KH Nicolaides, NJ Sebire, RJM Snijders

‘The hair is not black, as in the real Mongol, but of a brownish colour, straight and scanty. The face is flat and broad, and destitute of prominence. The cheeks are roundish, and extended laterally. The eyes are obliquely placed, and the internal canthi more than normally distant from one another. The palpebral fissure is very narrow. The forehead is wrinkled transversely from the constant assistance which the levatores palpebrarum derive from the occipito-frontalis muscle in opening of the eyes. The lips are large and thick with transverse fissures. The tongue is long, thick, and is much roughened. The nose is small. The skin has a slight dirty yellowish tinge, and is deficient in elasticity, giving the appearance of being too large for the body.’

The above is an extract from the paper ‘Observations on an ethnic classification of idiots’ by Langdon Down, published in 1866¹. Down, who was a physician at the London Hospital, coined the phrase Mongolian idiots because he felt that a subgroup of his patients had a resemblance to the Mongolian peoples and this fitted in with his theory of ‘retrogression’ of ethnic type. Down’s theory of ethnic regression was in keeping with Darwin’s contemporary scientific reasoning for evolution. In 1924, Crookshank suggested that the regression was not merely to a primitive Oriental human type but also to the orangutan². Even though the theory of ethnic regression was proven to be inaccurate, Down’s description of the appearance of the skin was the basis for the observation, made more than one century later, that affected individuals during the 3rd month of intrauterine life, have a subcutaneous collection of fluid behind the neck (Figure 1), which can be visualized by ultrasound as nuchal translucency (Figure 2).

Figure 1 - Fetus with subcutaneous collection of fluid at the back of the neck. Image kindly provided by Dr Eva Pajkrt, University of Amsterdam.	Figure 2 - Ultrasound picture of a 12-week fetus with trisomy 21, demonstrating increased nuchal translucency thickness

Langdon Down in 1866 and Fraser and Mitchell in 1876 recognized that the condition was congenital, dating from intrauterine life, and in 1914 Goddard found that there was no increased incidence within families^1,3,4. A number of conditions were advocated as potential causes of Down’s syndrome, including syphilis, tuberculosis, parental alcoholism, epilepsy, insanity, nervous instability and mental retardation in a close relative, thyroid deficiency, hypoplasia of the fetal adrenal glands, dysfunction of the fetal pituitary and abnormality of the fetal thymus^1,6–13.

The association between Down’s syndrome and increased maternal age was noted in 1909 by Shuttleworth⁶, who examined 350 cases and reported that:

‘It would seem fair inference... that more than half of the Mongolian imbeciles in institutions are last-born children, mostly of long families, and that in a considerable proportion – from one-half to one-third – the mothers were at the time of gestation approaching the climacteric period, and that in consequence the reproductive powers were at a low ebb. Which of the two factors – the advanced age of the mother or her exhaustion by a long series of previous pregnancies – is the more potent factor is open to doubt.’⁶

As a result of the above observation, hypotheses were based upon theoretical degeneration of the ovum^14–16. However, advanced maternal age could not be the only factor, because, in some cases, there appeared to be a hereditary factor as well. For instance, dizygotic twins were unequally affected whereas monozygotic twins were equally affected¹⁷. It was also noticed that the condition could be transmitted from mother to baby, and, when more than one member of a family was affected, the dependence on the mother’s age was weakened^18–21. The concept of non-dysjunction in Down’s syndrome was suggested by Waardenburg in 1932²². In 1934, Bleyer proposed that an unequal migration of chromosomes during cell division may result in trisomy¹⁶.

In 1956, Tjio and Levan, working with improved techniques on cultures of lung fibroblasts, established that the normal diploid chromosome number is 46²³. In the same year, Ford and Hamerton found that the haploid number was 23 in human spermatocytes²⁴. These discoveries led a number of laboratories to study the karyotype in various pathological conditions and in 1959 Lejeune et al. and Jacobs et al. demonstrated that an extra acrocentric chromosome was present in persons with Down’s syndrome, resulting in an aneuploid chromosome number of 47^25,26.

There were familial cases of Down’s syndrome which were not the result of trisomy. In 1960 Polani et al. examined the chromosomes of a child with Down’s syndrome from a 21-year-old mother, there were 46 chromosomes with a centric fusion of two chromosomes (15:21)²⁷. Familial transmission of this type of translocation was demonstrated by Penrose et al. in 1960 in a family with two Down’s syndrome sibs²⁸. In 1961, Clarke et al. reported on a 2-year-old girl with normal intelligence but some physical features suggestive of Down’s syndrome; she was discovered to be a mosaic for normal and trisomic cells²⁹.

Today we know that Down’s syndrome occurs when either the whole or a segment of the long arm of chromosome 21 is present in three copies instead of two. This can occur as a result of three separate mechanisms: non-dysjunction, found in about 95% of cases, translocation and mosaicism. In 1991, Antonarakis et al. examined DNA polymorphisms in Down’s syndrome infants and demonstrated that 95% of non-dysjunction trisomy 21 is maternal in origin³⁰. The region that codes for most of the Down’s syndrome phenotype is the distal portion of band q21.1 and bands q22.2 and q22.3. This region determines the facial features, heart defects, mental retardation and probably the dermatoglyphic changes in affected individuals³¹.

In 1966, 100 years after the original essay of Langdon Down, it became possible to diagnose trisomy 21 prenatally by karyotyping of cultured amniotic fluid cells^32,33.

The first method of screening for trisomy 21, introduced in the early 1970s, was based on the observation of Shuttleworth on the association with advanced maternal age⁶. It was apparent that amniocentesis carried a risk of miscarriage and this in conjunction with the cost implications, meant that prenatal diagnosis could not be offered to the entire pregnant population. Consequently, amniocentesis was initially offered only to women with a minimum age of 40 years. Gradually, as the application of amniocentesis became more widespread and it appeared to be ‘safe’, the ‘high-risk’ group was redefined to include women with a minimum age of 35 years; this ‘high-risk’ group constituted 5% of the pregnant population.

In the last 20 years, two dogmatic policies have emerged in terms of screening. The first, mainly observed in countries with private healthcare systems, adhered to the dogma of the 35 years of age or equivalent risk; since the maternal age of pregnant women has increased in most developed countries, the screen-positive group now constitute about 10% of pregnancies. The second policy, instituted in countries with national health systems, has adhered to the dogma of offering invasive testing to the 5% group of women with the highest risk; in the last 20 years, the cut-off age for invasive testing has therefore increased from 35 to 37 years. In screening by maternal age with a cut-off age of 37 years, 5% of the population are classified as ‘high risk’ and this group contains about 30% of trisomy 21 babies.

In the late 1980s, a new method of screening was introduced that takes into account not only maternal age but also the concentration of various fetoplacental products in the maternal circulation. At 16 weeks of gestation the median maternal serum concentrations of a-fetoprotein, estriol and human chorionic gonadotropin (hCG) (total and free-b) in trisomy 21 pregnancies are sufficiently different from normal to allow the use of combinations of some or all of these substances to select a ‘high-risk’ group. This method of screening is more effective than maternal age alone and, for the same rate of invasive testing (about 5%), it can identify about 60% of the fetuses with trisomy 21.

In the 1990s, screening by a combination of maternal age and fetal nuchal translucency thickness at 11–14 weeks of gestation was introduced. This method has now been shown to identify about 75% of affected fetuses for a screen-positive rate of about 5%.

Recent evidence suggests that maternal age can be combined with fetal nuchal translucency and maternal serum biochemistry (free b-hCG and pregnancy-associated plasma protein (PAPP-A)) at 11–14 weeks to identify about 90% of affected fetuses. Furthermore, the development of new methods of biochemical testing, within 30min of taking a blood sample, has now made it possible to introduce One-Stop Clinics for Assessment of Risk (Figure 3).

Figure 3 - Assessment of risk for chromosomal defects can be achieved by the combination of maternal age and history of previously affected pregnancies, ultrasound measurement of fetal nuchal translucency and biochemical measurement of maternal serum free b-hCG and PAPP-A in an OSCAR at 11-14 weeks of gestation. After counseling, the patient can decide if she wants fetal karyotyping, which can be carried out by chorionic villus sampling in the same visit.

Figure 4 - Maternal age-related risk for chromosomal abnormalities	Figure 5 -Gestational age-related risk for chromosomal abnormalities. The lines represent the relative risk according to the risk at 10 weeks of gestation.

Similar methods were used to produce estimates of risks for other chromosomal abnormalities⁴⁰. The risk for trisomy 18 and trisomy 13 increases with maternal age and decreases with gestation; the rate of intrauterine lethality between 12 weeks and 40 weeks is about 80% (Table 2 and Table 3). Turner syndrome is usually due to loss of the paternal X chromosome and, consequently, the frequency of conception of 45,X embryos, unlike that of trisomies, is unrelated to maternal age. The prevalence is about 1 per 1500 at 12 weeks, 1 per 3000 at 20 weeks and 1 per 4000 at 40 weeks. For the other sex chromosome abnormalities (47,XXX, 47,XXY and 47,XYY), there is no significant change with maternal age and since the rate of intrauterine lethality is not higher than in chromosomally normal fetuses the overall prevalence (about 1 per 500) does not decrease with gestation. Polyploidy affects about 2% of recognized conceptions but it is highly lethal and thus very rarely observed in live births; the prevalences at 12 and 20 weeks are about 1 per 2000 and 1 per 250000, respectively⁴⁰.