Genetic syndromes associated with isolated fetal growth restriction

Early onset fetal growth restriction (FGR) may be due to impaired placentation, environmental or toxic exposure, congenital infections or genetic abnormalities. Remarkable research, mainly based on retrospective series, has been published on the diverse genetic causes. Those have become more and more relevant with the improvement in the accuracy of the analysis techniques and the rising of breakthrough genomewide methods such as the whole genome sequencing. However, no publication has presented an integrated view of management of those fetuses with an early and severe affection. In this review, we explored to which extent genetic syndromes can cause FGR fetuses without structural defects. The most common chromosomal abnormalities (Triploidies and Trisomy 18), submicroscopic chromosomal anomalies (22q11.2 microduplication syndrome) and single gene disorders (often associated with mild ultrasound findings) related to early and severe FGR had been analysed. Finally, we addressed the impact of epigenetic marks on fetal growth, a matter of growing importance. At the end of this review, we should be able to provide an adequate counseling to parents in terms of diagnosis, prognosis and management of those pregnancies.     

Fetal cholecystomegaly: A prenatal marker of aneuploidy

The fetal gall bladder can now be easily identified during the second and third trimesters using high-resolution ultrasonography. In this report we present eight fetuses with an enlarged gall bladder detected on prenatal ultrasonography at a mean gestational age of 24.6 weeks (range 19–31 weeks). Additional ultrasonographic findings were present in four cases: fetal anomalies and intrauterine growth retardation in three and polyhydramnios in one. Of those cases associated with fetal anomalies, one woman underwent amniocentesis at 21 weeks revealing trisomy 18. The other two declined prenatal karyotyping; neonatal karyotyping revealed trisomy 13 in one and trisomy 18 in the other. Although an enlarged fetal gall bladder can be a normal variant in the second and third trimesters, the prenatal detection of cholecystomegaly should prompt a search for associated anomalies and other markers of aneuploidy. If found, prenatal karyotyping should be considered.     

Abnormal pregnancy sonogram and chromosomal anomalies: Four years' experience with rapid karyotyping

Over a four-year period, 140 pregnancies with different malformations detected by ultrasound were examined cytogenetically. Gestational age ranged from 13 to 36 weeks. Twenty-six fetuses (18.6 per cent) had abnormal karyotypes, including trisomies, triploidy, monosomy X, and structural anomalies. Similar malformations were found in fetuses with different chromosomal anomalies, indicating that the types of malformations are not specific for particular chromosomal anomalies. Chromosomal analysis was performed on amniotic fluid culture and by direct karyotyping of placental biopsies. Direct karyotyping is suggested to be the most rapid approach, especially if sonographic anomalies are detected close to the 24th week of gestation, shortly before delivery, and in cases of significant oligohydramnios.     

Turner syndrome-omphalocele association: Incidence,karyotype, phenotype and fetal outcome

Objective

Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith–Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes.

Method

Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound.

Results

680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive.

Conclusion

TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.     

Outcome of fetal echogenic bowel: A systematic review and meta-analysis

The main aim of this systematic review was to explore the outcome of fetuses with isolated echogenic bowel (EB) on antenatal ultrasound. Inclusion criteria were singleton pregnancies with isolated EB no associated major structural anomalies at the time of diagnosis. The outcomes observed were: chromosomal anomalies, cystic fibrosis (CF), associated structural anomalies detected only at follow-up scans and at birth, regression during pregnancy, congenital infections, intra-uterine (IUD), neonatal (NND) and perinatal (PND) death. Twenty-five studies (12 971 fetuses) were included. Chromosomal anomalies occurred in 3.3% of the fetuses, mainly Trisomy 21 and aneuploidies involving the sex chromosomes. Cystic fibrosis occurred in 2.2%. Congenital infections affected 2.2%, mainly congenital Cytomegalovirus (CMV) infection. The majority of fetuses with EB experienced regression or disappearance of the EB at follow-up scans. Associated anomalies were detected at a follow-up scan in 1.8%. Associated anomalies were detected at birth and missed at ultrasound in 2.1% of cases. IUD occurred in 3.2% of cases while the corresponding figures for NND and PND were 0.4% and 3.1%. Fetuses with EB are at increased risk of adverse perinatal outcome, highlighting the need for a thorough antenatal management and postnatal follow-up. Assessment during pregnancy and after birth should be performed in order to look for signs of fetal aneuploidy, congenital infections and associated structural anomalies.     

Genetic considerations in the prenatal diagnosis of overgrowth syndromes

Large (>90%) for gestational age (LGA) fetuses are usually identified incidentally. Detection of the LGA fetus should first prompt the provider to rule out incorrect dates and maternal diabetes. Once this is done, consideration should be given to certain overgrowth syndromes, especially if anomalies are present. The overgrowth syndromes have significant clinical and molecular overlap, and are associated with developmental delay, tumors, and other anomalies. Although genetic causes of overgrowth are considered postnatally, they are infrequently diagnosed prenatally. Here, we review prenatal sonographic findings in fetal overgrowth syndromes, including Pallister-Killian, Beckwith-Wiedemann, Sotos, Perlman, and Simpson-Golabi-Behmel. We also discuss prenatal diagnosis options and recurrence risks. Copyright © 2009 John Wiley & Sons, Ltd.     

Nuchal translucency thickness and outcome in chromosome translocation diagnosed in the first trimester

In order to determine the significance of nuchal translucency thickness on the subsequent natural history of first-trimester fetuses with a chromosome translocation, seven consecutive cases diagnosed between 11 and 13 weeks of gestation were reviewed. Nuchal translucency measurements were successfully obtained before chorionic villus sampling (CVS) in all cases. Three fetuses had an unbalanced translocation and all were associated with increased nuchal translucency and multiple anomalies at the detailed second-trimester scan. There were no survivors in this group. The remaining four fetuses had a balanced translocation; all had normal nuchal translucency thickness and no structural anomalies were detected in the second trimester. Three of these fetuses were born at ≥35 weeks of gestation and were phenotypically normal. However, an unexpected single fetal demise occurred in a dichorionic twin pregnancy at 28 weeks of gestation. It is concluded that nuchal translucency measurements provide important prognostic information on pregnancy outcome in first-trimester fetuses with a chromosome translocation. In parents with a known balanced translocation, the detection of increased nuchal translucency at 11–14 weeks of gestation is associated with unbalanced translocations, structural anomalies and poor pregnancy outcome. Copyright © 2001 John Wiley & Sons, Ltd.     

Increased nuchal translucency as a prenatal manifestation of congenital adrenal hyperplasia

We present two cases of pregnant women with a previous history of congenital adrenal hyperplasia. In both cases the only abnormal feature in the initial pregnancy had been increased nuchal translucency at 10–14 weeks of gestation. The fetal karyotype was normal and a diagnosis of congenital adrenal hyperplasia was made after delivery. In their current pregnancies, both fetuses also had increased nuchal translucency and normal fetal karyotype. Diagnosis of 21-hydroxylase deficiency was made prenatally by DNA analysis. These findings in four affected fetuses suggest that congenital adrenal hyperplasia should be added to the list of genetic anomalies associated with an increase in nuchal translucency. Copyright © 2001 John Wiley & Sons, Ltd.     

First trimester PAPP-A in the detection of non-Down syndrome aneuploidy

Combined first trimester screening using pregnancy associated plasma protein-A (PAPP-A), free β-human chorionic gonadotrophin, and nuchal translucency (NT), is currently accepted as probably the best combination for the detection of Down syndrome (DS). Current first trimester algorithms provide computed risks only for DS. However, low PAPP-A is also associated with other chromosome anomalies such as trisomy 13, 18, and sex chromosome aneuploidy. Thus, using currently available algorithms, some chromosome anomalies may not be detected. The purpose of the present study was to establish a low-end cut-off value for PAPP-A that would increase the detection rates for non-DS chromosome anomalies. The study included 1408 patients who underwent combined first trimester screening. To determine a low-end cut-off value for PAPP-A, a Receiver–Operator Characteristic (ROC) curve analysis was performed. In the entire study group there were 18 cases of chromosome anomalies (trisomy 21, 13, 18, sex chromosome anomalies), 14 of which were among screen-positive patients, a detection rate of 77.7% for all chromosome anomalies (95% CI: 55.7–99.7%). ROC curve analysis detected a statistically significant cut-off for PAPP-A at 0.25 MoM. If the definition of screen-positive were to also include patients with PAPP-A<0.25 MoM, the detection rate would increase to 88.8% for all chromosome anomalies (95% CI: 71.6–106%). This low cut-off value may be used until specific algorithms are implemented for non-Down syndrome aneuploidy. Copyright © 2001 John Wiley & Sons, Ltd.     

The causes and natural history of fetal ascites

The purpose of this study was to examine the natural history and differential diagnosis of ultrasound-detected, isolated fetal ascites. Retrospective review of our patient data base, from 1989 to 1993, revealed 18 patients with fetal ascites diagnosed sonographically. Fetuses presenting with generalized hydrops were excluded. One of the 18 fetuses with ascites had a chromosomal abnormality (trisomy 21), four fetuses had intrauterine infections, seven had gastrointestinal processes, two had genitourinary tract abnormalities, and four were labelled as ‘idiopathic’ (all four resulting in normal neonates). Seventeen of 18 fetuses survived; there was one fetal demise secondary to active syphilis. One fetus with parvovirus infection required intrauterine transfusion and did well. Two infants are developmentally retarded, including one with trisomy 21 and one with microcephaly secondary to cytomegalovirus infection. Fourteen of 18 fetuses had documented in-utero resolution of the ascites. Eleven of the 18 were associated with polyhydramnios sometime during fetal life. None of the fetuses developed hydrops. In conclusion, fetal ascites can result from many different aetiologies, including gastrointestinal and genitourinary anomalies. Chromosomal abnormalities and viral aetiologies must also be considered. Fetuses who have isolated ascites can have a good outcome with resolution of the ascites antenatally.     

Congenital heart disease and aneuploidy

Congenital heart disease (CHD) is one of the commonest prenatal diagnoses made on routine ultrasound screening. Overall, up to 33% of CHD are associated with fetal aneuploidy. However, some specific cardiac lesions have a significantly greater association with particular chromosomal abnormalities. The majority of fetuses with CHD and aneuploidy also have extra-cardiac anomalies and are best managed by a multidisciplinary team where the management and prognosis of the cardiac defect can be discussed in the context of the baby as a whole. It is therefore important for clinicians involved in the management of fetuses with CHD to be aware of the association of aneuploidy as well as the prognosis and management of these cases, so that they can appropriately counsel the parents. In this chapter, we review the frequency and types of aneuploidy associated with the commonly diagnosed CHD and discuss their management. Copyright © 2004 John Wiley & Sons, Ltd.     

Dilated coronary sinus in prenatal echocardiography; identification,associations and outcome

The dilated coronary sinus (DCS) has only recently been clearly visualised in the fetus due to progress in prenatal echography. This is a retrospective study of 22 fetuses presenting with DCS revealed by prenatal echography. We report the circumstances leading to the detection of a DCS and the neonatal outcome of these fetuses. The coronary sinus was defined as dilated depending on its visualisation in cross-section from the ‘4 chamber’ view, as well as a pseudo inter-atrial septal defect from a more posterior view. In each case the gestational age, circumstances of detection, associated anomalies and postnatal outcome are reported. The circumstances were: evaluation of a clearly identified DCS in four cases and during detailed fetal echocardiography because of suspected congenital heart disease in 18 cases. Five cases were associated with a cardiac anomaly, three with an extracardiac anomaly, six with both cardiac and extracardiac anomaly and eight were isolated. Postnatal outcome was related to the associated anomaly. In conclusion, it is important that the echography image be correctly interpreted, as a DCS often implies possible associated defects and therefore affects prognosis. When not associated with other anomalies this condition is not considered serious. Copyright © 2002 John Wiley & Sons, Ltd.     

Syndromes identified in fetuses with prenatally diagnosed cephaloceles

An evaluation of all fetuses from our institution with prenatally diagnosed cephaloceles was conducted to determine the frequency and spectrum of genetic syndromes associated with this abnormality. Review of the sonographic images, postnatal autopsy or pathology reports, delivery room records, paediatric neurosurgical findings, radiographs, and cytogenetic data were collected. Fifteen postnatally confirmed cases of prenatally diagnosed cephaloceles and two misdiagnosed cases were identified. Thirteen were midline occipital lesions, one was frontoparietal, and one was frontoethmoidal. Excluding microcephaly, hydrocephaly, and distortion of intracranial anatomy, 9 of 15 (60 per cent) had other associated anomalies, including two fetuses with aneuploidy. The prenatal diagnosis of a cephalocele should initiate a thorough search for other abnormalities. In this series, there were three multifactorial, two chromosomal, two sporadic, and two autosomal recessive syndromes identified. An accurate diagnosis is critical in determining the prognosis and providing appropriate genetic counselling.     

Diagnosis of polyhydramnios in early gestation: Indication for prenatal diagnosis?

Previously published reports have indicated that idiopathic polyhydramnios may be associated with trisomies 18 and 21 and that chromosomal analysis is indicated. Furthermore, the natural history and fetal outcome of polyhydramnios diagnosed in early gestation have not been well delineated. We identified 138 pregnancies with polyhydramnios prior to 26 weeks' gestation. Of 131 complete cases, 21 were diagnosed as severe, 18 as moderate, and 92 as mild polyhydramnios. Congenital abnormalities were noted in 18 of 21 severe cases (86 per cent). Two of the remaining three cases were twin-to-twin transfusion. Thirteen of 18 cases with moderate polyhydramnios (72 per cent) were associated with anomalies; six of the remaining cases were twin-to-twin transfusion. Sixteen of 92 cases of mild polyhydramnios (17 per cent) were associated with congenital abnormalities. In 69 of 76 cases of mild hydramnios not associated with anomalies (91 per cent), the hydramnios resolved prior to delivery. Only 2 of 16 (13 per cent) associated with anomalies resolved. In 4 of 5 cases (80 per cent) with moderate hydramnios and no anomalies, the amniotic fluid volume was normal on subsequent ultrasound. No case of moderate polyhydramnios associated with anomalies or maternal conditions nor any case of severe polyhydramnios resolved. There were seven cases of chromosomal abnormalities in this series; all were associated with sonographic findings in addition to the presence of polyhydramnios. On the basis of these data, we doubt the benefit of amniocentesis following the early diagnosis of idiopathic polyhydramnios in the absence of other ultrasound findings.     

The prognostic factors in the prenatal diagnosis of the echogenic fetal lung

The prenatal diagnosis of an echogenic fetal lung (EFL) is now often made in the early second trimester using high-resolution ultrasound. This ultrasound appearance is usually caused by a congenital cystic adenomatoid lung malformation (CCAM), an intrapulmonary lung sequestration or obstruction of a major airway. In order to provide prognostic guidelines to parents who may be considering termination of a fetus with these findings, we have analysed a series of 11 cases diagnosed in our centre over the past 2 years in conjunction with 60 cases from major published series. The data suggest that in the absence of non-immune hydrops fetalis (NIHF) or other anomalies, the outcome for the fetuses is excellent, with over 90 per cent survival. Neither early diagnosis (24 weeks) nor the presence of mediastinal shift is a poor prognostic indicator. In addition, it appears that if NIHF is absent at diagnosis, the chance that it will develop as the pregnancy continues is small (6 per cent). Furthermore, there is a significant (up to 30 per cent) chance that this ultrasound finding will resolve in utero. The development of in utero fetal surgical techniques may be the only hope for those hydropic fetuses who appear to have a dismal prognosis.     

Transvaginal sonography—detection of findings suggestive of fetal chromosomal anomalies in the first and early second trimesters

Over a 4-year period, 14 dyskaryotic fetuses were diagnosed by amniocentesis, performed after early detection of malformations using transvaginal sonography (TVS). These 14 dyskaryotic fetuses were detected out of 4878 sonographic screenings performed by TVS between 9 and 16 weeks' gestation. Twenty-eight per cent of the referrals were at high risk and 72 per cent were at low risk for fetal malformations. Two hundred and twenty-nine fetuses (4.7 per cent) of the screened population had 265 anomalies, 39 per cent of them being transient. In 7 of the 14 dyskaryotic fetuses (50 per cent), the sonographically detected anomalies were transient, being undetected by follow-up sonographic screenings at later gestational ages (⩾18 weeks). Postponing the first sonographic scan aimed at malformation detection to a later gestational age may lead to transient anomalies and their associated dyskaryosis being missed.     

Hyperechogenic fetal bowel and Down syndrome. Results of a French collaborative study based on 680 prospective cases

Hyperechogenic fetal bowel is prenatally detected by ultrasound during the second trimester of pregnancy in 0.1% to 1.8% of foetuses. It has been described as a normal variant and has often been associated with severe diseases, notably Down syndrome. The aim of the present study was to determine the risk of trisomy 21 in a prospective study of 680 fetuses with hyperechogenic foetal bowel. Karyotyping was performed on amniotic cells in 632 cases, and outcome was known in 655 cases. A 2.5% risk of Down syndrome and a 1% risk of other severe chromosomal anomalies were observed. Hyperechogenicity was isolated in 11/17 Down syndrome cases, and associated with other ultrasound anomalies in all seven cases of severe chromosomal anomalies. In conclusion, fetal bowel hyperechogenicity indicates a risk of chromosomal anomalies ten-fold higher than that expected on the basis of maternal age, therefore justifying invasive procedures. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis of congenital diaphragmatic hernia: A retrospective analysis of 28 cases

In a retrospective analysis of 28 cases of fetal diaphragmatic hernia, overall mortality was 86 per cent, but fell to 70 per cent when multiple anomalies were excluded. Congenital heart disease constituted the majority of associated anomalies. The incidence of an abnormal karyotype was 10·5 per cent, but rose to 20 per cent when only fetuses with multiple anomalies were included. Polyhydramnios, which occurred in 75 per cent, was a poor predictor of fetal outcome. The same applied to the intrathoracic position of the fetal stomach. In all four survivors, diaphragmatic hernia was diagnosed beyond 32 weeks of gestation.     

Prenatal detection of rubella-specific IgM in fetal sera

Serum specimens were obtained by fetoscopy at 19–25 weeks' gestation from four fetuses whose mothers had had confirmed rubella earlier in pregnancy. They were tested for rubellaspecific IgM by antibody capture radioimmunoassay. No specific IgM was detected in one fetus and a healthy infant was delivered at term. Specific IgM was detected in the other three fetuses. In one case the level was low (1 unit) and this pregnancy went to term resulting in a neonate with clinical and laboratory evidence of congenital rubella infection. The remaining two fetuses had 2.8 and 2.4 units of specific IgM and the pregnancies were terminated. Blood obtained from these two fetuses after abortion showed levels of 5.4 and 2.9 units respectively. No specific IgM was detected in sera from eleven other fetuses aborted because of maternal rubella but five of these cases were terminated before 19 weeks and in five the interval between rash and abortion was three weeks or less. The results show that the human fetus can produce detectable specific IgM antibody by 19–20 weeks' gestation after exposure to rubella sevella several weeks earlier. However, a larger study is required to define the reliablity of fetoscopic blood sampling for the diagnosis of intrauterine infection.     

Antenatal detection of a single umbilical artery: does it matter?

The presence of a single umbilical artery is recognised as a soft marker for congenital anomalies, aneuploidy, earlier delivery and low birthweight. Most of the available data are derived from case series or highly selected populations and are therefore likely to be unrepresentative. In this retrospective case-comparison study, we firstly aimed to determine the incidence of a single umbilical artery in an unselected population and secondly to examine the clinical significance of this soft marker. Over a 40-month period, 107 cases were identified from a cohort of 35 066 births giving an incidence of 3.1 per 1000 total births and late pregnancy losses. The antenatal detection rate was only 30%. Compared to fetuses with normal cord vasculature, fetuses with a single umbilical artery were more likely to be delivered at an earlier gestation and to weigh less, were 1.7 times more likely to be delivered by a Caesarean section and 19% of the cases had a congenital anomaly. The perinatal mortality was 49.0 per 1000 total births, which was 6 times higher than the background hospital rate. The presence of a single umbilical artery is associated with a poorer perinatal outcome compared to that in fetuses with three vessels in the cord. Unfortunately, the antenatal detection rate is poor. Recognising the importance of this soft marker in counselling and management of pregnancies should provide the stimulus to improve detection rates. Copyright © 2003 John Wiley & Sons, Ltd.