Prenatal diagnosis of β thalassaemia by reverse phase HPLC

Reverse phase HPLC of radioactive globin chains has been compared to classical carboxy methyl cellulose chromatography for the prenatal diagnosis of β thalassaemia. The two methods correlated highly (r = 0.97 p < 0.0005) and provided an identical diagnosis for 40 fetal blood samples of fetuses homozygous or heterozygous for β thalassaemia. The HPLC procedure was much faster and required fewer biochemical steps (no globin preparation). It was at least as accurate and more sensitive than the classical chromatography. A single column can be used for 150 analyses and is always ready to be used. Last but not least it is much less expensive than CMC chromatography.     

Selective survival of only the healthy fetus following prenatal diagnosis of thalassaemia major in binovular twin gestation

Selective feticide is the procedure of choice when, in twin binovular pregnancy, only one of the fetuses is shown to be affected. As the probabilities for this condition are almost 1:2 when the genetic disease is due to homozygosity for two autosomal recessive genes, the problem is expected to occur frequently among the ever increasing number of couples seeking prenatal diagnosis of thalassaemia and the haemoglobinopathies. The present report is the first case of this condition and the ninth in the overall medical literature.     

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.     

Prenatal diagnosis of haemoglobin disorders by cordocentesis at 12 weeks' gestation

Prenatal diagnosis of haemoglobin disorders is accepted to be a useful procedure to avoid births of infants with homozygous diseases. Advances in sampling and molecular techniques, such as polymerase chain reaction (PCR) and chorionic villus sampling (CVS), have made earlier and safer first-trimester prenatal diagnosis possible. However, these procedures need previous studies of at-risk couples, which can be very time-consuming when a number of different β-thalassaemia mutations occur in the region. We describe the possibility of making a first-trimester prenatal diagnosis by cordocentesis and fetal blood analysis at the 12th week of gestation. We found no statistically significant difference (p>0.05) between β/γ values in fetuses at the 12th and 18th weeks of gestation. In seven affected fetuses aborted at the 12th week of gestation, the diagnosis was confirmed in all cases by PCR analysis. These findings suggest that early cordocentesis could be an alternative procedure to CVS and PCR analysis.     

Prenatal diagnosis of isolated bilateral microphthalmia with confirmation by evaluation of products of conception obtained by dilation and evacuation

We describe the prenatal diagnosis of isolated bilateral fetal microphthalmia in a woman at increased risk of having a fetus with microphthalmia. Ultrasound examinations at 161 and 19-5 weeks' gestation demonstrated bilateral fetal microphthalmia with no other associated structural defects. The patient elected to terminate her pregnancy at 19.5 weeks. Pathological evaluation of the products of conception obtained by dilation and evacuation confirmed the prenatal diagnosis of isolated bilateral fetal microphthalmia.     

Prenatal diagnosis of campomelic dysplasia by ultrasonography

Consanguineous partners had a boy with campomelic dysplasia who died of increasing respiratory distress soon after birth. The next pregnancy was monitored frequently by ultrasonography and a healthy male infant was born at term. During a further pregnancy, ultrasonography suggested campomelic dysplasia in the 16th week of gestation. This was confirmed in the 18th week. The pregnancy was terminated and the fetus showed the typical radiological, anatomical and histological findings.     

Prenatal diagnosis of an intra-abdominal sacrococcygeal teratoma

The prenatal diagnosis of a presacral (type IV) sacrococcygeal teratoma (SCT) is described. The initial ultrasound appearance was suggestive of a lower urinary tract obstruction, but further ultrasonic examination and radiological imaging using contrast medium led to the diagnosis of SCT. This is the first prenatal diagnosis of a totally intra-abdominal SCT.     

Prenatal diagnosis of autosomal dominant microcephaly and postnatal evaluation with magnetic resonance imaging

A case of fetal autosomal dominant microcephaly was prenatally diagnosed with ultrasonography in a woman with previously undiagnosed microcephaly. At the time of initial ultrasonographic assessment, the mother was identified to have a markedly small cranium, consistent with maternal microcephaly. The ultrasonographic examination showed the fetal head size to be four standard deviations below the mean for gestational age. Gesta-tional dating from the other biometric parameters and from the last menstrual period was consistent with 31 weeks' gestation. Neurosonographic evaluation of the fetus revealed no obvious structural abnormalities. Serial ultrasonographic examinations at 35 and 38 weeks' gestation showed no changes in the fetal head size. A 2·64 kg male fetus was delivered at term. Neonatal assessment showed the fetal head circumference to be less than the second percentile for gestational age. Neurologic assessment of the neonate with magnetic resonance imaging showed abnormal development of the brain, with small cerebellar and cerebral hemispheres, and pachygyria. These images are compared with the magnetic resonance images of the mother. Our findings of maternal and fetal microcephaly are consistent with autosomal dominant microcephaly. To our knowledge, this is the first report of the prenatal diagnosis of autosomal dominant microcephaly.     

Prenatal diagnosis of the pterygium syndrome

We report two second trimester pregnancy terminations in the same woman following intrauterine ultrasonic findings of hydrops fetalis, polyhydramnios, lack of fetal movements, and short, fixed malformed limbs. One fetus also showed a cystic mass at the back of the head. Radiographic and anatomic studies of the fetuses demonstrated multiple pterygia, flexion contracture of multiple joints, abnormal facial appearance, cleft palate, pulmonary hypoplasia, and gracile bones. The cystic mass of the back of the head was found to be a cystic hygroma. These findings are consistent with the lethal variant of multiple pterygium syndrome. Early prenatal diagnosis of this condition is possible using ultrasonography.     

Prenatal diagnosis of exencephaly

This paper presents a sonographic diagnosis of exencephaly made during the last trimester of gestation. The sonogram showed the absence of bones in the cranial vault together with the presence of a disorganized cerebral mass, with loss of its normal anatomy. Post-partum examination of the newborn confirmed the findings of the sonogram. We briefly review the characteristics of exencephaly, its aetiology, and its relationship to anencephaly.     

Prenatal diagnosis of PIBIDS

In a well-documented PIBIDS family, two investigations of DNA excision repair showed a severe defect in lymphocytes from the index case (residual repair activities were 10.6–12.1 per cent). The values for the mother, father, and sister were within the normal range when compared with a healthy control. In the pregnant mother, a prenatal diagnosis of PIBIDS was made by measuring UV-induced unscheduled DNA synthesis in cultivated amniotic fluid cells. Results ranged between 12.5 and 26.1 per cent depending on the UV doses applied and were consistent with an affected fetus. The parents opted for a termination of pregnancy. Following a therapeutic abortion, fetal skin fibroblasts were tested and showed a severe DNA excision-repair defect of 9.2–13.5 per cent of residual activity.     

Prenatal diagnosis of hypochondroplasia

Prenatal diagnosis of a fetus at risk for hypochondroplasia, a short limb dwarfism condition similar to achondroplasia, was performed by ultrasound at 22 weeks' gestation. The limb bones were measured and shown to be decreased in length. The pregnancy was terminated. Post abortion X-ray did not show caudal narrowing in the lumbar spine but the pelvis had the features of hypochondroplasia.     

Prenatal diagnosis of tetrasomy 21

Amniocentesis and prenatal diagnosis were done for late maternal age and an abnormality consistent with Tetrasomy 21 (47,XX,+t(21;21)) was found in every cell examined of the initial amniotic fluid. Clinical examination revealed a fetus with many of the signs of Down Syndrome and pathological examination revealed gross abnormalities of the internal structures. Follow-up tissues showed mosaic Tetrasomy 21.     

Prenatal diagnosis of pelvic kidney

A 30-year-old woman had serial ultrasound scans from 28 weeks' gestation which revealed the presence of a cystic area in the fetal pelvis. The ‘cyst’ remained unchanged until delivery at 41 weeks. Fetal growth and amniotic fluid volume were normal throughout. A pelvic kidney was confirmed at birth. The differential diagnosis and antenatal management of this ‘cyst’ are discussed.     

Prenatal diagnosis of genetic microcephaly

True microcephaly can be diagnosed at an early stage of gestation by serial measurements of fetal head growth as demonstrated by this case report in which the diagnosis of genetic microcephaly was made but termination refused. True microcephaly was evident at birth.     

Prenatal diagnosis of chromosome mosaicism

The frequency of mosaicism and pseudomosaicism in the prenatal diagnosis of cytogenetic disorders is reported, based on 3000 pregnancies studied in our laboratory. Diagnosis of true mosaicism was only made when an abnomality was detected in two or more independent cultures established from an amniotic fluid sample. On this basis, 0.37 per cent of all cases were diagnosed as true mosaics. 1.07 per cent of all cases had pseudomosaicism involving more than one cell from the same culture with an identical abnormality. 4.13 per cent of cases had a single abnormal cell with an extra chromosome, loss of a sex chromosome (or part of a sex chromosome), or translocation. Details of the outcome and follow-up of cases is given. Particularly problematical were cases where multiple cells from one culture contained an abnormality which could have been clinically significant. A crude estimate of the extent to which true mosaicism might currently be misinterpreted as pseudomosaicism or entirely missed has been made, based on data from the U.S. survey (Hsu and Perlis, in press). It was concluded that even when two, and if necessary a third culture is extensively analysed with an average of 24 cells per culture counted, at least 4.5 per cent of cases of true mosaicism may be completely missed and at least 7 per cent could be misdiagnosed as pseudomosaicism. There is an urgent need for improved laboratory techniques which allow growth of a greater number of cell colonies and therefore a more broadly based analysis. Detailed long term follow-up of prenatally diagnosed mosaics is also essential for assessing the clinical significance of the laboratory findings.     

Mucolipidosis IV: Prenatal diagnosis by electron microscopy

Mucolipidosis IV (ML 1V) is a lysosomal storage disease presenting in infancy with cloudy cornea and psychomotor retardation. Our experience with 12 pregnancies at risk for ML IV, monitored by transmission electron microscopy (TEM) studies of cultured amniotic fluid cells, is presented. The prenatal diagnoses were confirmed in the 3 affected and the 8 un- affected pregnancies. In the one pregnancy where no definite diagnosis was reached the pregnancy was terminated. TEM examination of fetal tissues from this pregnancy showed no abnormal lysosomal storage bodies and a review of the cultured amniotic fluid cell sections revealed that the diagnosis of a normal fetus could have been made.     

Prenatal diagnosis of dyssegmental dwarfism

Fetal ultrasound evaluations at 18 weeks gestation on two consecutive pregnancies of a woman who previously gave birth to a stillborn female affected with dyssegmental dwarfism, resulted in accurate diagnoses of unaffected and affected fetuses. Marked disorganization of vertebral bodies and associated encephalocele found in two affected cases in this family are consistent with the original observation of this new syndrome as two major aspects which differentiate it from other forms of lethal dwarfism.     

Prenatal diagnosis of mandibulofacial dysostosis

Four fetuses at risk of the autosomal dominant Treacher—Collins syndrome were examined by fetoscopy in the second trimester of pregnancy. Findings were normal in two cases and healthy babies were delivered after uneventful pregnancies. Mandibular hypoplasia and abnormalities of the palpebra and auricles were seen in the other two fetuses; one had an associated cleft palate. These pregnancies were terminated and the diagnoses confirmed by post-mortem examination.