Prenatal diagnosis of a new syndrome: Holoprosencephaly with hypokinesia

Markedly decreased fetal activity (akinesia/hypokinesia) is usually readily apparent to experienced mothers, and frequently this concern leads to attempts at prenatal diagnosis. We report prenatal diagnosis of two fetuses with congenital contractures, markedly decreased fetal movement, and microcephaly due to severe holoprosencephaly. Such familial recurrence to phenotypically normal parents suggests a newly recognized autosomal recessive or X-linked syndrome that is readily detectable by prenatal ultrasonography.     

Heterogeneity in fetal akinesia deformation sequence (FADS): autopsy confirmation in three 20–21-week fetuses

Fetal akinesia deformation sequence (FADS) is a rare condition characterized by intrauterine growth retardation (IUGR), congenital limb contractures, pulmonary hypoplasia, hydramnios and craniofacial abnormalities. The present report comprises an autopsy study of three fetuses to illustrate the variable clinical manifestations and neuropathological findings. Fetus 1 had arthrogryposis and no movement on fetal ultrasound examination. Aborted at 21 weeks, the fetus showed micrognathia, bilateral joint contracture with pterygia at the elbow and axilla. Growth retardation and pulmonary hypoplasia were not major features. Neuropathologic examination revealed anterior horn cell loss and lateral corticospinal tract degeneration in spinal cord, with marked muscular atrophy. Fetus 2, 20 weeks' gestation, had fetal akinesia, nuchal thickening, left pleural effusion, and Dandy-Walker malformation on ultrasound examination. Autopsy showed low-set ears, ocular hypertelorism, cleft palate, flexion contractures with pterygia over axilla, elbow and groin, pulmonary hypoplasia, Dandy-Walker malformation, unremarkable spinal cord and skeletal muscle. Fetus 3, 21 weeks' gestation, was aborted for fetal akinesia, neck and limb webbing and severe arthrogryposis. At autopsy, similar facial abnormalities, contracture and pterygia in neck and multiple major joints were found. Borderline pulmonary hypoplasia and severe lumbar scoliosis were also present. The brain, spinal cord and muscle were unremarkable. In these three fetuses, the prenatal ultrasound and autopsy findings were characteristic of FADS. Neurogenic spinal muscular atrophy was the basis of fetal akinesia in Case 1. Dandy-Walker malformation was present in Case 2, but the pathogenetic mechanism of fetal akinesia was not clear as spinal cord and muscle histology appeared normal. The etiology of akinesia was undetermined in Case 3; no extrinsic or intrinsic cause was identified. Copyright © 2002 John Wiley & Sons, Ltd.     

Restrictive dermopathy and fetal behaviour

We report three siblings from consecutive pregnancies affected with restrictive dermopathy (RD). During the second pregnancy, fetal behavioural development and growth were studied extensively using ultrasound at 1–4 week intervals. Dramatic and sudden changes occurred in fetal body movements and growth but not until the end of the second trimester of pregnancy. Prominent at that time were prolonged periods of fetal quiescence and very low heart rate variability, together with abnormally executed body movements of short duration. Retarded femoral development and jerky abrupt fetal body movements (abnormal movement quality) were already present in the early second trimester of pregnancy. Facial anomalies emerged despite the presence of fetal mouth movements. The clinical features of RD were only partly explained by present knowledge of skin development and the fetal akinesia deformation sequence hypothesis. Quantitative assessment of fetal movements proved to be a poor early marker for antenatal diagnosis of this disorder. Copyright © 2001 John Wiley & Sons, Ltd.     

Genetic diagnosis and clinical evaluation of severe fetal akinesia syndrome

Objective

In this retrospective study, we describe the clinical course, ultrasound findings and genetic investigations of fetuses affected by fetal akinesia.

Materials and Methods

We enrolled 22 eukaryotic fetuses of 18 families, diagnosed with fetal akinesia between 2008 and 2016 at the Department of Obstetrics and Feto-Maternal Medicine at the Medical University of Vienna. Routine genetic evaluation included karyotyping and chromosomal microarray analysis. Retrospectively, exome sequencing was performed in the index case of 11 families, if stored DNA was available. Confirmation analyses and genetic diagnosis of siblings were performed by using Sanger sequencing.

Results

Whole exome sequencing identified pathogenic variants of CNTN1, RYR1, NEB, GLDN, HRAS and TNNT3 in six cases of 11 families. In three of these families, the variants were confirmed in the respective sibling.

Conclusions

The present study demonstrates a high diagnostic yield of exome sequencing in fetuses affected by akinesia syndrome, especially if family history is positive. Still, in a large part the underlying genetic cause remained unknown, whereas precise clinical evaluation in combination with exome sequencing shows to be the best tool to find the disease causing variants.     

Alpha-fetoprotein and acetylcholinesterase are not predictive of fetal junctional epidermolysis bullosa,Herlitz variant

Junctional epidermolysis bullosa, Herlitz variant (junctional EB-Herlitz) is a lethal autosomal recessive skin disorder currently amenable to prenatal diagnosis only by direct analysis of fetal skin. However, elevated levels of alpha-fetoprotein, as well as the presence of acetylcholinesterase in amniotic fluid, have been associated with other severe fetal genodermatoses. Fetal skin samplings were performed in ten pregnancies at risk for fetal junctional EB-Herlitz, with three fetuses affected on the basis of electron microscopic detection of blisters within the lamina lucida and abnormal hemidesmosomes. In neither affected nor unaffected pregnancies were maternal serum or amniotic fluid alpha-fetoprotein levels elevated. Moreover, alphafetoprotein levels in both maternal serum and amniotic fluid were not statistically different comparing affected and unaffected fetuses. Acetylcholinesterase was not present in the amniotic fluid samples of the three affected pregnancies. Unlike other severe fetal genodermatoses, neither alpha-fetoprotein nor acetylcholinesterase was predictive of junctional EB-Herlitz.     

Ultrasound diagnosis of the pena shokeir phenotype at 14 weeks of pregnancy

This report describes the early prenatal diagnosis of the Pena Shokeir phenotype in an at-risk patient at 14 weeks' gestation. The diagnosis was based on an abnormal fetal movement profile, in association with an abnormal position of the fetal limbs. Pena Shokeir phenotype describes an inherited condition characterized by arthrogryposis and dysmorphic features as a result of fetal akinesia. It is a lethal abnormality and early diagnosis allows safer surgical methods of termination.     

Early prenatal detection of diastrophic dysplasia

Diastrophic dysplasia, an autosomal recessive disorder, results in severe short-limbed dwarfism, progressive spinal and joint problems, and secondary psychosocial disability. The results of treatments are unsatisfactory. Four pregnant mothers at risk for an affected fetus were studied with an ultrasound scanner at 16 and 19 weeks of gestation. Each mother had a previous child with diastrophic dysplasia. The biparietal distance and the length of the long bones of the extremities were normal in three fetuses, whereas in one fetus there was a 30 per cent shortening of all long bones. The biparietal distance corresponded with the gestational age in all fetuses. In one fetus, diastrophic dysplasia was confirmed by fetoscopy and fetal radiograph at 19 weeks of gestation after the parents had decided to terminate the pregnancy. The skeletal radiograph and autopsy findings of the fetus verified the diagnosis. All other mothers were followed with repeated ultrasound examinations, and they delivered healthy babies. The retrospective follow-up of the four previous pregnancies and of the present one with affected fetuses disclosed that two mothers had had vaginal bleeding, two lymphedema, one abdominal pains, and one mother had had polyhydramnios. These complications were, however, mild and transient, and they could not be regarded as specific for pregnancies with affected fetuses.     

Karyotype,phenotype and parental origin in 19 cases of triploidy

The parental origin of triploidy in 19 cases was examined by inheritance of DNA microsatellites and by methylation patterns of SNRPN or PW71 (where parents' blood was unavailable). The fetal and placental morphology on these cases was reviewed. The phenotype of the fetuses with non-mosaic triploidy was assessed in relation to the two types described by McFadden and Kalousek. Of the diandric fetuses three of the six showed mild-to-moderate symmetrical growth retardation and the other three had growth characteristics in accordance with their gestational ages. This study would suggest the fetal triploid ‘Type 1’ definition be modified to ‘well grown to moderate symmetrical IUGR’ to allow for such variation. In the digynic fetuses (McFadden/Kalousek Type 2) there were poor growth characteristics with IUGR being more severe and asymmetrical. The diandric fetuses were as common as digynic fetuses in this series. The ratio of diandric to digynic specimens was 11:8 but if only fetal specimens (not embryos or mosaic children) were included the ratio was 6:5. Many diandric conceptions end as partial moles but later in gestation diandric fetuses may be well grown. It is proposed that there may be a survival barrier for diandric fetuses early in gestation (possibly based on the proportion of vascularised placental villi), although once this is passed the diandric fetuses are comparatively more viable and better grown than digynic fetuses. In the XXY triploid fetuses, 5/6 had hypoplastic or ambiguous external genitalia (two were recorded as of female phenotype) as has been reported previously. In these, the gonadal histology was testicular in all the diandrics but in the single digynic XXY case, sex reversal was complete with normal uterus and Fallopian tubes and the gonads were histologically ovaries. Two triploid/diploid mosaics were proven to be due to digyny. The probable cause is delayed incorporation of the second polar body into a blastomere and there was evidence of identical alleles from the same sperm being present in both diploid and triploid cells. In one of these triploid/diploid mosaics in which there was a termination of pregnancy (TOP) after prenatal karyotyping the diploid cell line had trisomy 16 which was not evident in the triploid line. This trisomy was probably of post-zygotic origin and we suggest the fetus was rescued by the prominence of the triploid line. Copyright © 2001 John Wiley & Sons, Ltd.     

Ultrasound movement patterns of fetuses with chromosome anomalies

Fetal movements were examined by ultrasound in 24 pregnancies in which an abnormal karyotype was detected in fetal cells and compared to ultrasound fetal movement patterns in normal pregnancies. The main features in fetuses with chromosome anomalies observed at 18–20 weeks of gestation are the persistence of global, jerky movements with twitches usually seen at 13–14 weeks of gestation in normal fetuses. This fetal motor behaviour is inconstant in trisomy 21. In trisomy 18 the hand deformities are easily detected.     

Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)—Aetiology,diagnosis, and management

Arthrogryposis multiplex congenita (AMC) refers to an aetiologically heterogenous condition, which consists of joint contractures affecting two or more joints starting prenatally. The incidence is approximately one in 3000 live births; however, the prenatal incidence is higher, indicating a high intrauterine mortality. Over 320 genes have been implicated showing the genetic heterogeneity of the condition. AMC can be of extrinsic aetiology resulting from intrauterine crowding secondary to congenital structural uterine abnormalities (eg, bicornuate or septate uterus), uterine tumors (eg, fibroid), or multifetal pregnancy or intrinsic/primary/fetal aetiology, due to functional abnormalities in the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, bones, restrictive dermopathies, tendons and joints. Unlike many of the intrinsic/primary/fetal causes which are difficult to treat, secondary AMC can be treated by physiotherapy with good response. Primary cases may present prenatally with fetal akinesia associated with joint contractures and occasionally brain abnormalities, decreased muscle bulk, polyhydramnios, and nonvertex presentation while the secondary cases usually present with isolated contractures. Complete prenatal and postnatal investigations are needed to identify an underlying aetiology and provide information regarding its prognosis and inheritance, which is critical for the obstetrical care providers and families to optimize the pregnancy management and address future reproductive plans.     

First-trimester diagnosis of hunter syndrome: Very low iduronate sulphatase activity in chorionic villi from a heterozygous female fetus

Iduronate sulphatase activity was determined in uncultured chorionic villi from four fetuses at risk for Hunter syndrome. AH fetuses were shown to be female by chromosome analysis. Biopsy material from three fetuses showed iduronate sulphatase activity within normal limits whilst the fourth fetus showed activity reduced to 7 per cent of our control mean. The importance of fetal sexing in prenatal diagnosis of this condition is emphasized as female carrier fetuses may show iduronate sulphatase activity reduced to levels observed in affected males.     

Prenatal sex diagnosis: Testosterone and fsh levels in mid-trimester amniotic fluids

We studied the validity of mid-trimester amniotic fluid testosterone and FSH in the diagnosis of fetal sex in abnormal fetuses and in twins. It was found that the testosterone/FSH ratio, but not the level of the individual hormones, was an excellent criterion for fetal sex diagnosis. In a control group of 32 female and 34 male fetuses, the testosterone/FSH ratio was diagnostic. In two cases the values were indeterminate and fetal sex could not be predicted, but there were no false diagnoses. The abnormalities of the fetuses were diagnosed by karyotype analyses or raised levels of α-fetoprotein. It was found that neither autosomal trisomies nor X-chromosome aneuploidy or neural tube defect interfered with the diagnostic value of the hormonal approach. The twin study included 14 pairs, three of whom were discordant for sex. In all twins the fetal sex diagnosis was appropriate. In co-twins of the same sex the hormone levels were very close to each other.     

Prenatal diagnosis of citrullinemia: Elevated levels of citrulline in the amniotic fluid in the three affected pregnancies

In three pregnancies at risk for citrullinemia affected fetuses were predicted both by strongly increased levels of citrulline in the amniotic fluid and by the reduced incorporation of ¹⁴C-citrulline into TCA-precipitable material in cultured amniotic fluid cells. The prenatal diagnoses of affected fetuses were confirmed after termination of the pregnancies by direct and indirect assays of argininosuccinate synthetase in the fetal livers and fibroblasts respectively. Measurement of the citrulline concentration in amniotic fluid appears to be a valuable adjunct in the prenatal diagnosis of citrullinemia.     

The history of the second-trimester sonographic markers for detecting fetal Down syndrome,and their current role in obstetric practice

This review summarizes the development, history and use of second-trimester sonographic markers for the detection of fetal Down syndrome over three decades. Starting with the nuchal fold thickening in 1985 and culminating in the genetic sonogram in the 1990s. The combination of second-trimester serum screening with the ultrasound markers improved the detection rate of affected fetuses but also allowed patients to decrease their risk of carrying a fetus with Down syndrome if the genetic sonogram was normal. More recently the role of the genetic sonogram and its markers have changed with the wide spread use of first-trimester screening. This prior screening ultimately decreases the prevalence of fetal Down syndrome in the second trimester to less than 85% of what it was in the first-trimester as most fetuses with Down syndrome are now identified early. Current interpretation of the second-trimester Down syndrome markers must be based on the result of the first trimester and combined screening to achieve the most accurate risk estimate of an affected fetus. Copyright © 2010 John Wiley & Sons, Ltd.     

Prenatal exclusion of X-linked hydrocephalus-stenosis of the aqueduct of sylvius sequence using closely linked DNA markers

X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence (H-SAS, MIM number 307 000) is a rare genetic disorder characterized by hydrocephalus, macrocephaly, adducted thumbs, spasticity, mental retardation, and cerebral malformations. This regularly lethal condition is usually diagnosed at birth or prenatally by ultrasound, but hydrocephalus may be moderate or even undetectable on fetal ultrasound examination. Moreover, since heterozygous women are asymptomatic, carrier detection is at present impossible before the birth of an affected son. Therefore, mapping the H-SAS locus to distal Xq (Xq28) was of primary importance for genetic counselling and prenatal diagnosis. Here, we report prenatal exclusion of H-SAS with a probability of 97.6 per cent in two male fetuses with a 50 per cent a priori risk of being affected using closely linked Xq28 DNA markers.     

Fetal behaviour in growth retardation: Its relationship to fetal blood flow

The fetal behaviour of asymmetrical growth retarded fetuses was compared with that of a control group of healthy fetuses. Fetuses underwent simultaneous cardiotocographic and echographic examinations for two consecutive hours at 36–38 weeks of gestation. The distribution of gross fetal body movements, fetal breathing movements and fetal eye movements was analysed during the different fetal heart rate patterns. Furthermore, the incidence and organization of fetal behavioural states was investigated. The degree of vascular peripheral resistance was also evaluated by means of pulsed doppler ultrasonic equipmznt. Growth retarded fetuses were divided into two groups on the basis of the presence or absence of end diastolic flow in the fetal thoracic descending aorta. Growth retarded fetuses showed a delay in the integration of behavioural patterns and a lower coincidence of behavioural states. These findings are particularly evident in the fetuses with a severe increase of peripheral vascular resistance (absence of end diastolic flow in descending aorta). Thus, we suggest that a delay in central nervous system development is present in asymmetrical growth retarded fetuses and that there is a possible relationship of this delay to the degree of peripheral vascular resistance.     

Prenatal diagnosis of citrullinaemia: Review of a 10-year experience including recent use of DNA analysis

Prenatal diagnosis of citrullinaemia has been accomplished by three different methods to date: (1) enzyme assay of cultured fetal cells; (2) quantification of citrullirie in amniotic fluid supernatant; and (3) incorporation of [¹⁴C]citrulline into protein by cultured fetal cells. Our laboratory has used these methods to perform prenatal diagnosis for 28 fetuses over a 10-year period. More recently, DNA polymorphisms were used for prenatal diagnosis by linkage analysis. Of the 28 fetuses studied, 23 were predicted to be unaffected, four were predicted to be affected, and results were conflicting in one case where [¹⁴C]citrulline incorporation erroneously indicated an affected fetus but linkage analysis correctly predicted an unaffected fetus. Because of low levels of enzyme activity in heterozygotes and in certain amniotic fluid cell types, biochemical diagnosis of citrullinaemia is complicated by the risk of false affected results, although [¹⁴C]citrulline incorporation is relatively reliable. When informative, linkage analysis is the preferable method for cases with a 25 per cent risk. The risk of false affected results makes prenatal diagnosis for cases with less than 25 per cent risk of questionable value.     

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.     

False-negative prenatal exclusion of Wiskott-Aldrich syndrome by measurement of fetal platelet count and size

The study of the fetal platelet count and size can, according to the literature, be used for the prenatal diagnosis of the Wiskott-Aldrich syndrome (WAS). So far, no affected fetuses have been identified by this method. All pregnancies in which this method had been applied to resulted, as correctly predicted, in the birth of normal children. Here we report on a familial case of WAS where the haematological parameters failed to reveal the affected second child. Hence we assume that the platelet count and size of platelets remain normal in fetuses with WAS to the gestational age of 22 weeks and cannot be used for prenatal diagnosis.     

Prenatal diagnosis of chinese homozygous α-thalassaemia 1 and haemoglobin H disease by analysis of α- and φζ-globin genes in chorionic villi and amniocytes

Eighty-eight high-risk pregnancies, 81 for homozygous α-thalassaemia 1 and 7 for haemoglobin (Hb) H disease, were collected in this study. Chorionic villus sampling (CVS) was done in 63 cases and amniocentesis in 25 cases to obtain fetal cells. Southern blotting and DNA hybridization with α- and φζ-globin gene probes were used to determine the α-globin gene status. In two non-informative families with non-deletional mutations, DNA analysis failed to rule out the affected condition, and fetal blood sampling (FBS) and Hb electrophoresis were used for the final diagnosis. In the 81 fetuses at risk for homozygous α-thalassaemia 1, 17 (13 by CVS and 4 by amniocentesis) were afffected, 30 were α-thalassaemia 1 heterozygotes, 19 were normal, and the remaining 15 were either normal or heterozygous. In the seven fetuses at risk for Hb H disease, one was normal, three were α-thalassaemia 1 heterozygotes, two were α-thalassaemia 2 heterozygotes, and one was affected with Hb H disease and developed hydrops fetalis. DNA analysis on fetal cells enabled us to diagnose prenatally severe α-thalassaemias, to prevent the birth of infants with Hb H disease, and to minimize maternal obstetrical complications from harbouring a fetus with Hb Bart's hydrops fetalis.