First-trimester Screening for Down Syndrome and Other Aneuploidies

Abstract

Down syndrome, which is synonymous with trisomy 21 (47, +21), is the most common chromosomal anomaly in live born children. In 1866 John Langdon Down first described children with common phenotypically features distinct from other children with mental retardation . These children were referred by Down as ‘mongoloids’, based on the typical facial characteristics of individuals with Down syndrome. Specific characteristics of newborns with Down syndrome include a flat nasal bridge, epicanthic folds, small ears, a protruding tongue, a short neck and hypotonia . Beside the visual features, newborns with Down syndrome have an increased risk of congenital structural anomalies such as heart defects, gastrointestinal defects, hearing and ophthalmic problems, hypothyroidism and leukemia. In 1956 Joe Hin Tjio and Albert Levan reported that the total number of human chromosomes in ‘normal subject’ is 46, rather than 48 as was supposedly established some three decades earlier. The importance of this finding was not the total number of chromosomes itself, but rather the ability to distinguish the number of 46 chromosomes from numerical chromosomal abnormalities. In fact, it was three years later (1959) when Lejeune et al demonstrated that Down syndrome is associated with the presence of an additional chromosome 21. Due to this extra copy of chromosome 21, the clinical condition Down syndrome is also known as trisomy 21. As a result of the technical advances in chromosomal analysis of human amniotic-fluid cells demonstrated by Steele and Breg , the first prenatal diagnosis of Down syndrome by amniocentesis was reported in 1968. Because of the development of the new obstetric techniques together with the advances in direct analysis of spontaneous mitoses in fetal tissue it was possible from 1989 to carry out prenatal chromosome diagnosis in the first trimester of pregnancy. Chorionic villi, which typically have the same genotype as the fetus, were obtained by gentle suction under constant realtime ultrasound guidance. These techniques enabled pregnant women to choose between chorionic villus sampling (CVS) at the 9th to 11th week of gestation and amniocentesis at the 16th to 18th week of gestation. These invasive procedures are associated with an iatrogenic miscarriage rate of 0.3- 0.5% . For The Netherlands nowadays the estimated birth prevalence of Down syndrome is per 10.000 with around 322 total annual births 19,20. The relatively high prevalence of this condition and the association with perinatal morbidity and mortality has been one of the main reasons for the implementation of prenatal screening for Down syndrome.