What is it?

Down syndrome is the most common form of congenital intellectual disability. It is caused by an extra copy or piece of chromosome 21 in all or most of the person’s cells. Down syndrome is also known as a trisomy 21 because ther are three copies of chromosome 21 rather than the usual two. The characteristic features of Down syndrome are due to an error in cell division that occurs before, or shortly after, conception. This error affects the physical and mental development of a person.

Chromosomes hold the body’s genetic blueprint. Most cells in the body contain 22 pairs of chromosomes and a 23rd set of either XX (in females) or XY (in males) for a total of 46 chromosomes. Reproductive cells, eggs and sperm, contain a single set of 23 chromosomes that combine to form a complete set of 46 when an egg is fertilised (half from each parent). In most cases of Down syndrome, random chance leads to an extra copy of chromosome 21 appearing in either the egg or sperm. This extra copy becomes part of the fertilised egg and is replicated in the embryo’s cells. This form of trisomy 21, accounts for about 95% of cases.

The error may also occur after conception, in the developing embryo. During development, some cells may replicate 47 chromosomes, while others have 46. This  is called mosaic trisomy 21.

In another rare form of the syndrome called translocation trisomy 21, where a piece of chromosome 21 becomes joined to another chromosome before or at conception. Even though the fetus has 46 chromosomes, each cell contains an extra portion of chromosome 21 in its cells.

Individuals with additional chromosome 21 genetic material, regardless of the cause, will develop some of the features of Down syndrome. The most common features associated with Down syndrome include: low muscle tone ( babies appear "floppy"), flat facial features, with a small nose, almond-shaped eyes, small skin folds on the inner corner of the eyes, small and abnormally shaped ears, single deep crease across the centre of the palm. About half of the babies with Down syndrome have heart defects and approximately 1 in 10 will have gastrointestinal problems.

Approximately 1 in 1,100 babies in Australia are born with Down syndrome. This is less than the worldwide birth rate of around 1 in 700 due to the high termination rates in Australia. The chance of having a baby with Down syndrome increases significantly with a woman's age. Among pregnant women aged 30 years, 1 in 890 will have a fetus with Down syndrome. By 35 years of age, the chance of having a fetus with Down syndrome is 1 in 355 and by 44 years of age, the chance increases to 1 in 35 pregnancies.

Most (66%) fetuses with Down syndrome occur in women under 35 years of age.

Signs and symptoms

Although individuals with Down syndrome share common features such as characteristic facial features, intellectual and physical disability, the clinical presentation of the syndrome is 'complex and variable' with a wide range of disabilities and medical problems including defects of the heart, gastrointestinal tract and thyroid gland and have a significantly increased chance of developing childhood leukaemia.

Tests

All pregnant women should be offered screening for foetal anomalies. The goal of laboratory testing is to screen for and diagnose Down syndrome.

Prenatal screening tests provide pregnant women with the option to refine the probability of having a foetus with a common foetal chromosomal anomaly such as Down syndrome or a structural defect such as spina bifida.

Screening tests aim to identify foetal Down syndrome during the early stages of pregnancy while minimising unnecessary invasive diagnostic tests. Invasive diagnostic tests can lead to procedure-related miscarriages and high costs of obstetric procedures and laboratory tests. The majority of screening tests are performed in the first trimester of pregnancy between 9 weeks and 13 weeks 6 days. However, second trimester screening remains an important option for women who present later in pregnancy or those residing at great distances from major health centres.

The accuracy of first and second trimester screening results are very dependent on the accuracy of the gestational age for the baby and this is why a dating ultrasound scan is recommended prior to screening. If the gestational age of the baby is not correct, the screening result may be falsely high or low. An early ultrasound scan will show the possibility of twins or triplets and these will result in high maternal AFP levels. Before having an NIPT, an ultrasound scan can determine the gestational age.

Prenatal diagnostic tests for Down syndrome involve invasive procedure such as chorionic villous sampling (CVS), which is performed between 9 and 11 weeks of gestation, or aminocentesis, which is performed between 14 and 18 weeks of gestation, followed by karyotyping (chromosomal studies) fo the fetal cells.

Laboratory tests

Screening may be done in either the first or second trimester of a woman’s pregnancy. Screening tests are not diagnostic nor are they perfect; they can indicate the probability of the foetus having Down syndrome or some other structural or chromosomal abnormality. The detection rate for Down syndrome in the first trimester using conventional blood markers is approximately 83%; among those women screened, 3.4% will have a screen positive result and of those, one fetus with Down syndrome will be detected for every 13 women who have invasive diagnostic tests.

First trimester NIPT testing ( see below) has a higher detection rate and a lower false-positive rate but is expensive.
Second trimester screening will detect 60% of Down syndrome pregnancies and 5% of all women screened will have a screen positive result. Among those positive screens, one fetus with Down syndrome will be identified in 65 women who have invasive diagnostic tests.

Prenatal diagnostic tests may be performed when screening tests are abnormal or when the owman has a relevant history that suggests the woman has a high chance of fetal abnormality. Invasive diagnostic tests involve taking samples of the fluid ( amniocentesis) or placental tissues (CVS) surrounding the baby and analysing them for changes in the number or structure of the chromosomes. This is called karyotyping the chromosomes. There is a very small chance (less than 1 in 200) of miscarriage associated with these diagnostic procedures.

Diagnostic testing performed after birth involves taking a sample of blood from the baby and analysing the chromosomes.  Some of the physical complications associated with chromosomal anomalies such as heart defects and gastrointestinal obstructions, may be present at birth. Others such as hearing loss, vision disorders, leukaemia, and thyroid disease may develop at any time during the patient’s life.

Testing includes:

Prenatal screening (see Maternal screening)
First trimester screening for Down syndrome is usually available from the 9th week of pregnancy ( 9 weeks to 13 weeks 6 days). Second trimester screening for Down syndrome and neural tube defects (spina bifida) are usually available from 14 weeks to 20 weeks of pregnancy.

• First trimester screening – assay of maternal serum pregnancy-associated plasma protein A (PAPP-A), and free beta human chorionic gonadotropin (free β-hCG) in combination with ultrasound measurement of nuchal translucency (non-laboratory test, see below). The test results are combined to calculate the probability of the fetus having Down syndrome. .
• PAPP-A is one of several proteins produced by the placenta. The PAPP-A concentrations increase throughout pregnancy in the mother’s blood until term and low levels of maternal serum PAPP-A are associated with fetal Trisomy 21.
• Free β-hCG is a hormone produced by the placenta. Concentrations of the free β-hCG increase to a peak at around 8-12 weeks of gestation and then decline to 10% to 15% of the peak concentrations and plateau from 20 weeks until term. Free β-hCG provides a more sensitive marker of Down syndrome than total hCG.
• Second trimester screening (or ‘triple test’) – measurement of maternal serum alpha-fetoprotein (AFP), free β-hCG,  and unconjugated oestriol (uE3); for a ‘quadruple test’ (or ‘quad screen’), inhibin A results are added to the risk calculation. Second trimester maternal serum screening tests are usually performed from14 to 20 weeks of gestation. Similar to first trimester screening, the test results are combined in a computer risk algorithm to calculate the probability of the fetus having Down syndrome, or trisomy 13 or trisomy 18 or a neural tube defects, such as spina bifida. It is recommended that a woman does NOT have both first and second trimester screening because the tests are not independent and combining the results would lead to a greater chance of a screen positive result, without increasing the detection rate.
• Alpha-fetoprotein (AFP) is the major blood protein produced in early fetal life and it is excreted into the amniotic fluid by the immature fetal kidneys. AFP passively diffuses into the maternal blood. The AFP concentration peaks in fetal blood between 12 and 14 weeks of gestation and in maternal serum between 28 and 32 weeks of gestation. An abnormal increase in maternal serum AFP is the basis of the serum screening test for neural tube defects between 15 and 18 weeks of pregnancy.
• Human chorionic gonadotrophin (hCG) is a hormone produced by the placenta. Concentrations of free β-hCG provide a more sensitive marker of Down syndrome than total hCG.
• Unconjugated oestriol (uE3) is a hormone produced by the placenta from precursor hormones produced by the baby, so it requires both placenta and baby to be healthy and developing normally. It is usually measured at about 15-18 weeks of gestation. All these test results are interpreted with reference to the gestation of the pregnancy, the age of the mother, her weight and other factors such as family history and smoking, to assess the chance of the baby having a foetal anomaly. Only a very small proportion of women with a result in the higher risk category will have a baby with a chromosomal syndrome.

All these test results are interpreted with reference to the gestation of the pregnancy, the age of the mother, her weight and other factors such as family history and smoking, to assess the chance of the baby having a foetal anomaly. Only a very small proportion of women with a result in the higher risk category will have a baby with a chromosomal syndrome.

Non-invasive prenatal testing or (NIPT) is a new test for detecting an abnormal number of chromosomes by analysing the circulating cell-free DNA (cfDNA) in the mother’s blood. Cell-free DNA from both foetus and mother can be detected in the mother’s blood. In a pregnancy with a Down syndrome foetus, the proportion of chromosome 21 fragments increases due to the trisomy 21 in the foetus. NIPT has a higher detection rate (99.5%) and lower false-positive rate (0.5%) than the other screening tests. However, NIPT is expensive and is not covered by Medicare. Because NIPT is not diagnostic, a positive NIPT result still requires confirmatory invasive diagnostic testing (CVS or amniocentesis).

Prenatal diagnosis

Chorionic Villus Sampling (CVS)
CVS is a diagnostic test offered between 11 and 14 weeks of pregnancy. CVS requires the doctor to insert a needle through the abdomen, guided by ultrasound, to obtain a small sample of the developing placenta (chorionic villi) for foetal karyotyping.

Amniocentesis
Amniocentesis is a diagnostic test performed between between 15 and 20 weeks of pregnancy. Amniocentesis requires a needle inserted through the abdomen, guided by ultrasound, to obtain a small sample (10-15 mL) of amniotic fluid for foetal karyotyping.

Chromosomal karyotyping is the process of pairing and ordering all the chromosomes from an individual. Traditional “banding” karyotypes are prepared using standardized staining procedures that reveal characteristic structural features. Karyotypes can reveal changes in the number of chromosomes associated with conditions, such as trisomy 21, trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome). Careful analysis of karyotypes can also reveal more subtle structural changes, such as chromosomal deletions, duplications, translocations, or inversions.

For purposes of prenatal testing, newer techniques are used for chromosome studies by genome-wide oligonucleotide array (also called chromosomal microarray, molecular karyotype, and array CGH) to identify both large (5-10Mb) and sub-microscopic (< 5-10Mb) DNA variations across all chromosomes.

Chromosomal microarrays (CMAs) assess the foetal genome at a higher resolution than the conventional karyotype, but do not identify balanced chromosome rearrangements (e.g., balanced translocations) or the majority of mutations causing single gene disorders.

Where an ultrasound scan identifies structural anomalies, CMA can detect significantly more pathogenic chromosomal anomalies than conventional karyotype. As a result, CMA is recommended as the ‘first-tier’ test in the presence of a structural foetal condition and replaces the need for banded karyotype testing.

Non-laboratory tests

Prenatal

• Nuchal translucency – an ultrasound measurement of the fluid-filled space under the skin at the back of the foetus’ neck. Increased nuchal translucency is associated not only with Down syndrome but also with other chromosomal defects, major heart defects and several other genetic conditions. This test requires a person with specialised ultrasound training to perform and interpret.
• Second trimester high-resolution ultrasound – can help monitor foetal growth and development and can detect malformations such as cardiac, renal and gastrointestinal defects

At or soon after birth

• Echocardiogram and chest x-rays (to help detect cardiac defects)
• Ultrasound and/or MRI (magnetic resonance imaging) to evaluate any suspected congenital conditions such as cardiac defects and gastrointestinal obstructions
• Hearing evaluation

Treatment

Currently there is no way to prevent or cure Down syndrome. Prenatal screening and diagnosis is performed to detect the condition in the foetus and to allow the pregnant woman and her family to make informed choices including termination of pregnancy. Early diagnosis allows the family and doctor to work together to monitor the baby and to prepare for complications that may require attention shortly after birth. Medical treatments may include surgical interventions, such as repairing cardiac defects and gastrointestinal obstructions, and starting medications for conditions such as thyroid disease.

The average lifespan of those with Down syndrome has increased in recent years from just 12 years of age in the 1950s to approximately 60 years in 2012.

More information

RCPA Manual: Down syndrome pre-natal risk test

Healthdirect Australia - Down syndrome

Murdoch Childrens Research Institute: Prenatal screening tests in pregnancy