Fetal de novo heterozygous variant in the isocitrate dehydrogenase 1 gene associated with growth restriction,skeletal, cerebral and vascular anomalies

Germline pathogenic variants in isocitrate dehydrogenase 1 (IDH1) can lead to a rare neurodevelopmental disorder called metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, including severe skeletal and cerebral anomalies. To the best of our knowledge, no prenatal case of an IDH1 pathogenic variant has been reported in literature. Somatic sequence variants in IDH1/2 genes are described in distinct cancers, premalignant diseases and rare inherited metabolic disorders. Amniocentesis and further genetic testing including trio exome sequencing were performed due to suspicious findings on a second trimester routine prenatal ultrasound examination. The fetus was found to have growth restriction, cerebral abnormalities (ex vacuo hydrocephalus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis), brachycephaly, narrow chest, persistent left superior vena cava, liver calcifications, hyperechogenic bowel, short tubular bones and joint contractures. A de novo heterozygous variant in the IDH1 gene was detected via trio exome sequencing. The prenatal diagnosis of a de novo pathogenic variant in IDH1 in a fetus with the described phenotype, obtained through trio exome sequencing, helped parents and providers with an informed decision making about pregnancy management.     

Abnormalities of the foetal cerebral cortex

Prenatal ultrasound has concentrated on readily visible cerebral structures including head size, shape, ventricles, CSP (cavum septi pellucidi), cerebellar size/vermian presence and cisterna magna. However, apart from these easily visible structures it is important to evaluate the brain itself. Patients who initially appear to have mild isolated findings such as borderline ventriculomegaly in fact can have many more subtle findings that significantly alter prognosis and management that can be detected on detailed examination of the brain. There has been rapid evolution in imaging these foetuses, especially with neurosonography and MRI, and a revolution in understanding the underlying genetic and biochemical mechanisms. There is increasing emphasis to detect cortical abnormalities as early as possible. This article reviews development of the cerebral cortex, the classification, aetiologies and clinical manifestations of cortical disorders, normal and abnormal appearances at ultrasound and MRI, and approaches to investigation. Copyright © 2009 John Wiley & Sons, Ltd.     

Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation

We describe prenatal diagnosis in a male fetus at 21 weeks of gestation with atelosteogenesis type I (AO I). Fetal ultrasonography (US) revealed absent or deficient ossification of the posterior neural arches of the thoracic spine, humeri, radii, ulnae, fibulae, and short tubular bones other than the distal phalanges, in addition to extremely short, thick femora. Fetal magnetic resonance imaging (MRI) using an ultrafast imaging sequence depicted dysmorphic features, pulmonary hypoplasia, and large cisterna magna. Postmortem radiographs warranted a diagnosis of AO I. Autopsy corroborated not only pulmonary hypoplasia but also laryngeal stenosis. The chondro-osseous histological findings were consistent with those of AO I. Meticulous evaluation using fetal US and MRI permits a definitive prenatal diagnosis of AO I to be made. Copyright © 2002 John Wiley & Sons, Ltd.     

Post-natal investigations: management and prognosis for fetuses with CNS anomalies identified in utero excluding neurosurgical problems

The suspicion of an abnormality of the central nervous (CNS) system raises difficult questions for the clinician and the family and will inevitably lead to considerable anxiety. These questions include what it means for the child's future, whether it can be treated and whether it will happen again in subsequent pregnancies. For many disorders accurate prenatal diagnosis remains elusive, as even with fetal magnetic resonance imaging (MRI), early recognition and characterisation are simply not possible because of the immature state of brain development at that stage of pregnancy. The natural history of many prenatally diagnosed CNS disorders remains to be elucidated which means that an accurate prognosis cannot be given in all cases. We review the current state of knowledge regarding the investigation, management and prognosis of the most common and important CNS malformations. We also discuss the post-natal management of these conditions both in the neonate and subsequent pregnancies for the families. Copyright © 2009 John Wiley & Sons, Ltd.     

Disorders of prosencephalic development

Abnormal ventral induction may result in disorders of formation, cleavage, and midline development of prosencephalic structures. Holoprosencephaly is a developmental field defect of impaired cleavage of prosencephalon. The most widely accepted classification of holoprosencephaly recognizes three major varieties: the alobar, semilobar and lobar types, according to the severity of the malformation. The brain malformations, characterized by the fusion of the cerebral hemisphere along the midline are commonly associated with facial anomalies. Corpus callosum agenesis and septo-optic dysplasia are disorders of prosencephalic midline development, and usually have less severe presentations but still, affected subjects may suffer from neurodevelopmental retardation, and/or endocrinologic and visual disorders. In this article we report an up-to-date of pathogenesis, prenatal sonographic findings, differential diagnosis and prognosis of the aforementioned anomalies. Copyright © 2009 John Wiley & Sons, Ltd.     

Prenatal diagnosis of Juberg–Hayward syndrome

Juberg–Hayward syndrome is a rare autosomal recessive syndrome characterised by the association of growth retardation, microcephaly, cleft lip and palate, and thumb and radial ray abnormalities. To date, no prenatal cases have been reported. Here, we report on the first prenatal case of Juberg–Hayward syndrome. The diagnosis was established following fetopathological study. Besides the cardinal features of the syndrome, this prenatal case was remarkable for the severity of the short arm malformation and by the finding of big toe agenesis and cerebral abnormalities including hydrocephalus, agenesis of corpus callosum, and cerebellar hypoplasia. We conclude that the diagnosis of Juberg–Hayward syndrome can be discussed prenatally following ultrasound diagnosis of the association of intrauterine growth restriction, microcephaly, thumb/radial anomalies, and cleft lip/palate. Copyright © 2005 John Wiley & Sons, Ltd.     

Molecular prenatal diagnosis: the impact of modern technologies

Originally prenatal diagnosis was confined to the diagnosis of metabolic disorders and depended on assaying enzyme levels in amniotic fluid. With the development of recombinant DNA technology, molecular diagnosis became possible for some genetic conditions late in the 1970s. Here we briefly review the history of molecular prenatal diagnostic testing, using Duchenne muscular dystrophy as an example, and describe how over the last 30 years we have moved from offering testing to a few affected individuals using techniques, such as Southern blotting to identify deletions, to more rapid and accurate PCR-based testing which identifies the precise change in dystrophin for a greater number of families. We discuss the potential for safer, earlier prenatal genetic diagnosis using cell free fetal DNA in maternal blood before concluding by speculating on how more recent techniques, such as next generation sequencing, might further impact on the potential for molecular prenatal testing. Progress is not without its challenges, and as cytogenetics and molecular genetics begin to unite into one, we foresee the main challenge will not be in identifying the genetic change, but rather in interpreting its significance, particularly in the prenatal setting where we frequently have no phenotype on which to base interpretation. Copyright © 2010 John Wiley & Sons, Ltd.     

X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus

We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. A healthy Finnish couple was initially referred to the Fetomaternal Medical Center because of suspected fetal choroid plexus cyst at 11 + 2 weeks of pregnancy. At 20 + 0 weeks, multiple abnormalities were observed with ultrasound including narrow thorax, slightly enlarged heart, hypoplastic cerebellum, absent cerebellar vermis and ventriculomegaly. Autopsy and genetic analyses were performed after the termination of pregnancy. The findings of macroscopic examination included cleft palate, abnormally overlapping position of fingers and toes and dysmorphic facial features. Neuropathological examination confirmed the absence of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Nodular neuronal heterotopia was also observed. Trio exome sequencing revealed a novel hemizygous de novo variant c.1144C>T p.(Gln382*) in the PDHA1 gene, classified as likely pathogenic. We suggest that inherited metabolic disorders should be kept in mind as differential diagnoses in fetuses with structural brain abnormalities.     

Fetal two-dimensional doppler echocardiography (colour flow mapping) and its place in prenatal diagnosis

One hundred and fifty fetuses between 16 and 38 weeks of gestation were studied by fetal echocardiography using colour-coded two-dimensional Doppler echocardiography. Two-dimensional, M-mode, and Doppler spectral analyses were also performed. In 14 fetuses, structural and/or functional abnormalities were detected. Abnormalities were correctly ruled out in all the other fetuses. The advantages of two-dimensional Doppler echocardiography are (1) rapid screening for flow abnormalities in the fetal heart, and thus shortening of the Doppler examination time; (2) rapid diagnosis of valvular regurgitation, valvular stenosis, and abnormal shunting of blood across the interatrial and interventricular septa; and (3) facilitation of the diagnosis of complex congenital heart defects which in certain cases is possible only by using two-dimensional Doppler echocardiography.     

In utero diagnosis and treatment of fetal goitrous hypothyroidism,caused by maternal use of propylthiouracil

A fetal goitre is a potentially dangerous phenomenon because of mechanical obstruction and possible fetal thyroid function disorders. In this report we describe a patient with Graves' disease diagnosed in early pregnancy and treated with propylthiouracil, which resulted in a large fetal goitre and fetal hypothyroidism. The diagnostic problems are discussed and we focus on the need for fetal thyroid hormone serum evaluation. The only reliable way to obtain information about the fetal thyroid status is percutaneous fetal umbilical cord blood sampling, since amniotic fluid levels do not properly represent the fetal thyroid function. Fetal hypothyroidism can thus be diagnosed in utero and treated with intra-amniotic injections of thyroxine. The recommended dose and frequency of injections are only based on a few case reports and for that reason we performed a second fetal blood sampling 1 week later to evaluate our therapy. Weekly intra-amniotic injections of 250 μg of thyroxine seem to be sufficient to reduce a fetal goitre and give a normal thyroid hormone level.     

SAFE—The Special Non-invasive Advances in Fetal and Neonatal Evaluation Network: aims and achievements

In this short review, the objectives and work of SAFE—the Special Non-invasive Advances in Fetal and Neonatal Evaluation Network, a European Union Framework VI network of excellence is described. We demonstrate how this network facilitates the implementation of non-invasive prenatal diagnosis (NIPD) for single gene disorders, fetal rhesus typing, aneuploidy and pregnancy complications. Copyright © 2008 John Wiley & Sons, Ltd.     

The time of appearance and disappearance of fetal DNA from the maternal circulation

A single copy Y-chromosome DNA sequence was amplified using the polymerase chain reaction (PCR) from the peripheral blood of 30 women who had achieved a pregnancy through an in vitro fertilization (IVF) programme. The time of conception was known precisely and was confirmed by serial ultrasound scans. Conceptions were dated as the number of weeks after fertilization plus 2, to give a time equivalent to the obstetric menstrual dating of the pregnancy (LMP). Y-chromosome-specific DNA was detected in all pregnancies with a male fetus (18/30). The earliest detection was at 4 weeks and 5 days, and the latest at 7 weeks and 1 day. Y-chromosome-specific sequences were no longer detected in any of the male pregnancies 8 weeks after delivery. No Y-chromosome sequences were detected in any of the pregnancies where only female babies were delivered. This demonstrates that fetal DNA appears in the maternal circulation early in the first trimester, that it can be identified in all pregnancies tested by 7 weeks, that it continues to be present throughout pregnancy, and that it has been cleared from the maternal circulation 2 months after parturition. Early non-invasive prenatal diagnosis for aneuploidies and inherited disorders will be possible in all pregnancies if fetal cells can be isolated free from maternal contamination (or identified accurately in the presence of maternal cells) without problems of contamination from previous pregnancies.     

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.     

The early diagnosis of neural tube defects

The sonographic diagnosis of fetal neural tube defects (NTDs) has been enhanced by the recognition of associated brain and skull anomalies. Previous reports have found these anomalies to be accurate in predicting spina bifida after 16 weeks' gestation, and an inverse correlation was suggested between the presence of these sonographic markers and gestational age. Therefore, we assumed that early second-trimester sonography would be at least as accurate as that performed after 16 weeks' gestation. To examine this hypothesis, we looked for the presence of these cranial sonographic markers suggestive of open NTDs in 8011 low-risk cases, using transvaginal sonography (TVS), between the 12th and 17th week of gestation (menstrual age). Fetal NTDs were identified in ten cases (l.25%o). The NTDs were cervico-cranial in three, lumbo-sacral in six, and thoracal in one of the ten cases. None of the seven cases examined was dyskaryotic. Cerebellar dysmorphism, ‘banana’ sign, cerebellar absence, and hypoplasia were detected in all the low NTDs, usually before the detection of the spinal lesion. All the sonographically diagnosed malformations were confirmed by post-abortal examination except in one case, where the patient decided to continue the pregnancy and refused follow-up. We therefore conclude that transvaginal sonographic examination of the fetal skull before the 17th week of gestation is an accurate method for the detection of low NTDs.     

Prenatal ultrasound diagnosis of rhizomelic chondrodysplasia punctata in a primigravida

Rhizomelic chondrodysplasia punctata (RCDP) is a sublethal autosomal recessive disorder characterized by skeletal dysplasia, microcephaly, mental retardation, congenital cataracts, joint contractures, skin changes, and failure to thrive. Prenatal ultrasound diagnosis has been reported during the second trimester of pregnancy. Prenatal diagnosis is also possible from the first trimester onwards by demonstration of peroxisomal dysfunction in cultured chorionic villous or amniotic fluid cells. In all cases reported hitherto, the prenatal diagnosis was established after the birth of a previous affected child. In contrast to these studies in pregnant multiparous women at risk for RCDP, we report on the first case of prenatal ultrasound diagnosis of RCDP at 19 weeks' gestation in a primigravida. In addition, a complex cardiac malformation associated with hypoplasia of the thymus (DiGeorge anomaly) is described.     

Trisomy 16 fetus surviving into the second trimester

A 27-year-old gravida 4, para 3 was found to have anhydramnios at 14 weeks' gestation following a size/date discrepancy noted at her routine prenatal visit. A detailed ultrasound revealed multiple fetal anomalies including congenital heart defect, chest hypoplasia, and bilateral dysplastic kidneys. Karyotype revealed trisomy 16 in 15/15 cells from a tissue specimen obtained from the fetal cord insertion site following elective pregnancy termination.     

Ultrasound diagnosis of structural abnormalities in the first trimester

The advances in ultrasound technology have made it possible to identify fetal structural abnormalities and genetic syndromes in the first trimester. First trimester prenatal diagnosis of fetal central nervous system, renal, gastrointestinal, cardiac, and skeletal abnormalities is reviewed. Copyright © 2002 John Wiley & Sons, Ltd.     

Hyperechoic fetal bowel: The perinatal consequences

A number of publications have reported an association between the finding of hyperechoic fetal bowel on prenatal sonogram and disorders such as aneuploidy and cystic fibrosis. To define more precisely the significance of this finding, we systematically reviewed the published material on the subject. Based on a total of 357 reported cases, we documented a high prevalence of cystic fibrosis (25·6 per cent) and chromosome abnormality (12·4 per cent) associated with increased bowel echogenicity in the fetus. High rates of intrauterine growth retardation (14·9 per cent), fetal demise (9·0 per cent), and prematurity (15·3 per cent) were also found. The data were obtained from a population at high a priori risk for aneuploidy and included fetuses at 1 in 4 risk for cystic fibrosis reported in two studies. This increased the bias towards an adverse outcome. The rate of complications when a hyperechoic abdomen is noted in a low-risk fetal population has so far not been delineated. Although the high frequency of complications found is of concern and warrants investigation, extrapolation of these risk figures to a fetal population at low a priori risk may not be appropriate.     

Prenatal diagnosis in a family with X-linked hydrocephalus

The neural cell adhesion molecule L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs). Its expression is essential during embryonic development of the nervous system and it is involved in cognitive function and memory. Mutations in the L1CAM gene are responsible for four related L1 disorders; X-linked hydrocephalus/HSAS (H ydrocephalus as a result of S tenosis of the A queduct of S ylvius), MASA (M ental retardation, A phasia, S huffling gait, and A dducted thumbs) syndrome, X-linked complicated spastic paraplegia type I (SPG1) and X-linked A genesis of the C orpus C allosum (ACC). These four disorders represent a clinical spectrum that varies both between and within families. The main clinical features of this spectrum are C orpus callosum hypoplasia, mental R etardation, A dducted thumbs, S pastic paraplegia and H ydrocephalus (CRASH syndrome). Since there is no biochemically assayed disease marker, molecular analysis of the L1CAM gene is the only means of confirming a clinical diagnosis. Most L1CAM mutations reported to date are point mutations (missense, nonsense, splice site) and only a few patients with larger rearrangements have been documented. We have characterised a rare intragenic deletion of the L1CAM gene in a sample of DNA extracted from a chorionic villus biopsy (CVB) performed at 12 weeks' gestation. Copyright © 2005 John Wiley & Sons, Ltd.     

A comparative study of prenatal ultrasound findings and post-mortem examination in a tertiary referral centre

This retrospective study compares the findings of prenatal ultrasound, performed in a tertiary fetal medicine centre, with the results of post-mortem examination in pregnancies complicated by suspected fetal abnormality that results in fetal loss. The study was carried out over a year at a teaching hospital, Fetal Medicine Centre and Regional Centre for Perinatal Pathology. Results were directly compared and the level of agreement between the ultrasound and post-mortem findings described. These were classified as having complete agreement; major agreement or major disagreement. The group of cases with major agreement between findings was further divided into those with significant, or minor, additional findings at post-mortem examination. Over the 12-month period, 153 ultrasound cases were identified, of which 47 were also examined by autopsy and were thus suitable for comparison in this study (30.7%). Complete agreement between ultrasound and post-mortem findings was found in 22 cases (46.8%). In 24 cases (51.1%), major agreement between ultrasound and post-mortem findings was seen. Of these, 11 had minor additional findings at post-mortem examination and 13 were found to have significant additional findings at post-mortem (27.7%), adding to the eventual diagnosis. In 12.8% of cases, post-mortem examination provided a definitive diagnosis. Only in one case was there complete discordance in the findings of the ultrasound examination and the autopsy (2.1%). No major disagreement between ultrasound and post-mortem findings was seen in 98% of cases. This study confirms the accuracy of prenatal ultrasound diagnosis in specialist centres, whilst emphasising the continuing importance of post-mortem examination in cases of fetal malformation to refine and, in some cases, define the diagnosis. Copyright © 2004 John Wiley & Sons, Ltd.