syndrome. Since the referral was in the second trimester, targeted ultrasound and fetal echocardiography were performed at the time of amniocentesis. The skeletal abnormality consisted of a bifid thumb, while an enlarged right atrium, not associated with tricuspid insufficiency, was detected on fetal echocardiography (Figure 1). The results of molecular analysis on amniocytes confirmed that the fetus was affected by Holt–Oram syndrome and the couple opted for termination of pregnancy.
Case 2 A pregnant woman was referred to our center at 22 weeks of gestation because of fetal ventricular disproportion
Figure 1 Case 1: fetal echocardiographic image, at 20 weeks of gestation, showing significant enlargement of the right atrium and a widely patent foramen ovale (arrow) in the four-chamber view. LV, left ventricle; RA, right atrium.
and right atrial enlargement. In this case, on fetal echocardiography, a large foramen ovale flap and significant enlargement of the right atrium were noted (Figure 2a). Tricuspid regurgitation was also absent in this case. On follow-up echocardiography carried out at 28 gestational weeks, the right atrial enlargement was confirmed and, in addition, two tiny muscular ventricular septal defects were detected (Figures 2b and c). The pregnancy went to term and a female neonate weighing 3030 g was delivered by Cesarean section. The neonate was clinically stable, but on external examination a threephalangeal thumb was noted. Neonatal echocardiography confirmed both the right atrial enlargement and the two small muscular ventricular septal defects. The foramen ovale remained patent and follow-up echocardiography
Correspondence to: Prof. D. Paladini, Giannina Gaslini Institute, Fetal Medicine and Surgery Unit, Via Gerolamo Gaslini, Genoa 16148, Italy (e-mail: [email protected]) Accepted: 17 October 2013
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
CASE REPORT
Paladini et al.
476
Figure 2 Case 2: fetal echocardiographic images. At 22 weeks of gestation (a), the right atrium was rather enlarged. At 28 gestational weeks (b, c), the degree of right atrial enlargement was observed to have increased and color Doppler showed a tiny muscular ventricular septal defect (c, arrow) not evident on gray-scale imaging. LV, left ventricle; RA, right atrium.
was scheduled for 3 months later. Holt–Oram syndrome was suspected on the basis of the phenotype and was confirmed using a blood sample.
DISCUSSION Holt–Oram syndrome, also called atriodigital dysplasia, is a rare condition that was reported for the first time in 19601 . It has an incidence of 1/100 000 liveborn infants and is an autosomal dominant disorder with complete penetrance. It is due to mutations in the TBX3 and TBX5 genes on chromosome 12q22 . These mutations are responsible for the range of skeletal and cardiac anomalies seen in these patients. Skeletal anomalies typically affect the upper limbs and range from phocomelia to subtle abnormalities of the radial ray, such as a triphalangeal or bifid thumb and radial-ulnar anomalies. Cardiac anomalies vary from simple atrial or ventricular septal defects to major left heart lesions (hypoplastic left heart syndrome or coarctation of the aorta) and conotruncal defects (tetralogy of Fallot, common arterial trunk, double outlet right ventricle)3,4 . Prenatal molecular diagnosis using chorionic villi is feasible in families at risk, but 30–40% of the cases result from de novo mutations5 . Prospectively, Holt–Oram syndrome may be suspected when an upper arm abnormality, especially if involving the radial ray, is detected in association with congenital heart defects6 – 8 . However, this diagnosis may be impossible if both the skeletal and the cardiac anomalies are subtle (e.g. triphalangeal or bifid thumb and atrial septal defect). It is interesting to note that in both index cases of this report, the major cardiac finding was a significant and isolated right atrial enlargement and, at the same time, the upper limb anomaly was trivial and difficult or impossible to recognize sonographically (a bifid thumb in one case, a triphalangeal thumb in the other). The association of significant right atrial enlargement with Holt–Oram syndrome has not been previously described, in either pediatric or fetal literature. We believe it is important to consider that the rare and unexplainable finding of isolated right atrial enlargement may indeed
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
be the only sonographically detectable sign of underlying Holt–Oram syndrome. Differential diagnosis should take into consideration the obvious cases in which right atrial enlargement is the consequence of tricuspid insufficiency and the socalled idiopathic giant right atrium. In the former, an Ebstein anomaly and/or a pulmonary atresia with an intact ventricular septum associated with tricuspid dysplasia are found in most cases. In the latter case, the degree of atrial dilatation is much higher, although tricuspid regurgitation is also absent in this case. In conclusion, we think that, should right atrial enlargement be detected in a fetus, especially if associated with ventricular septal defect, a thorough search for subtle upper limb abnormalities should be performed. In addition, an invasive procedure for genetic assessment of the possible presence of Holt–Oram syndrome should be discussed with the parents.
REFERENCES 1. Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J 1960; 22: 236–242. 2. Basson Ct, Bachinsky DR, Lin RC. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 1997; 15: 30–35. 3. Sletten Lj, Pierpont ME. Variation in severity of cardiac disease in Holt-Oram syndrome. Am J Med Genet 1996; 65: 128–132 4. Bossert T, Walther T, Gummert J, Hubald R, Kostelka M, Mohr FW. Cardiac malformations associated with the HoltOram syndrome–report on a family and review of the literature. Thorac Cardiovasc Surg 2002; 50: 312–314. 5. Huang T. Current advances in Holt-Oram syndrome. Curr Opin Pediatr 2002, 14: 691–695. 6. Brons JT, van Geijn HP, Wladimiroff JW, van der Harten JJ, Kwee ML, Sobotka-Plojhar M, Arts NF. Prenatal ultrasound diagnosis of the Holt-Oram syndrome. Prenat Diagn 1988; 8: 175–181. 7. Sepulveda W, Enriquez G, Martinez JL, Mejia R. Holt-Oram syndrome: contribution of prenatal 3-dimensional sonography in an index case. J Ultrasound Med. 2004; 23: 983–987. 8. Sunagawa S, Kikuchi A, Sano Y, Kita M, Ono K, Horikoshi T, Takagi K, Kawame H. Prenatal diagnosis of Holt-Oram syndrome: role of 3-D ultrasonography. Congenit Anom (Kyoto) 2009; 49: 38–41.
Ultrasound Obstet Gynecol 2014; 43: 475–476.
Unexplained right atrial enlargement may be a sign of Holt–Oram syndrome in the fetus D. PALADINI*, M. TIESI*, D. BUFFI*, G. TUO† and M. MARASINI† *Fetal Medicine and Surgery Unit - G.Gaslini Institute, Genoa, Italy; †Pediatric Cardiology - G.Gaslini Institute, Genoa, Italy
K E Y W O R D S: atriodigital dysplasia; fetal echocardiography; fetus; right atrium; skeletal anomaly
ABSTRACT Two cases of ultrasound diagnosis of Holt–Oram syndrome are described. Both were characterized by significant right atrial enlargement that was not due to concurrent tricuspid regurgitation or other cardiac anomalies. In both cases the associated skeletal anomaly was subtle and barely visible using ultrasound. Interestingly, despite the fact that Holt–Oram syndrome is also called atriodigital dysplasia, unexplained right atrial enlargement has not been described in this context in the fetus before. When such a finding is detected, we believe a thorough search for upper limb abnormalities should be carried out and genetic testing for Holt–Oram syndrome should be discussed with the parents. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
CASE REPORTS Case 1 In this case, the couple had been referred to our center for prenatal diagnosis because the mother was affected by Holt–Oram syndrome. Since the referral was in the second trimester, targeted ultrasound and fetal echocardiography were performed at the time of amniocentesis. The skeletal abnormality consisted of a bifid thumb, while an enlarged right atrium, not associated with tricuspid insufficiency, was detected on fetal echocardiography (Figure 1). The results of molecular analysis on amniocytes confirmed that the fetus was affected by Holt–Oram syndrome and the couple opted for termination of pregnancy.
Case 2 A pregnant woman was referred to our center at 22 weeks of gestation because of fetal ventricular disproportion
Figure 1 Case 1: fetal echocardiographic image, at 20 weeks of gestation, showing significant enlargement of the right atrium and a widely patent foramen ovale (arrow) in the four-chamber view. LV, left ventricle; RA, right atrium.
and right atrial enlargement. In this case, on fetal echocardiography, a large foramen ovale flap and significant enlargement of the right atrium were noted (Figure 2a). Tricuspid regurgitation was also absent in this case. On follow-up echocardiography carried out at 28 gestational weeks, the right atrial enlargement was confirmed and, in addition, two tiny muscular ventricular septal defects were detected (Figures 2b and c). The pregnancy went to term and a female neonate weighing 3030 g was delivered by Cesarean section. The neonate was clinically stable, but on external examination a threephalangeal thumb was noted. Neonatal echocardiography confirmed both the right atrial enlargement and the two small muscular ventricular septal defects. The foramen ovale remained patent and follow-up echocardiography
Correspondence to: Prof. D. Paladini, Giannina Gaslini Institute, Fetal Medicine and Surgery Unit, Via Gerolamo Gaslini, Genoa 16148, Italy (e-mail: [email protected]) Accepted: 17 October 2013
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
CASE REPORT
Paladini et al.
476
Figure 2 Case 2: fetal echocardiographic images. At 22 weeks of gestation (a), the right atrium was rather enlarged. At 28 gestational weeks (b, c), the degree of right atrial enlargement was observed to have increased and color Doppler showed a tiny muscular ventricular septal defect (c, arrow) not evident on gray-scale imaging. LV, left ventricle; RA, right atrium.
was scheduled for 3 months later. Holt–Oram syndrome was suspected on the basis of the phenotype and was confirmed using a blood sample.
DISCUSSION Holt–Oram syndrome, also called atriodigital dysplasia, is a rare condition that was reported for the first time in 19601 . It has an incidence of 1/100 000 liveborn infants and is an autosomal dominant disorder with complete penetrance. It is due to mutations in the TBX3 and TBX5 genes on chromosome 12q22 . These mutations are responsible for the range of skeletal and cardiac anomalies seen in these patients. Skeletal anomalies typically affect the upper limbs and range from phocomelia to subtle abnormalities of the radial ray, such as a triphalangeal or bifid thumb and radial-ulnar anomalies. Cardiac anomalies vary from simple atrial or ventricular septal defects to major left heart lesions (hypoplastic left heart syndrome or coarctation of the aorta) and conotruncal defects (tetralogy of Fallot, common arterial trunk, double outlet right ventricle)3,4 . Prenatal molecular diagnosis using chorionic villi is feasible in families at risk, but 30–40% of the cases result from de novo mutations5 . Prospectively, Holt–Oram syndrome may be suspected when an upper arm abnormality, especially if involving the radial ray, is detected in association with congenital heart defects6 – 8 . However, this diagnosis may be impossible if both the skeletal and the cardiac anomalies are subtle (e.g. triphalangeal or bifid thumb and atrial septal defect). It is interesting to note that in both index cases of this report, the major cardiac finding was a significant and isolated right atrial enlargement and, at the same time, the upper limb anomaly was trivial and difficult or impossible to recognize sonographically (a bifid thumb in one case, a triphalangeal thumb in the other). The association of significant right atrial enlargement with Holt–Oram syndrome has not been previously described, in either pediatric or fetal literature. We believe it is important to consider that the rare and unexplainable finding of isolated right atrial enlargement may indeed
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
be the only sonographically detectable sign of underlying Holt–Oram syndrome. Differential diagnosis should take into consideration the obvious cases in which right atrial enlargement is the consequence of tricuspid insufficiency and the socalled idiopathic giant right atrium. In the former, an Ebstein anomaly and/or a pulmonary atresia with an intact ventricular septum associated with tricuspid dysplasia are found in most cases. In the latter case, the degree of atrial dilatation is much higher, although tricuspid regurgitation is also absent in this case. In conclusion, we think that, should right atrial enlargement be detected in a fetus, especially if associated with ventricular septal defect, a thorough search for subtle upper limb abnormalities should be performed. In addition, an invasive procedure for genetic assessment of the possible presence of Holt–Oram syndrome should be discussed with the parents.
REFERENCES 1. Holt M, Oram S. Familial heart disease with skeletal malformations. Br Heart J 1960; 22: 236–242. 2. Basson Ct, Bachinsky DR, Lin RC. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 1997; 15: 30–35. 3. Sletten Lj, Pierpont ME. Variation in severity of cardiac disease in Holt-Oram syndrome. Am J Med Genet 1996; 65: 128–132 4. Bossert T, Walther T, Gummert J, Hubald R, Kostelka M, Mohr FW. Cardiac malformations associated with the HoltOram syndrome–report on a family and review of the literature. Thorac Cardiovasc Surg 2002; 50: 312–314. 5. Huang T. Current advances in Holt-Oram syndrome. Curr Opin Pediatr 2002, 14: 691–695. 6. Brons JT, van Geijn HP, Wladimiroff JW, van der Harten JJ, Kwee ML, Sobotka-Plojhar M, Arts NF. Prenatal ultrasound diagnosis of the Holt-Oram syndrome. Prenat Diagn 1988; 8: 175–181. 7. Sepulveda W, Enriquez G, Martinez JL, Mejia R. Holt-Oram syndrome: contribution of prenatal 3-dimensional sonography in an index case. J Ultrasound Med. 2004; 23: 983–987. 8. Sunagawa S, Kikuchi A, Sano Y, Kita M, Ono K, Horikoshi T, Takagi K, Kawame H. Prenatal diagnosis of Holt-Oram syndrome: role of 3-D ultrasonography. Congenit Anom (Kyoto) 2009; 49: 38–41.
Ultrasound Obstet Gynecol 2014; 43: 475–476.
