Prenatal diagnosis of neurofibromatosis type 1: sonographic and MRI findings

Prenatal ultrasound and magnetic resonance imaging (MRI) demonstrated a large oropharyngeal tumor, and cardiac and cranial abnormalities consistent with neurofibromatosis type 1 (NF1) in a third-trimester fetus, which were confirmed on postmortem examination. Sonographic features of NF1 are generally nonspecific; MR examination provided significant additional information, facilitating prenatal diagnosis. Copyright © 2006 John Wiley & Sons, Ltd.     

Prenatal diagnosis of friedreich ataxia: Improved accuracy by using new genetic flanking markers

Friedreich ataxia is a neurodegerative disorder with autosomal recessive inheritance. Since the gene causing mutation has not yet been identified, prenatal, predictive, and carrier diagnoses are based on indirect haplotype analysis with closely linked markers. Until recently, only distal markers were available and their physical distance to the Friedreich ataxia (FRDA) gene remained elusive. The identification of close flanking markers that mark out the boundaries of the FRDA locus and reduce the critical genomic region which contains the gene allows for the first time misdiagnosis due to undetectable recombination to be avoided and diagnosis accuracy to be greatly improved. In this sense, we have verified a prenatal diagnosis in which the fetus was diagnosed as an unaffected carrier last year with a confidence of 95 per cent. By using the new flanking markers, the diagnosis improved and confidence reached almost 100 per cent.     

Prenatal diagnosis of complete sole trisomy 1q

The prenatal diagnosis of a complete trisomy of the long arm of chromosome 1 is reported. Major ultrasound findings included: nuchal thickening, bi-temporal narrowing, a single choroid plexus cyst, andmild ventriculomegaly. There was a mass in the chest and abdomen, pleural effusion, ascites and a hyperechoic bowel. Skin edema was present. The fetus died at 26 weeks' gestation. A literature review is presented of 17 de novo and two inherited cases with only trisomy 1q. Of note is the fact that 3/5 prenatally detected 1q trisomies have teratomas. A review of the literature reveals a dismal outcome fortrisomy 1q cases if the duplication involves bands 1q25→q32. Copyright © 2001 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.     

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.     

First application of preimplantation genetic diagnosis to neurofibromatosis type 2 (NF2)

Neurofibromatosis type 2 (NF2) is a dominantly inherited cancer predisposition syndrome that is caused bymutations in the NF2 gene. We report here the first clinical preimplantation genetic diagnosis (PGD) forNF2. A protocol was developed to simultaneously amplify the mutation and a single nucleotide polymorphism (SNP) located within the gene. The mutation and polymorphism were analysed by simultaneous fluorescent single-strand conformation polymorphism (SSCP) on an automated DNA sequencer. The mutation, carried by the male partner, was a single base pair substitution affecting a splice site in intron 4 of the gene. The female partner was infertile due to polycystic ovary syndrome and would require IVF to conceive. The couple was found to be informative at a linked intragenic SNP situated in the 5′ untranslated region of the gene. The SNP was included in the assay to reduce the risk of misdiagnosis due to allele dropout (ADO). The couple underwent three cycles of treatment during which a total of 43 blastomeres were biopsied from 31 embryos. Amplification at both loci was obtained in 35 cells (81%). A total of five embryos were transferred, two in the first cycle, two in the second and one in the third. No pregnancy ensued. The results of the diagnoses indicated that, in this couple, the inheritance of the mutation may be non-Mendelian. Out of a total of 32 embryos tested only four were found not to carry the mutation. The reasons for this apparent skew remain unknown. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis and prenatal imaging features of fetal monosomy 1p36

Deletion of the distal end of the short arm of chromosome 1 (1p36) is thought to be a common terminal chromosomal deletion. However, few cases prospectively diagnosed prenatally have been reported. In this case, prenatal ultrasound at 21 weeks of gestation noted the fetus to have mild ventriculomegaly (Vhanterior = 11 mm and Vhposterior = 12 mm) and increased nuchal edema (6 mm). Maternal serum α-fetoprotein was normal unlike in a majority of previously described cases. The prenatal ultrasound features were further clarified with fetal MRI. Chromosome analysis following amniocentesis demonstrated a 1p36 deletion, which was confirmed by fluorescence in situ hybridization (FISH). The syndrome associated with 1p36 deletion is well described in infants and is characterized by typical facial features (prominent forehead, straight eyebrows. deep-set eyes, flat nasal bridge and a pointed chin). Other associated features are neurodevelopmental delay, seizures, cardiomyopathy and neurosensory hearing impairment. This case supplements our knowledge of the prenatal features of 1p36. Identification of this deletion by direct chromosomal analysis can be technically difficult and vigilance is required to improve diagnosis. FISH analysis is an important diagnostic adjunct where the diagnosis is suspected following classical G-banding techniques. However, in this chromosomal anomaly there remain few characteristic prenatal signs that are readily diagnosed with prenatal imaging. Copyright © 2007 John Wiley & Sons, Ltd.     

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 diagnosis of werdnig-hoffmann disease: DNA analysis of a mummified umbilical cord using closely linked microsatellite markers

We present a case of prenatal diagnosis of Werdnig-Hoffmann disease, the most severe type of spinal muscular atrophy (SMA). DNA obtained from a mummified umbilical cord of a deceased affected brother of the index case was analysed with four closely linked microsatellite markers [EF1/2a and EF13/14 (D5S125), MAP1B, and JK53CA (D5S112)], flanking the SMA gene, on chromosome 5q11·2-13·3. The fetus was diagnosed as homozygous for the deleterious SMA gene.     

Prenatal diagnosis of autosomal recessive osteopetrosis,infantile type,by X-ray evaluation

Prenatal diagnosis for infantile osteopetrosis was attempted during the third pregnancy of a first-cousin marriage whose family history revealed an affected previous child. At the 25th week of pregnancy, fetal X-ray evaluation revealed marked sclerosis of osteopetrotic bone and metaphyseal splaying and clubbing of both femurs. The pregnancy was terminated and repeated X-rays and histopathological examination of fetal bone (femur) confirmed the diagnosis.     

Prenatal diagnosis of osteogenesis imperfecta type III

Ultrasonographic and radiographic evaluation of a fetus at risk for osteogenesis imperfecta (O.I) type III was performed. Real-time ultrasound measurements at 15 weeks gestation were interpreted as normal, but at 20 and 22 weeks of gestation revealed marked shortening of the long bones and deformity of the femurs. The findings were confirmed by fetal radiography at 22 weeks gestation. Radiographic and histologic changes characteristic of O.I. were observed in the aborted fetus. Thus the antenatal manifestations of O.I. type III maybe severe enough to make prenatal diagnosis possible in the second trimester for families at risk for recurrence of this disorder.     

Prenatal diagnosis of extrahepatic biliary duct atresia

A rare case of extrahepatic biliary atresia was diagnosed by a combination of prenatal ultrasound and measurements of fetal digestive enzymes in amniotic fluid. Ultrasound at 15 and 18 weeks' gestation failed to detect the gall bladder, and amniotic fluid digestive enzyme values were below the fifth percentile. The patient decided to terminate the pregnancy. Post-abortal pathological examination confirmed the diagnosis. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis of a fetus with pure partial trisomy 1q32-44 due to a familial balanced rearrangement

We diagnosed a pure partial trisomy of the long arm of chromosome 1 in a fetus with multiple malformations detected prenatally. The father was a carrier of a balanced rearrangement involving 46,XY,inv(1)(qter→p36::q32→qter::p36→q32). The fetus had preaxial polydactyly, low-set ears, macrocephaly, a prominent forehead, a broad and flat nasal bridge, a small mouth, an arched palate, micrognathia and unilateral renal agenesis. The couple had previously an infant with the same phenotypic abnormalities. The aberration was initially detected on amniocentesis with GTG banding and was confirmed by fluorescence in situ hybridization (FISH). Our case and other published pure trisomy 1q32-44 cases showed similarities, which allowed the further delineation of the trisomy 1q syndrome. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis for women aged 37 years and over: to have or not to have

Forty percent of pregnant women aged 37 years and over do not have prenatal diagnosis despite being eligible for a free test. The present study aimed to determine how often, and which, untested women were making a choice about this, how many declined an offer and why. A questionnaire was given to untested women, aged 37 years and over, at no less than 24 weeks gestation. A total of 375 (81.5%) women declined, 72 (16%) were not offered a test and 13 presented too late antenatally. There was a three-fold increased likelihood (OR 3.10 95% CI 1.44, 6.65) of no offer for urban non-English speaking background women, compared with the reference group (metropolitan, English speaking). Unpartnered women were also significantly less likely to receive an offer (OR 3.18, 95% CI 1.19, 8.46). Risk to the baby was the main reason for declining. When offered non-invasive prenatal screening, most decliners of prenatal diagnosis accepted, even those who declined because they were opposed to abortion. We estimate that overall 33% of older pregnant women were being offered and declining amniocentesis and/or chorion villus sampling (CVS). Only 6% were not offered a test, but this small proportion is over-represented by minority groups who must be given equal opportunity to make this choice. Copyright © 2001 John Wiley & Sons, Ltd.