A novel L1CAM mutation with L1 spectrum disorders

X-linked hydrocephalus, HSAS (hydrocephalus due to stenosis of aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs), and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) syndromes are allelic disorders. X-linked hydrocephalus and associated phenotypes are due to mutations in the L1CAM gene, which has been identified as a coding neural cell adhesion molecule. We report two cases of L1 spectrum disorders within the same family. The first case was diagnosed by ultrasonographic examination prenatally and the second case was diagnosed postnatally. Both patients and their mothers carry a novel mutation of the L1CAM gene. In this family, nine X-linked hydrocephalus and five female carriers were found in three generations, and molecular genetic analysis was performed to detect the asymptomatic carriers. Copyright © 2005 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.     

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.     

Prenatal ultrasound diagnosis of a case of Pfeiffer syndrome without cloverleaf skull and review of the literature

Pfeiffer syndrome is characterized by bilateral coronal craniosynostosis, midface hypoplasia, beaked nasal tip, broad and medially deviated thumbs and great toes. Originally, it was described in eight persons from three generations in a pedigree consistent with an autosomal dominant transmission. Since then, several reports have documented its high clinical and genetic heterogeneity. The condition is usually detected in the newborn period or later, and very few prenatal ultrasound diagnoses have been reported. We present a case of Pfeiffer syndrome prenatally diagnosed at 20 weeks' gestation, in which the sonographic features of craniosynostosis, hypertelorism associated with an extreme proptosis, and broad thumb led to the diagnosis, confirmed after termination of pregnancy by dysmorphological, pathological and radiological evaluation. DNA analysis of the fibroblast growth factor receptor 2 (FGFR2) showed a missense mutation consisting in a transversion G → C at nucleotide 870. This led to a Trp290Cys amino acidic substitution. We discuss the relevant findings of our and previously published cases. Our report demonstrates that a careful sonographic examination can lead to an early prenatal diagnosis of Pfeiffer syndrome also in cases without cloverleaf skull. Copyright © 2004 John Wiley & Sons, Ltd.     

The prenatal diagnosis of the Walker-Warburg Syndrome

On the basis of physical features and autopsy findings, a child with congenital hydrocephalus, bilateral microphthalmia, myopathy, severe developmental retardation and multiple brain malformations was diagnosed to have the Walker-Warburg Syndrome (WWS). During a subsequent pregnancy in this family, a fetus at risk for this autosomal recessive condition was evaluated with serial ultrasound examinations. At 15 weeks of gestation an encephalo-cele was noted. Disproportionately slow growth of the head compared to the body was noted at 36 weeks. At birth, the diagnosis of WWS was confirmed in the child due to the presence of microcephaly, an encephalocele, a meningocele and bilateral microphthalmia. This is the first reported case of the early prenatal diagnosis of this recently categorized genetic condition, in which the major features are hydrocephalus, multiple central nervous system malformations, microphthalmia with ocular malformations, severe psychomotor retardation, congenital myopathy and a very limited life expectancy.     

Prenatal diagnosis of X-linked hydrocephalus in a Chinese family with four successive affected pregnancies

We report on a woman with four successive pregnancies affected with X-linked hydrocephalus (XLH). The first child had prenatal craniocentesis and died in utero. The second child had a postnatal shunting operation, but suffers from severe growth and mental retardation at 5 years of age. In the third pregnancy, prenatal ultrasound detected hydrocephalus at the 16th and 20th weeks of gestation and the pregnancy was terminated. In the fourth pregnancy, ultrasound scanning at the 17th and 20th weeks of gestation revealed no remarkable findings, but hydrocephalus was detected at the 24th week. Autopsy confirmed the prenatal diagnosis. DNA polymorphism analysis of the Bell site of exons 17–18 of factor VIII gene of the woman and her last two fetuses seemed to be compatible with a linkage between the XLH locus and factor VIII gene. Although XLH has a variable presentation of ventriculomegaly, ultrasound scanning is still a useful tool for prenatal diagnosis at present. Earlier and more accurate prenatal diagnosis will be feasible with molecular analysis of the XLH locus or its flanking regions.     

Familial orofaciodigital syndrome type I revealed by ultrasound prenatal diagnosis of porencephaly

Porencephaly is a rare central nervous system (CNS) abnormality that can be caused by an intraparenchymal destructive process or a developmental defect. Here we report on a prenatal ultrasound diagnosis of complex CNS abnormalities including agenesis of the corpus callosum, agenesis of the cerebellar vermis, bilateral hydrocephaly, and bilateral porencephaly in fetus at 33 weeks' gestation. The diagnosis of familial orofaciodigital syndrome type I (OFD I) was raised after fetal autopsy, clinical examination of the family, and the X-linked dominant inheritance pattern. This is the fourth report of porencephaly in association with OFD I. We discuss the difficulties in genetic counselling since OFD I shows variable expressivity of the phenotypic features. Furthermore, we emphasize the importance of a detailed ultrasound examination after a prenatal diagnosis of porencephaly. Copyright © 2001 John Wiley & Sons, Ltd.     

Early second-trimester sonographic appearance of occipital haemangioma simulating encephalocele

Encephalocele is the most common cause of occipital midline extracranial mass associated with hydrocephalus. A case is presented where an occipital extracranial mass associated with hydrocephalus which was detected on second-trimester ultrasound examination turned out to be a haemangioma, a relatively benign lesion. We suggest that haemangioma should be considered in the differential diagnosis of extracranial masses detected prenatally.     

Prenatal sonographic diagnosis of Malpuech syndrome

Malpuech syndrome (MS) is a rare autosomal recessive syndrome featuring pre- and post-natal growth deficiency, mental retardation, facial dysmorphism, cleft lip and palate (typically midline or bilateral), caudal appendage, renal malformations and male genital abnormalities. A prenatal diagnosis of MS was made in this fetus based on the family history and a combination of conventional and 3D prenatal ultrasound findings. The family were consanguineous with an affected first child. Prenatal ultrasound in the second pregnancy demonstrated bilateral cleft lip and palate in association with intrauterine growth retardation on serial prenatal ultrasound scans. Dysmorphic facial features and a small penis consistent with the diagnosis were confirmed on 3D scanning. Post-natal examination of the neonate confirmed the diagnosis of MS. To the best of our knowledge, this is the first prenatal diagnosis of this syndrome. Copyright © 2006 John Wiley & Sons, Ltd.     

Prenatal diagnosis of Pfeiffer syndrome type II

Pfeiffer syndrome is an autosomal dominant disorder characterized by coronal craniosynostosis, midface hypoplasia, broad thumbs and great toes. On the basis of clinical findings, three subtypes have been delineated. The clinical variability of Pfeiffer syndrome as well as other causes of craniosynostosis can make a prenatal diagnosis based on sonography alone difficult. We describe a fetus in whom sonographic findings (including 3D ultrasound) suggested a Pfeiffer syndrome type II and in which subsequent molecular analysis verified the diagnosis by identifying a de novo mutation in the FGFR2 gene. To the best of our knowledge, this is the first report of a prenatal molecular diagnosis of Pfeiffer syndrome in a patient without family history. Copyright © 2004 John Wiley & Sons, Ltd.     

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.     

Magnetic resonance imaging of the fetus: A study of 20 cases performed without curarization

Twenty patients underwent magnetic resonance imaging (MRI) at a mean gestational age of 32 weeks. There were 12 patients with suspected fetal brain abnormality and four with intrauterine growth retardation (IUGR), while the remaining four cases were studied for other reasons. The MRI examinations were performed on a 0.5 Tesla machine, with surface coils. One minute acquisition time T1 sequences were used. All the studies were performed without fetal curarization, and only under maternal sedation using flunitrazepam given per os 1 h before MRI examination. Three examinations were incomplete because of fetal movement artefacts. In the remaining cases, MRI allowed the examination of fetal brain anatomy. In five cases, it helped to differentiate isolated hydrocephalus and corpus callosum agenesis. Sub-ependymal nodules were depicted in a case of fetal tuberous sclerosis. One suspected arachnoid cyst was proved to be an ultrasound artefact. Decreased fetal fat on MR images was correlated with low birth weight in cases of IUGR. Due to its better spatial resolution, ultrasonography was more accurate for the diagnosis of facial and lumbar anomalies. Fetal MRI may be performed without curarization. Surface coils allow the detailed analysis of brain parenchyma, and thus MRI is especially useful in the difficult prenatal diagnosis of fetal brain abnormalities.     

Fetal toxoplasmosis and negative amniocentesis: necessity of an ultrasound follow-up

Prenatal diagnosis of congenital toxoplasmosis relies on the PCR test on amniotic fluid and ultrasound follow-up of the fetus. We report two cases of toxoplasma infection during the first trimester of gestation with a discrepant diagnosis of fetal infection. PCR performed more than four weeks after the estimated date of contamination was negative. Ultrasound follow-up was normal up to the third trimester when major hydrocephalus was detected, leading to pregnancy termination. In both cases, post-mortem examination revealed a diffuse infection with severe brain lesions. These observations confirm the necessity to continue a monthly ultrasound follow-up, even if amniocentesis is negative, in case of fetal toxoplasma infection in pregnancy. Copyright © 2003 John Wiley & Sons, Ltd.     

The prenatal diagnosis of joubert's syndrome of familial agenesis of the cerebellar vermis

The prenatal diagnosis by ultrasound examination of Joubert's syndrome of familial agenesis of the cerebellar vermis is described allowing termination of pregnancy ai 26 weeks gestation. The diagnosis was made by a comparison of the prenatal ultrasound examination with computerized axial tomography obtained from the siblings with the same condition.     

Fetal hydrops caused by a novel pathogenic MECOM variant

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post-mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post-mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss-of-function variant in MECOM (NM_004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). RUSAT-2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT-2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post-mortem examination, and of using a broad sequencing approach.     

Prenatal diagnosis of Joubert syndrome: a case report

Joubert syndrome is a rare, autosomal recessive condition, first described by Joubert in 1969. We present a case of Joubert syndrome from a consanguineous family in which, apart from the cerebellar vermis agenesis, ventriculomegaly, bilateral postaxial polydactyly of hands and right foot and micropenis, episodes of fetal breathing pattern with an increased respiratory rate were also demonstrated by prenatal ultrasound scan. At birth the infant showed an odd face and bilateral fleshy nodules of the tongue. He had an abnormal breathing pattern of alternating tachypnea and apnea. Cranial MRI showed molar tooth sign, hydrocephalus and Dandy–Walker malformation. He had nystagmus, and electroretinography showed retinal dystrophy. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal sonographic diagnosis of autosomal recessive polycystic kidney disease (arpkd) during the early second trimester

Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary disease with a high neonatal mortality. Currently, prenatal diagnosis is possible only during the second half of pregnancy, when bilaterally enlarged, echogenic kidneys are visible by ultrasound. We describe a case in which a diagnosis of ARPKD was sought in the first half of pregnancy. High-resolution ultrasonography revealed echogenic, normal-sized kidneys at 15+4 weeks. Microsatellite DNA analysis of a chorionic villus sample, parental blood, and blood of an affected sibling showed that the fetus had the maternal haplotype and a recombination of the paternal haplotype. Thus, no distinction between homo- and heterozygosity for the ARPKD mutation in the fetus was possible. A further ultrasound examination at 19+4 weeks confirmed the previous results, indicating that the fetus was likely to be affected. After termination of the pregnancy, the diagnosis was confirmed on microscopic examination.     

Prenatal diagnosis of de novo (7;19)(q11.2;q13.3) translocation associated with a thick corpus callosum and Wilms tumor of the kidneys

We present a case of prenatal diagnosis of a de novo (7;19)(q11.2;q13.3) translocation associated with ultrasound features, including enlarged cisterna magna, normal vermis, thick corpus callosum, micrognathia, small and low-set ears and right hyperechogenic kidney. Karyotyping was performed at 24 weeks of gestation. Termination of pregnancy was accepted at the parents' request. Postmortem examination confirmed the prenatal findings, but revealed bilateral Wilms tumors of the kidneys. Parental karyotype was normal. Copyright © 2005 John Wiley & Sons, Ltd.     

Trisomy 10: ultrasound features and natural history after first trimester diagnosis

We report on the ultrasound features and natural history of trisomy 10. At 12 weeks' gestation in a routine scan examination, the fetus presented with increased nuchal translucency thickness, mild skin oedema, bilateral pleural effusion, marked micrognathia, cardiomegaly, unilateral talipes and reversed A-wave in the ductus venosus blood flow. Karyotyping on chorionic villus sampling (CVS) led to the diagnosis of trisomy 10, which was confirmed by fetal blood sampling at 22 weeks' gestation. As the parents opted to continue with the pregnancy, the natural history and following ultrasound features are described. This is the third case of trisomy 10 in the literature reporting on the physical features. The most frequent ultrasound findings presented in trisomy 10 are increased nuchal translucency, micrognathia, renal agenesis, facial cleft, limbabnormalities, cardiac defects and early severe growth retardation. Copyright © 2001 John Wiley & Sons, Ltd.     

Prenatal diagnosis of fetal glioblastoma multiforme

Intracerebral tumours of the fetus are very rare conditions, most often presenting clinically as polyhydramnios and hydrocephalus. These conditions can be diagnosed with ultrasound and clearly differentiated from hydrocephalus and other intracranial lesions. The following report is of a case of an intracerebral tumour (glioblastoma multiforme) diagnosed at 33 weeks in utero using ultrasound. The prognosis for this condition is universally poor.