Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis. A 47,xxy male heterozygous for a missense point mutation

Identification of iduronate-2-sulphatase (IDS) gene mutations in patients with mucopolysaccharidosis type II (MPS II, Hunter syndrome) allows fast and reliable carrier detection and prenatal diagnosis. We describe here three cases of prenatal diagnosis by direct detection of the gene mutation. In addition to two affected male fetuses from two different families, a 47,XXY fetus carrying both the normal and the mutant allele was diagnosed in a third family. The latter pregnancy was carried to term and the child is obviously not affected by MPS II.     

Temporal changes in Ohio amniocentesis utilization during the first twelve years (1972–1983), and frequency of chromosome abnormalities observed

The history of amniocentesis utilization in the seventh largest state of the United States is documented from its inception in 1972 through the first half of 1984. Amniocentesis utilization ratios for Ohio residents aged ⩾35 have increased from 0.21 per cent (19/9091) in 1972 to 23.4 per cent (1655/7531) in 1983, representing an average annual growth rate of 43.1 per cent. Of the amniocenteses performed from January 1, 1978–July 1, 1984, 71 per cent were referred for advanced maternal age (⩾35), 15 per cent for maternal anxiety (30–34), 10 per cent for family history or previous child with a genetic defect, and 4 per cent for other reasons. Between 1978-1983 utilization by women 45 years of age was only 20 per cent higher than women 35 even though their risk of giving birth to a Down syndrome child was about one order of magnitude higher. In addition, various factors were tested as to whether they affected utilization of amniocentesis by women ⩾35 during 1978 1983. A strong correlation of +0.89 existed between county population size and utilization ratios. No difference in utilization was found between whites and nonwhites, regardless of county population size. When utilization ratios were compared separately between Protestants, Catholics and other religions in Ohio's most populated county, no statistical differences were found. From 1978–July 1, 1984, the frequency of all cytogenetically abnormal chromosome results observed in Ohio amniocenteses to women ⩾35 was 2.48 per cent (187/7536). Of these, 2.15 per cent (162/7536) had unbalanced karyotypes. Future maximum amniocentesis utilization for women ⩾35 is estimated at 60–70 per cent.     

Prenatal diagnosis by in situ hybridization on uncultured amniocytes: Reduced sensitivity and potential risk of misdiagnosis in blood-stained samples

Maternal cell contamination was assessed in 18 macroscopically blood-stained amniotic fluid samples from male fetuses. The samples were analysed by double-target fluorescent in situ hybridization (ISH) with Y and X chromosome-specific probes. The only sample with an aberrant karyotype (47, XY, +18) was also analysed by hybridization with a chromosome 18-specific probe. An interpretation of extensive maternal cell contamination was made in two samples, one of which was the sample with trisomy 18. ISH with the chromosome 18-specific probe on this latter sample showed that the sensitivity of the ISH method for chromosome enumeration of uncultured amniotic fluid samples may be reduced in bloodstained samples. It was calculated that by using ISH for chromosome enumeration of the two extensively contaminated samples, a case of trisomy 21 might have been overlooked in both samples, while a case of trisomy 18 might only have been overlooked in one of the samples. It is concluded that ISH should not be used for chromosome enumeration of uncultured amniotic fluid samples that are macroscopically blood-stained without further technical developments.     

The impact of prenatal diagnosis on the occurrence of chromosome abnormalities

From the public health point of view, several formal attempts have been made to measure the impact of prenatal diagnosis (PND) on the incidence of Down's Syndrome (DS), but the results have varied widely. The impact of PND (reduction in the birth rate of chromosomally abnormal neonates) is related to utilization rates but quantitative estimates of this have not been established. In a three-year (1981–1983) total population study from Queensland, Australia, we present results to measure the impact of a voluntary PND programme on the birth incidence of DS, and also other chromosomally abnormal births. Utilization rates for the PND service were 15·5 per cent in that population of mothers 35 years and over. Numbers and rates of all cases of chromosomal abnormalities are presented, subclassified by type of diagnosis–-either by PND or by clinical diagnosis after birth. For the total population, 7·3 per cent of cases of DS were detected prenatally, and 15·4 per cent of all chromosome abnormalities. (A method for measuring the impact of PND is described.) Using this in conjunction with our demographic data, we estimate that with a 15 per cent utilization rate of PND by older mothers, 14 per cent of DS births can be prevented in this age group, or a 5 per cent overall reduction can be achieved if mothers of all ages are considered. One index–-the ratio of the percentage of DS births which are preventable compared with the population utilization rates of PND–-has potential for widespread use. Queensland data for this ratio is 0·34, a figure consistent with that from other studies. Thus a 3·5 per cent drop in the overall DS birth rate may be expected for each 10 per cent increase in the utilization rates of PND for mothers of 35 years and over. A diagram is presented which may serve as a model for improved data collection and better impact estimates in the future.     

Vegetation dynamics in abandoned crop fields on a Mediterranean island: Development of succession model and estimation of disturbance thresholds

This case study on the Sifnos island, Greece, assesses the main factors controlling vegetation succession following crop abandonment and describes the vegetation dynamics of maquis and phrygana formations in relation to alternative theories of secondary succession. Field survey data were collected and analysed at community as well as species level. The results show that vegetation succession on abandoned crop fields is determined by the combined effects of grazing intensity, soil and geological characteristics and time. The analysis determines the quantitative grazing thresholds that modify the successional pathway. Light grazing leads to dominance by maquis vegetation while overgrazing leads to phryganic vegetation. The proposed model shows that vegetation succession following crop abandonment is a complex multi-factor process where the final or the stable stage of the process is not predefined but depends on the factors affecting succession. An example of the use of succession models and disturbance thresholds as a policy assessment tool is presented by evaluating the likely vegetation impacts of the recent reform of the Common Agricultural Policy on Sifnos island over a 20–30-year time horizon.     

Conceiving a fetus for bone marrow donation: An ethical problem in prenatal diagnosis

We present a family who sought prenatal diagnosis in order to bear a healthy child to serve as an HLA–identical bone marrow donor for their son affected with Wiskott–Aldrich syndrome. They intended to abort HLA-incompatible fetuses who would have been unsuitable bone marrow donors. This case led us to conclude that prenatal diagnosis should not be used to benefit a third party or facilitate the conception or abortion of a fetus for the purpose of generating an organ for transplantation. The limits of parental autonomy and physician responsibility are discussed.     

Prenatal diagnosis of a new syndrome: Holoprosencephaly with hypokinesia

Markedly decreased fetal activity (akinesia/hypokinesia) is usually readily apparent to experienced mothers, and frequently this concern leads to attempts at prenatal diagnosis. We report prenatal diagnosis of two fetuses with congenital contractures, markedly decreased fetal movement, and microcephaly due to severe holoprosencephaly. Such familial recurrence to phenotypically normal parents suggests a newly recognized autosomal recessive or X-linked syndrome that is readily detectable by prenatal ultrasonography.     

Prenatal diagnosis of pseudo arylsulphatase a deficiency

Prenatal diagnosis was performed on a pregnancy at risk for metachromatic leukodystrophy (MLD) in a family with the pseudo arylsulphatase A deficiency trait. Extracts of cultured amniotic fluid cells were deficient in arylsulphatase A indicating that the fetus was either affected with MLD or had the benign pseudodeficiency trait. In the cerebroside sulphate loading test, the at risk cells hydrolysed sulphatide like control cultured amniotic fluid cells implying that the fetus had pseudodeficiency. The pregnancy was carried to term and a male child was delivered. Placenta, urine and fibroblasts had very low activities of arysulphatase A. However, no sulphatide could be detected in urine and growing fibroblasts responded normally in the cerebroside sulphate loading test, suggesting pseudodeficiency. At 29 months, the infant is healthy and shows no stigmata of MLD. The prediction based on the results of the cerebroside sulphate loading test on cultured amniotic fluid cells appeared to be borne out.     

46,XY/47,XY,+ 17p+ mosaicism in amniocytes associated with fetal abnormalities despite normal fetal blood karyotype

46,XY/47,XY, + 17p + mosaicism was found in two primary amniotic fluid cultures (AFCs). Fetal blood karyotype was normal, but ultrasonography revealed Dandy-Walker malformation and bilateral choroid plexus cysts. Following termination of pregnancy, fetal examination revealed post-axial polydactyly and neuroblastoma-in-situ affecting both adrenals in addition to the cerebellar abnormalities. Mosaicism for the aberrant cell line was confirmed in all fetal tissues sampled and in the placenta.