Prenatal diagnosis of citrullinaemia: Review of a 10-year experience including recent use of DNA analysis

Prenatal diagnosis of citrullinaemia has been accomplished by three different methods to date: (1) enzyme assay of cultured fetal cells; (2) quantification of citrullirie in amniotic fluid supernatant; and (3) incorporation of [¹⁴C]citrulline into protein by cultured fetal cells. Our laboratory has used these methods to perform prenatal diagnosis for 28 fetuses over a 10-year period. More recently, DNA polymorphisms were used for prenatal diagnosis by linkage analysis. Of the 28 fetuses studied, 23 were predicted to be unaffected, four were predicted to be affected, and results were conflicting in one case where [¹⁴C]citrulline incorporation erroneously indicated an affected fetus but linkage analysis correctly predicted an unaffected fetus. Because of low levels of enzyme activity in heterozygotes and in certain amniotic fluid cell types, biochemical diagnosis of citrullinaemia is complicated by the risk of false affected results, although [¹⁴C]citrulline incorporation is relatively reliable. When informative, linkage analysis is the preferable method for cases with a 25 per cent risk. The risk of false affected results makes prenatal diagnosis for cases with less than 25 per cent risk of questionable value.     

First-trimester prenatal diagnosis of hypophosphatasia: Experience with 16 cases

We have carried out first-trimester prenatal diagnosis of hypophosphatasia in 1 6 pregnancies with a 1 in 4 risk of this condition. The liver/bone/kidney isoenzyme of alkaline phosphatase was measured in chorionic villus samples using a specific monoclonal antibody and an enzymatic amplification system. Fifteen of the 16 pregnancies were correctly predicted, while one has been lost to follow up. We suggest that this assay system is likely to be superior to DNA-base methods for the first-trimester prenatal diagnosis of hypophosphatasia.     

Prenatal diagnosis of turner syndrome using cells cultured from cystic hygromas in two pregnancies with normal maternal serum alpha-fetoprotein

In two cases of prenatally detected cystic hygroma with oligohydraminos, successful cytogenetic diagnosis of Turner syndrome was achieved using cells obtained from direct aspiration of the cystic hygroma. Exceptionally high levels of alpha-fetoprotein were found in the cystic hygroma fluid, as might be expected. However, the maternal serum alpha-fetoprotein levels were within normal limits. Elevated alpha-fetoprotein levels in ‘amniotic fluid’ noted previously in the literature may have resulted because of inadvertent tapping of the cystic hygroma. It is clear from our cases that maternal serum levels of alpha-fetoprotein will not necessarily be elevated and will not serve as a screening mechanism for cystic hygromas.     

First trimester diagnosis of Wolman's disease

Wolman's disease was diagnosed in the first trimester of pregnancy by the direct demonstration of acid lipase deficiency in chorionic villi. The diagnosis was confirmed by studies on cultured chorionic villus cells and fetal skin fibroblasts. Acid lipase activity was assayed with both 4-methylumbelliferyl-palmitate and radiolabelled cholesterol oleate as substrates. The higher specificity of the enzyme for the latter, natural, substrate makes it superior in prenatal diagnosis.     

Alphafetoprotein,cholinesterases and rapidly adhering cells in the prenatal diagnosis of neural tube defects

Amniotic fluid cholinesterases tested on polyacrylamide gel and rapidly adhering cell analysis were compared in their efficiency at diagnosing fetal neural tube defects in three cases where the alphafetoprotein results were equivocal. While rapidly adhering cells were also equivocal, the cholinesterases consistently gave a clear indication of fetal abnormality.     

United states survey on chromosome mosaicism and pseudomosaicism in prenatal diagnosis

The survey of the incidence of chromosome mosaicism and pseudomosaicism detected in prenatal diagnosis included data from approximately 60 000 genetic amniocenteses in the United States. There were 59 participating cytogenetic laboratories nationwide. The overall incidence of chromosome mosaicism was 0.25 per cent (range of 0–0.89 per cent). The average frequency of pseudomosaicism involving multiple cells or clones was 0.7 per cent (range of 0–11.21 per cent). The frequency of single cell or clone pseudomosaicism was 2.47 per cent (range of 0–11.49 per cent). In cases of pseudomosaicism with trisomy, the most frequently involved chromosome was number 2; occurrence rates of trisomies 7,X,9,17 and 20 were also relatively high. In cases of pseudomosaicism with structural abnormalities, this survey showed an association between relative chromosome size and the frequency of involvement in structural rearrangement. Data on a total of 185 cases of chromosome mosaicism collected in this survey as well as from other documented sources showed 89 cases involved an autosome, 13 cases a sex chromosome, and 23 a marker chromosome. The frequency of noticeable phenotypic abnormalities was highest (37.8 per cent) in the autosomal mosaics and lowest (10.5 per cent) in the sex chromosome mosaics. The average rate for cytogenetic confirmation was 70 per cent.     

Trisomic pregnancies have normal human chorionic gonadotropin bioactivity

Sera from women carrying either chromosomally normal or aneuploid fetuses in the first half of pregnancy were assayed for human chorionic gonadotropin (hCG) bioactivity in order to determine whether differences might provide the basis for a useful antenatal screen for aneuploidy. A mouse uterine weight assay was used to assess hCG bioactivity in sera from 35 patients undergoing chorionic villus sampling (12 normal pregnancies and 23 trisomic pregnancies) and in sera from 18 patients undergoing elective second-trimester abortion (12 presumed normal pregnancies, 3 trisomic pregnancies, and 3 pregnancies with neural tube defects). The hCG bioactivity to immunoactivity (B:I) ratio of normal pregnancies progressively decreased from 7.7±1.3 at 4–5 menstrual weeks, to 4.7±0.4 at 9–12 menstrual weeks, to 3.3±0.5 at 16–20 menstrual weeks. There were no significant differences in the B:I ratios between normal and aneuploid pregnancies in either the first-trimester (4.7±0.4 versus 5.2±0.3) or the second-trimester samples (3.3±0.5 versus 2.6±0.3), despite significantly greater hCG concentrations in the trisomic pregnancies. We conclude that while aneuploid pregnancies display dysfunctional regulation of hCG expression, the bioactivity of their hCG is normal and does not appear to form the basis for a useful screen for aneuploidy.     

Karyotypic differences between cells from placenta and other fetal tissues

Six cases are reported with discrepancies between the karyotypes of placental cells and cells from other fetal tissue. The respective findings were: (a) 48,+7,+18 resp. 47,+18. (b) 46, i(18q) resp. 46, del18(p11). (c) 46, XX resp. 46, XX/47, XXX. (d) 46, X, Yq+ and 46, XY resp. 46, XY. (e) 46/47,+12 resp. 46. (f) 46/47,+5 resp. 46. These differences were found in both early and term pregnancies. Care should be taken in deducing the fetal karyotype from the chromosomal pattern of placental cells.     

Early prenatal diagnosis of short rib-polydactyly (SRP) syndrome type I (Majewski) by ultrasound in a case at risk

Short rib-polydactyly (SRP) syndrome Type I was diagnosed accurately in an at-risk fetus at 16 weeks of gestation by real-time sonography. The most important findings were a narrow thorax, significant shortening of the long bones, particularly the tibiae, and–by directed search–the polydactyly.     

Prenatal diagnosis of del(11)(p13p15)

Prenatal diagnosis of del(11)(p13p15) was made on cultured amniotic fluid cells and confirmed on fetal skin fibroblasts after termination of pregnancy. Both irides appeared behind schedule in development by 2–3 weeks in reference to the gestational age of the fetus. It is suggested that the aniridia of the aniridia-Wilms tumour association is due to developmental arrest. Confirmation of this complex is difficult at mid-gestation without critical pathological study of the eyes.