Fetal renal anomalies and genetic syndromes

Renal abnormalities are some of the commonest and most easily detectable anomalies on ultrasound. Many are an isolated finding but the prognosis may be altered considerably by the detection of other anomalies which could indicate a genetic disorder or syndrome. It is often easier to detect presupposed anomalies and the purpose of this article is to introduce and discuss those syndromes that may present with a renal abnormality on ultrasound. Common renal findings are presented with the range of additional anomalies that should be sought and suggested diagnostic tests. It should be remembered that although for many genetic conditions specific mutation analysis is now available, this usually requires pre‒pregnancy investigations. Furthermore, in some cases the definitive diagnosis may not be suspected until post mortem. By this time it may be too late to establish a cell line to confirm the suspicion using laboratory methods. It is therefore important to take tissue samples antenatally where possible, or at delivery, as postnatal samples may have a high culture failure rate. Copyright © 2001 John Wiley & Sons, Ltd.     

Amniocentesis rate and the detection of down syndrome and other chromosomal anomalies in Israel

We investigated the contribution of different screening criteria to the prenatal detection of Down syndrome (DS) as well as other chromosomal anomalies in the Jewish population in Israel during 1990 and 1992. There was a significant decrease (P<0·03) in the incidence of DS live-births during 1992 (40:78 442) compared with 1990 (69:73 751) which paralleled a marked increase in total prenatal testing and in DS cases detected prenatally. Private laboratories, which perform amniocenteses mostly for women with a low risk of DS and without genetic counselling, had a significantly lower detection rate (1:917) compared with that of the genetic institutes, which following genetic counselling test both women ≥ 37 years of age (1:91) and women younger than 37 years (1:113). The detection of chromosomal anomalies other than DS was less affected by the reason for amniocentesis. Amniocentesis indicated by maternal serum marker screening of women younger than 37 years identified a greater number of chromosomal anomalies other than DS than amniocentesis based on age (≥37 years) alone (111:9604 versus 94:9810; P<0·06). Prenatal detection of DS is most effective when the indication for amniocentesis follows genetic counselling. The increasing use of maternal serum marker screening leads to a significant improvement in the positive detection rate of chromosomal anomalies other than DS in young women.     

Syndromic associations with congenital anomalies of the fetal thorax and abdomen

Anomalies of the thorax and abdomen can be found in a number of genetic syndromes. Whilst it may not be possible to make a definitive diagnosis before birth, knowledge of the potential associations can be useful for the prenatal diagnostician when examining the fetus and counselling the parents. In this article, we describe conditions where other features may be detectable using prenatal ultrasound. We describe the features, potential diagnostic aids and prognosis. The tables list other potential features that may be identified. The range of conditions that can occur emphasises the value of genetic input in the management of a fetus with an apparently normal karyotype and multiple anomalies, the need to save material for future molecular analysis and the requirement of a detailed examination after delivery. These are needed in order to make accurate diagnoses and advise parents with regard to recurrence risks and the potential for prenatal diagnosis in future pregnancies. Copyright © 2008 John Wiley & Sons, Ltd.     

Chromosomal and subchromosomal anomalies associated to small for gestational age fetuses with no additional structural anomalies

Objectives: To assess the chromosomal and subchromosomal anomalies in small for gestational age (SGA) fetuses with no additional structural anomalies and their clinical outcomes. Methods: This study retrospectively reviewed the 128 SGA fetuses with no additional anomalies and underwent genetic testing with karyotyping and chromosomal microarray analysis (CMA). Stratified analysis was performed according to the existence of maternal risk factors for SGA (yes or no), gestational age at onset (before or after 32 weeks), presence of oligohydraminos (yes or no), and umbilical artery Doppler flow (normal or abnormal). Results: Chromosomal anomalies were identified in 6 (4.7%) SGA fetuses and pathogenic subchromosomal anomalies in 4 (3.1%) by microarray analysis. Chromosomal and subchromosomal anomalies were more frequently observed in cases with oligohydraminos (P = .017) and with early-onset SGA (P = .042). No differences were observed in relation to the existence of maternal risk factors and abnormal umbilical artery Doppler flow. Overall survival rate was 75.0% with different rates in the early and the late onset group (P < .001). Conclusions: There is a 3.3% incremental yield of subchromosomal anomalies in CMA above karyotyping in SGA fetuses. Chromosomal microarray analysis is recommended in SGA fetuses with no additional structural anomalies, especially coexisting with oligohydraminos and being early onset.     

Fetal diaphragmatic hernia and upper limb anomalies suggest Brachmann-de Lange syndrome

We describe two independent cases of Brachmann-de Lange syndrome (BDLS) in which second trimester fetal sonographic studies showed the presence of a diaphragmatic hernia and upper limb anomalies. In both cases the karyotypes were normal. Intrauterine growth restriction (IUGR) developed in the third trimester. Postnatal and postmortem physical examinations demonstrated typical physical findings associated with BDLS. The prenatal diagnosis of diaphragmatic hernia with associated anomalies should prompt consideration of an underlying genetic etiology. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT)

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute 20% of all congenital malformations occurring in one in 500 live births. Worldwide, CAKUT are responsible for 40% to 50% of pediatric and 7% of adult end-stage renal disease. Pathogenic variants in genes causing CAKUT include monogenic diseases such as polycystic kidney disease and ciliopathies, as well as syndromes that include isolated kidney disease in conjunction with other abnormalities. Prenatal diagnosis most often occurs using ultrasonography; however, further genetic diagnosis may be made using a variety of testing strategies. Family history and pathologic examination can also provide information to improve the ability to make a prenatal diagnosis of CAKUT. Here, we provide a comprehensive overview of genetic considerations in the prenatal diagnosis of CAKUT disorders. Specifically, we discuss monogenic causes of CAKUT, associated ultrasound characteristics, and considerations for genetic diagnosis, antenatal care, and postnatal care.     

Increased nuchal translucency in euploid fetuses—what should we be telling the parents?

Nuchal translucency (NT) measurement between 11 and 14 weeks' gestation is an undisputed marker for aneuploidies. When conventional karyotyping is normal, enlarged NT is a strong marker for adverse pregnancy outcome, associated with miscarriage, intrauterine death, congenital heart defects, and numerous other structural defects and genetic syndromes. The risk of adverse outcome is proportional to the degree of NT enlargement. Although the majority of structural anomalies are amenable to ultrasound detection, unspecified genetic syndromes involving developmental delay may only emerge after birth. Concern over these prenatally undetectable conditions is a heavy burden for parents. However, following detection of enlarged NT the majority of babies with normal detailed ultrasound examination and echocardiography will have an uneventful outcome with no increased risk for developmental delay when compared to the general population. Counseling should emphasize this to help parents restore hope in normal pregnancy outcome and infant development. Copyright © 2010 John Wiley & Sons, Ltd.     

Comprehensive prenatal diagnostics: Exome versus genome sequencing

Objective

This study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis.

Methods

A total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases.

Results

The trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its higher sequencing depth.

Conclusions

Prenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples.     

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.     

Prenatal ultrasonographic diagnosis of radial-ray reduction malformations

Radial-ray reduction malformations (RRRMs) may occur isolated or in association with other anomalies. The data of seven fetuses born with RRRMs were collected. Six fetuses had associated lethal abnormalities of the central nervous system, urogenital system, and/or heart, detected by ultrasound. In five cases, it was possible to establish the precise diagnosis, enabling an informed prognosis and subsequent genetic counselling. The diagnoses were: Edwards syndrome (n=3), VACTERL association (n=1), and Poland-Moebius-like complex (n= 1). In two cases, a complete diagnosis was not possible because of inadequate evaluation of these fetuses before and/or after birth. A proposal is given for the diagnostic approach for infants with RRRMs detected in the antenatal period by means of ultrasonography.     

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.     

Prenatal diagnosis of congenital head,face, and neck malformations—Is complementary fetal MRI of value?

Objectives

The aim of this study was to evaluate the role of fetal magnetic resonance imaging (MRI) as a complement to ultrasound (US) in the prenatal diagnosis of craniofacial anomalies.

Methods

A historical cohort study including all pregnant women who were referred for fetal MRI because of antenatal diagnosis of craniofacial anomalies on screening US. Prenatal diagnostic US, MRI, and postnatal diagnosis were compared for consistencies and discrepancies.

Results

Forty-five pregnant women with 73 suspected fetal craniofacial anomalies diagnosed by US underwent MRI. In 40 out of 73 anomalies (54.8%), US and MRI findings were in complete agreement with postnatal diagnoses. MRI correctly ruled out the diagnosis of 24 anomalies suspected on US and diagnosed four additional pathologies that were not demonstrated by US. Out of the 85 anomalies (suspected by imaging or confirmed postnatally), confident diagnosis could be made by MRI in 68 anomalies (80%), not diagnosed in 10 (11.8%), and over-diagnosed in seven (8.2%). By US, confident diagnosis could be made in 44 anomalies (51.8%), not diagnosed in 11 (12.9%), and over-diagnosed in 30 (35.3%).

Conclusion

MRI is valuable in the antenatal evaluation of fetal craniofacial anomalies and may be useful as an adjunct to US in the prenatal work-up of craniofacial anomalies.     

Application of fluorescent in situ hybridization for ‘de novo’ anomalies in prenatal diagnosis

Fluorescent in situ Hybridization (FISH) was carried out for three cases of abnormal karyotypes in prenatal studies. Two concerned de novo structural anomalies and the third a marker chromosome. The origin of the extra material could be defined in all three cases, which gives a better insight into the relationship between genotype and phenotype and makes more adequate genetic counselling possible.     

Trisomy 20 mosaicism

A further case of trisomy 20 mosaicism found at amniocentesis is presented. Pregnancy was terminated, the fetus showed facial dysmorphia and minor cardial and renal anomalies. 19 published reports of true trisomy 20 mosaicism at amniocentesis are reviewed. Five pregnancies resulted in obviously normal newborns. The significance of mostly minor anomalies found at autopsy of 7 fetuses remains unclear. With regard to genetic counselling the significance of trisomy 20 mosaicism is summarized as follows: (1) true trisomy 20 mosaicism in amniotic fluid cells reflects mosaicism of the fetus; (2) severe malformation is not a major feature of trisomy 20 mosaicism; (3) the risk of mental retardation is still undetermined, due to limited experience. However, there is no definite proof that the condition is harmful at all.     

西双版纳南坡铜矿区植物地球化学异常特征及形成机理

对西双版纳南坡铜矿区植物与土壤地球化学剖面研究发现:发育在Ⅰ线研究剖面山脊隐伏矿床上方和山坡脚近溪流处的Ⅰ号和Ⅱ号植物综合异常,其赋存空间、物质来源及发育状态受不同成因类型的土壤异常的控制。Ⅰ号异常反映了土壤气体异常、碎屑异常和上移水成异常;Ⅱ号异常反映了土壤侧移水成异常和部分水化学异常。由于元素在植物根际环境的地球化学赋存状态及其生物有效性,植物对元素吸收的选择性和屏障效应等因素,植物中某些异常元素同土壤异常中的相应元素具有不协调性。植物地球化学异常库和所有的地球化学异常库都发生关系,它们在一定的时空、环境和动力条件下发生一系列复杂的界面反应,使元素向植物迁移转化,导致植物地球化学异常的形成。     

The solitary median maxillary central incisor (SMMCI) syndrome: Associations,prenatal diagnosis,and outcomes

Solitary median maxillary central incisor (SMMCI) syndrome is a complex disorder consisting of multiple, developmental defects involving midline structures of the head, which includes the cranial bones, the maxilla, and its container dentition (specifically the central incisor tooth germ), together with other midline structures of the body. SMMCI may appear as an isolated trait or in association with other midline developmental anomalies. We describe the case of a patient with SMMCI. He presented with a solitary median maxillary incisor, short stature, corpus callosum anomalies and a microform of holoprosencephaly (HPE), diabetes insipidus, and neurodevelopmental delay. The diagnosis was performed postnatally based on clinical features, radiological imaging, and a comprehensive genetic study. SMMCI can be diagnosed during the prenatal or neonatal periods or during infancy. Evaluation of the superior maxillary bone is important for prenatal diagnosis. Direct evaluation through bidimensional ultrasound or the use of multiplanar ultrasound or tridimensional reconstruction should be performed in cases of brain or face malformations. Early diagnosis can contribute to improved prenatal assessment and postnatal management.     

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.     

Current Controversies in Prenatal Diagnosis 1: Should MRI be performed on all fetuses with mild ventriculomegaly?

A ventricular diameter of 10 mm correlates with more than two standard deviations of the normal and hence is qualified as ventriculomegaly. The relevance of this is dependent on whether there are associated infectious, genetic, or structural problems. The chance for neurodevelopmental delay in isolated ventriculomegaly less than 15 mm is 7.9% (4.7-11.1), and less if it is unilateral. It can be further divided in mild (10-12) or moderate (13-15), though this is not widely accepted. As part of the workup, structural assessment today may include ultrasound or magnetic resonance imaging, or both. Discussants agreed that the diagnostic performance of both methods is as good as the expertise with which the images are acquired and interpreted. Discussants agreed that when the initial neurosonogram is normal, the likelihood of finding significant findings on MRI is low. Nevertheless, some anomalies may only be picked up or better worked out by fetal MRI. In utero follow-up is advocated, as progression may indicate a poorer outcome, and some conditions are only obvious late in pregnancy. Most benefit for future patients is expected from appropriate training in prenatal neuroimaging.     

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US

Objective

There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies.

Method

We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics.

Results

Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers.

Conclusion

Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.     

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.