Cat‐eye syndrome in a fetus with increased nuchal translucency: three‐dimensional ultrasound and echocardiographic evaluation of the fetal phenotype
Year: 2004
Type: article
Study design: Case Report
Abstract: Cat-eye syndrome (CES) is a rare disorder of chromosome 22 characterized by tetrasomy of the region that spans the chromosome 22p arm, and part of 22q11 (CES chromosome)1. We report a case of CES diagnosed prenatally through cytogenetic and fluorescence in-situ hybridization (FISH) analysis following chorionic villus sampling performed for increased nuchal translucency thickness (NT) at 12 weeks' gestation. Two-dimensional (2D) and three-dimensional (3D) ultrasound and echocardiography were performed, and disclosed some peculiar CES findings such as preauricular skin tags, and, for the first time prenatally, an anomalous connection of the left pulmonary veins to a dilated coronary sinus. This 29-year-old Caucasian primigravida was referred at 12 weeks' gestation because the fetal NT was increased; the fetal crown–rump length was 57 mm and the NT was 2.6 mm. Cytogenetic analysis showed the presence of a supernumerary bisatellite chromosome, distamycin A/4′-6′-diamindino-2′-phenylindole (DA-DAPI) negative, in 12 metaphases from a direct preparation, and 30 cells of 10 colonies examined on three different slides from in-situ cultures of chorionic villi (Figure 1a). The marker showed positive hybridization signals on FISH analysis performed with centromere-22 specific alphoid DNA probe (Figure 1b), and chromosome 22 painting probe. Both analyses indicated the chromosome 22 origin2. In contrast, no signals were detected on the CES chromosome using the Tuple 1 probe (Vysis, Downers Grove, IL, USA) for the DiGeorge syndrome critical region (22q11). The parents were informed of the result and counseled according to the available literature on CES, and they elected to continue the pregnancy. (a) Chromosome preparation showing the pair of QFQ-banded (Q-banded by fluorescence using quinacine) chromosomes 22 and the bisatellite cat-eye syndrome (CES) chromosome on the right. (b) Fluorescence in-situ hybridization (FISH) analysis, using a centromere-22 specific alphoid probe. The signals were present on normal chromosomes 22 (arrows) and the CES chromosome (arrowhead). 2D ultrasound performed at 12, 16, and 22 weeks' gestation did not reveal any anomalies. 3D ultrasound examination of the fetal face at 22 weeks revealed mild ear hypoplasia and small preauricular tags (Figure 2). Echocardiography performed at 16 weeks was normal, while at 22 weeks it revealed a dilated coronary sinus. In addition, an anomalous connection of the left pulmonary veins to the dilated coronary sinus was suspected on the four-chamber view (Figure 3), and confirmed on the basis of the flow pattern with spectral Doppler mapping. All ultrasound examinations were performed with a Voluson 730 (Kreztechnik AG, Zipf, Austria) ultrasound machine. Three-dimensional surface reconstruction demonstrating preauricular skin tags (arrowheads). The arrows indicate the ear. Apical four-chamber view of the heart of a normal fetus (a) and the fetus in our case with cat-eye syndrome (b). (a) A normal coronary sinus (arrows) can be seen running in the atrioventricular groove between the left ventricle and atrium. (b) Dilated coronary sinus (arrowheads) at 22 weeks' gestation with anomalous connection of the left pulmonary veins (arrows). LV, left ventricle; RV, right ventricle. A male infant was delivered by spontaneous vertex delivery at 37 + 4 weeks. Birth weight was 2.910 kg and Apgar scores were 9 at 1 and 5 min. Postnatal assessment of the infant confirmed the prenatal diagnosis. The head appeared normal, but both ears were small, and posteriorly angulated with pretragal tags. There were antimongoloid slant of the palpebral fissures, epicanthal folds, and right iris colobomata. The neck, chest, abdomen and genitalia were normal. There was evidence of imperforate anus or rectovaginal fistulae. The central nervous system, renal and abdominal ultrasound investigations were normal. 2D echocardiography confirmed the prenatal anomalies. The clinical phenotype of CES patients appears variable, ranging from mild disabilities to the presence of severe mental retardation and/or severe congenital malformations leading to early death3, 4. FISH and molecular studies have permitted classification of the supernumerary marker chromosome characterizing CES into two types based on the location of the breakpoints generating them5, 6. The absence of hybridization signals with the Tuple-1 probe indicated that in our case the CES was probably of type I. However, unlike other conditions, i.e. the invdup(15) bisatellite dicentric marker, the CES phenotype does not appear to correlate with the size of the marker chromosome5, 6. No features can raise the suspicion of CES prenatally, because the major features of this condition are non-specific and/or not usually detectable at routine ultrasound prenatal screening (i.e. anorectal malformations, ocular coloboma, preauricular skin tags and/or typical facial features). Therefore, prenatally CES may be diagnosed by chance in pregnant women undergoing invasive diagnostic investigations for other reasons: the presence of an increased NT in our case represented an interesting clue strengthening the suspicion of CES. It is difficult to establish genotype–phenotype correlations in cases of CES, with the aim of better orienting genetic counseling in prenatally detected cases. In the light of our case, some relevant aspects regarding the usefulness, roles and limitations of 2D and 3D ultrasound and echocardiographic examination can be pointed out. Facial evaluation is an integral part of the fetal ultrasound examination during pregnancy, whether in a screening setting or during targeted analysis. The use of 3D and 4D ultrasound imaging allows easier and more rapid diagnosis in the screening setting, and a more precise evaluation of the facial features in the analysis setting7. In our report the presence of mild ear hypoplasia and small preauricular tags was only established at 3D ultrasound analysis. Another relevant point is the role of ultrasound investigations in evaluating the presence of associated major malformations, especially echocardiography for heart defects. The coronary sinus is formed by the confluence of the three coronary veins. Its dilation is of interest in prenatal diagnosis: in most cases there is persistent left superior vena cava drainage into the coronary sinus leading to its enlargement but it could be a sign of the rare condition of anomalous pulmonary venous drainage, as in our case. In both cases the increased caliber of the coronary sinus may be an important indirect marker of central venous drainage abnormalities8. A partial anomalous pulmonary venous connection (PAPVC) is characterized by connection of one or more, but not all, of the pulmonary veins to the right atrium or a tributary; in our case, only the left pulmonary veins were anomalously connected to the coronary sinus. This malformation is very rare and concordant with the well-known association existing between a total anomalous pulmonary venous connection (TAPVC) and CES (15/80, 19%)4. Anomalous connection of the pulmonary veins is notoriously misdiagnosed prenatally, especially when isolated. The fetal echocardiographic clues to the diagnosis of TAPVC include failure to demonstrate a direct pulmonary venous connection to the left atrium, the finding of confluence of the pulmonary veins behind the atrium and the visualization of an ascending or descending vertical vein9, 10. In cases of PAVPC, the visualization of at least one direct pulmonary vein connection to the left atrium makes the suspicion of this anomaly even less likely to be raised. In fact, in our case, diagnosed prenatally, only the presence of a dilated coronary sinus and the fact that the occurrence of pulmonary vein anomalies has been noted postnatally in some cases of CES oriented the ultrasound identification. The drainage of the TAPVC into the dilated coronary sinus was not obstructed; when there is no obstructive lesion, nor associated cardiac anomalies, the course of a PAVPC is usually benign, with no serious implications. In most cases the patient is asymptomatic and may not present until later in childhood, with clinical features consistent with a left-to-right shunt9. In conclusion, we stress that in the presence of CES, accurate fetal ultrasound and echocardiography, complemented with 3D/4D facial evaluations, is important in defining prognosis and neonatal outcome, especially regarding major life-threatening malformations. On the contrary, no reassurance can be given regarding appropriate mental development using cytogenetic, FISH or ultrasound examination data.
DOI: 10.1002/uog.1723
Authors: P. Volpe, A. L. Buonadonna, G. Campobasso, A. Di Carlo, A. Stanziano, M. Gentile
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2094375358