Lesch—Nyhan syndrome: Carrier and prenatal diagnosis

We report the results of carrier and prenatal diagnosis for hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency, Lesch—Nyhan syndrome, by carrier testing of 83 women and prenatal analysis of 26 pregnancies. Our diagnostic methodologies include mutation detection and linkage analysis for probands and their families and biochemical measurement of HPRT enzyme activity for at-risk pregnancies. Identification of the mutation in the index case of each family permits precise carrier diagnosis using polymerase chain reaction (PCR) amplification of HPRT gene sequences and automated DNA sequencing. We demonstrate 100 per cent sensitivity for the detection of mutations in the HPRT gene of affected males and highly efficient carrier testing of at-risk females. Two other molecular methods proven to have high utility include PCR-based dosage analysis and linkage analysis by PCR amplification of a short tandem repeat (STR) in intron 3 of the HPRT gene. As a result, 45 at-risk women, 56 per cent of those tested, were identified not to be carriers of their family's HPRT gene mutation. Seven of these women were the mothers of affected males and prenatal testing for future pregnancies was recommended because of the possibility of gonadal mosaicism. Thirty-eight of these women were more distant relatives of affected males, thereby eliminating the need for future prenatal procedures. These studies illustrate the utility and precision of molecular methodologies for carrier and prenatal diagnosis of Lesch—Nyhan syndrome. These studies also illustrate that molecular diagnostic studies of affected males and carrier testing prior to pregnancy can clarify genetic risk predictions and eliminate unnecessary prenatal procedures.     

Three-dimensional ultrasound in prenatal diagnosis of skeletal dysplasia

A lethal form of bone dysplasia, platylospondylic lethal chondrodysplasia, was diagnosed prenatally using three-dimensional ultrasound. The various types of three-dimensional imaging mode provided diagnostic details not available by conventional two-dimensional ultrasound. The diagnosis was made after referral in the 23rd week of gestation, allowing termination of pregnancy due to the poor prognosis. Prenatal sonograms were compared with postnatal radiographs.     

Prenatal prediction in families with autosomal recessive proximal spinal muscular atrophy (5q11.2–q13.3): Molecular genetics and clinical experience in 109 cases

Prenatal prediction in families at risk for autosomal recessive proximal spinal muscular atrophy (SMA) mainly of type I is often requested due to the high incidence and the fatal outcome of the disease. So far, only indirect genotype analysis can be performed in SMA families, since the gene has not yet been identified. We present our experience of 109 prenatal diagnoses obtained in 91 families by use of single- and multi-locus polymorphic microsatellites of the region 5q11.2–q13.3. The marker combinations and specific features of the closest microsatellites are described in detail. From 137 requests for prenatal prediction of SMA between October 1991 and August 1994, 28 families were excluded, mostly because the clinical diagnosis was uncertain or doubtful. Others had to be classified as ‘SMA-variants’ or showed autosomal dominant transmission of SMA. Of the 109 prenatal diagnoses performed, 29 fetuses were diagnosed to be at high risk (>99 per cent) of developing the disease, while in seven additional pregnancies no exact prediction could be made due to a recombination event in one parental haplotype. Altogether, recombinations between closely flanking markers were observed in 14 cases. In 35 cases, the parents decided to terminate the pregnancy. Of the remaining pregnancies, 32 could be followed beyond term. All infants were reported to develop normally without signs of SMA. Two children were born with transverse reduction defects of one hand, which was most likely related to early chorionic villus sampling at 9 and 10 weeks' gestation. No further abnormalities could be detected. The limits of indirect genotype analysis and the problems of diagnostic accuracy and heterogeneity of proximal SMA are discussed.     

Short-rib polydactyly syndrome (SRPS) type III diagnosed during routine prenatal ultrasonographic screening. A case report

The prenatal diagnosis of skeletal dysplasias is often initiated by the finding of a shortened extremity during a routine sonographic examination. Second-trimester diagnosis of these anomalies allows the couple to consider the option of terminating a pregnancy when a lethal anomaly is detected. A 21-year-old Bedouin woman underwent routine ultrasonographic screening at 20 weeks' gestation. Severe micromelia, a narrow thorax with shortened ribs, and postaxial polydactyly were detected. The patient delivered a male dwarf at 20 weeks' gestation following prostaglandin induction of labour for a diagnosis of short-rib polydactyly syndrome type III. The prenatal ultrasonographic diagnosis of short-rib polydactyly syndrome type III was made at 20 weeks' gestation, allowing termination of the pregnancy. A proper sonographic approach to skeletal dysplasias allows both early detection and differentiation between lethal and non-lethal anomalies.     

Prenatal analysis of the insulin receptor gene in a family with leprechaunism

We report on the prenatal diagnosis of a fetus at risk of leprechaunism. We had previously determined the nature of the causative mutation in the insulin receptor gene in this family. The mutation removes a restriction site for the enzyme Mbo II. Genomic DNA was extracted from a chorionic villus sample and the 3′ half of exon 2 was amplified by the polymerase chain reaction (PCR) followed by restriction digest. Using this method, we correctly predicted an unaffected child.     

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.     

Cardiac flow after fetal blood sampling in normally grown and growth-retarded fetuses

The objective of this study was to evaluate the effect of fetal blood sampling on cardiac flow velocity waveforms. Flow velocity waveforms were measured from the ascending aorta and pulmonary artery immediately before and after fetal blood sampling in 29 normally grown and 12 growth-retarded fetuses. The latter group was characterized by abnormal Doppler indices in the umbilical artery and middle cerebral artery suggestive of uteroplacental insufficiency as the causative factor of the impaired growth. The flow velocity parameters studied were the peak velocity, the time to peak velocity, and the left and right cardiac output and their ratio. In normally grown fetuses, the peak velocity and right and left cardiac output values increased significantly after fetal blood sampling, while no significant changes were observed in the other indices considered. The gestational age at the time of the procedure was positively related to the amplitude of these changes. In growth-retarded fetuses, fetal blood sampling did not induce any significant increase in cardiac output or peak velocities, while in more than 50 per cent of the fetuses these Doppler indices decreased. The amplitude of the decrease was significantly related to the severity of acidosis in the umbilical vein. In conclusion, the cardiac haemodynamic response to fetal blood sampling differs between normally grown and growth-retarded fetuses. This difference may explain the higher rate of complications occurring in the latter group of fetuses after blood sampling.     

Prenatal analysis of the insulin receptor gene in a family with leprechaunism

Leprechaunism is an autosomal recessive disease characterized by intrauterine and postnatal growth restriction, loss of glucose homeostasis, and severe insulin resistance. This disease is caused by a failure of function of the insulin receptor and is lethal early in life. Here we report the prenatal diagnosis of leprechaunism in one consanguineous family, Atl-1, in which two homozygous-affected siblings died with leprechaunism. The mutation in their insulin receptor impaired insulin binding and altered receptor signalling. Prenatal diagnosis could not be accomplished using insulin binding to cultured amniocytes, but was possible using mutational analysis of the insulin receptor gene in DNA from amniotic cells.     

Paralytic ileus in a fetus–neonate after maternal intake of benzodiazepine

Paralytic ileus of the small bowel was diagnosed in a fetus at 32 weeks' gestation after referral because of polyhydramnios. The mother had taken clonazepam, a benzodiazepine, and carbamazepine during the entire pregnancy for epilepsy. All known causes for the ileus were ruled out and at 20 months the boy has developed normally. We conclude that maternal anticonvulsant drug intake was very likely the cause of the paralytic ileus. This side-effect is known in experimental and clinical pharmacology but has not yet been described in human fetuses.