Down syndrome - symptoms, causes, diagnosis

International Classification (ICD)	Q90.-
Symptoms	maldevelopment of organs and tissues, Heart Defects, Malformations in the gastrointestinal tract, high susceptibility to infections, Hypothyroidism, intellectual impairment, mental disorders
Possible causes	Error in germ cell production (21st chromosome)
Possible risk factors	high gestational age of the mother, certain gene variants, harmful radiations, excessive cigarette smoking, Alcohol abuse, viral infection at the time of fertilization
Possible therapies	Physiotherapy, Speech therapy

Basics

Down syndrome cannot be called a disease in the classical sense, but rather a chromosomal abnormality. The number of chromosomes (carriers of genetic material) deviates here from the normal value of 46.

Humans normally have 44 autosomes (determine the sex-independent characteristics) and additional sex chromosomes (XX in women and XY in men). In total, each cell (except germ cells) has 23 pairs of chromosomes.

In trisomy 21, the affected person has 47 chromosomes instead of 46, because the 21st chromosome is present in triplicate. "Tri" means "three" and "somie" means chromosome. Instead of trisomy 21, the term "Langdon-Down disease" is also sometimes used, which goes back to the English discoverer and physician John Langdon Down. He first described the syndrome in the mid-19th century.

In the vernacular, the syndrome was formerly also referred to as "mongolism" and the affected persons as "mongoloid". This term is no longer in use today, as it is a denigration of people with Down syndrome.

Chromosomenverteilung bei Trisomie 21 (iStock / Rujirat Boonyong)

Häufigkeit

Down syndrome is one of the most common so-called numerical chromosomal abnormalities and occurs in both female and male children. A chromosomal abnormality is a deviation from the normal number of chromosomes in a cell.

In Austria, approximately one in 650 newborns is born with Down syndrome. The total number of affected persons in Austria is 9,000, which is about 0.1% of the total population. As the mother's gestational age increases, so does the risk of giving birth to a child with Down syndrome. Overall, Down syndrome is the most common cause of intellectual disability in humans.

Forms of Down syndrome

Free trisomy 21	95% of all people affected by Down syndrome have free trisomy 21. In this form, all body cells contain the 21st chromosome three times (karyotype 47, XX + 21 or 47, XY + 21). This form of trisomy is called a spontaneous mutation because it occurs suddenly and for no apparent reason.
Mosaic trisomy 21	Mosaic trisomy affects only 1-2% of people with Down syndrome. In this case, some body cells have a normal set of chromosomes, while some have the 21st chromosome again in a triple version (karyotype 46, XX/47,XX+21 or 46,XY/47,XY+21). The strength of the expression of typical Down syndrome features depends on whether the affected person has predominantly cells in double chromosome execution or trisomy cells.
Translocation trisomy 21	This form of trisomy affects 3-4% of cases and occurs frequently in families (30% of cases are hereditary). It is called translocation trisomy when one of the three chromosomes 21 merges with one of the other 46 chromosomes. This can happen spontaneously after fertilization, or it can be transferred from one parent to the child.
Partial (= partial) trisomy 21	This form of trisomy 21 is extremely rare, with an estimated few hundred cases worldwide. Here, a section of chromosome 21 is duplicated, making the chromosome slightly longer and the genetic information threefold.

Causes

a) Error in cell division

Free trisomy 21

The most common form of trisomy occurs when there is an error in germ cell production (egg or sperm). A cell division error is causative for trisomy 21 in 95% of cases.

The germ cells themselves develop from precursor cells that have a normal double set of chromosomes. Generally, these are 22 pairs of autosomes, plus two sex chromosomes - either XX in females or XY in males. Thus, in total, each cell comes up with 46 chromosomes or 23 pairs of chromosomes. Normally, during germ cell formation, the information of the genetic material is divided equally among the germ cells, which means that each germ cell has a single set of chromosomes (22 autosomes plus 1 sex chromosome = 23). The purpose of this is that in the event of subsequent fertilization, the fusion of male (sperm) and female germ cells (egg), simple sex cells, will again result in an organism with a double set of chromosomes.

During germ cell formation, however, mistakes can happen. If both duplicated chromosomes 21 land in a germ cell, it now has 24 chromosomes instead of 23. Later, after fusion with another "normal" germ cell, this results in a trisome cell, since it has chromosome 21 in triplicate. All cells derived from this cell have the same set of chromosomes and therefore also have a trisomy.

Mosaic trisomy 21

Rarely, it can also happen that during subsequent cell division, chromosome 21 is lost again in some cells ("trisomy rescue"), but not in others. Thus, some cells of the affected person contain 46 and others 47 chromosomes. This condition can also occur if errors occur during embryonic development and during the division of a single cell, 3 chromosomes 21 suddenly end up in a daughter cell (the other daughter cell therefore contains only 1 chromosome 21). As a result, both normal and trisomic cells develop.

Translocation trisomy 21

In this form of trisomy only 2 of 3 chromosomes 21 are free in the cell. The third chromosome is linked to another chromosome (usually 13, 14, 15 or 22). This type of trisomy occurs when the mother or father is a silent carrier (i.e. does not show any clinical symptoms). In this case, the affected parent with the attached chromosome (i.e. translocation) is called a "balanced" translocation 21.

b) Age of the mother

It has been proven that as the age of the mother increases at the time of conception, the risk of Down syndrome increases. In the age group of 35 to 40-year-old women, the probability is 1:260, and in 40 to 45-year-old women, the risk is as high as 1:50. In general, however, it can be said that with every pregnancy there is a possibility that a child will be born with a genetic defect - such as Down syndrome.

The increasing risk of Down syndrome with increasing age of the mother is explained by the fact that egg cell division is more susceptible to disruption at an older age, which makes it easier for chromosomes to be maldistributed. The age of the father is not important, as far as is currently known.

c) Other risk factors

Researchers suspect that in addition to endogenous (internal) causes, such as certain gene variants, exogenous causes may also play a role in the development of Down syndrome. These include ionized radiation, excessive cigarette consumption, alcohol abuse, use of oral contraceptives, or viral infections at the time of fertilization. However, these factors are controversial and have not yet been scientifically proven.

Symptoms

The extent of the symptoms and the expression of Down syndrome vary from child to child. In general, however, the triple chromosome 21 leads to malformations of the skeleton, musculoskeletal system, central nervous system and the skin.

People with Down syndrome may show the following characteristics:

Appearance: slanted eyes, small head, small oral cavity with large tongue.
Heart defects: about one in two newborns with Down syndrome has a heart defect
Visual disturbances
Hearing disorders
Malformations in the gastrointestinal tract (e.g. duodenal stenosis)
Thyroid disorders(hypo- or hyperthyroidism)
Increased risk of autoimmune diseases
Weak immune system
Increased risk of leukemia
Increased risk of Alzheimer's dementia
Mental disorders (e.g. depression or anxiety disorder)
Problems with bones and joints

(iStock / Halfpoint)

Health effects

Down syndrome affects the health of affected individuals at various levels. For example, heart defects are more common, with a so-called AV canal (atrioventricular canal) being particularly common. An AV canal is a septal defect between the atria and the ventricles. As a result of the AV canal defect, there may be respiratory distress, growth failure, and also recurrent pneumonia. It is also not uncommon to have a non-continuously closed cardiac septum between the ventricles (ventricular septal defect).

A high susceptibility to infections, especially respiratory infections, can be explained by the fact that the immune system of affected individuals is often not as resistant or not fully developed. If respiratory tract infections occur frequently, it may also be necessary to take antibiotics repeatedly. Affected individuals also develop acute leukemia (a form of blood cancer) significantly more often (up to 20 times more frequently). This can be explained by the fact that chromosome 21 contains genes that are important for the development of certain types of leukemia.

Men affected by Down syndrome are usually infertile. Women may have limited fertility, with about a 50% chance of passing on the chromosomal abnormality.

Mental disorders

People with Down syndrome have an increased risk of behavioral and psychiatric disorders (such as ADHD or autism). Those affected also often suffer from anxiety disorders or depression as concomitant disorders.

Mental abilities

Down syndrome is one of the most common congenital disabilities. Since affected children usually have poorer hearing, this affects their ability to speak, which often develops later. When learning new things, they often have difficulty retaining what they have already learned. The development of motor skills also generally begins later - crawling and walking, for example, are often delayed.

Even though intellectual abilities are often limited by trisomy 21, mental development can be strongly influenced individually. A child with Down syndrome benefits - like any other child - from good intellectual support.

Special talents

People with Down syndrome often possess great empathy and a sunny disposition. Among the essential character traits of many affected individuals are: Kindness, cheerfulness, tenderness and a loving manner. Often, there may also be a pronounced musical talent with an exceptionally good sense of rhythm.

Diagnosis

Due to their typical appearance, newborns with Down syndrome can be easily recognized. The diagnosis of trisomy 21 in children is therefore usually made as a visual diagnosis by the attending physician. Even though typical features such as a round face and slanted eyes are often not so easily recognizable in babies, they become more prominent over time. The so-called brushfield spots ("porcelain spots") of the iris are often very visible. These spots disappear with time, due to pigment deposits in the iris.

Prenatal diagnostics can be used to determine before birth whether a child is affected by trisomy 21 or not. Some examination methods are suitable for this purpose:

First-trimester screening (ultrasound, blood tests) and the triple test (blood tests) are non-invasive methods that are completely safe for mother and child. First trimester screening (at the end of the first trimester of pregnancy) often allows reliable conclusions to be drawn about whether or not Down syndrome is present in the unborn child.

To be sure, a direct analysis of the chromosomes is often performed, either by taking tissue from the placenta (chorionic villus sampling) or by examining amniotic fluid (amniocentesis). There is also the possibility of fetal blood sampling. These three methods are called invasive because they involve direct intervention on the mother or the newborn. Since they are associated with a certain risk for the child and the mother, they are usually only used in certain suspected cases (increased age of the mother, unclear ultrasound findings).

Ultraschalluntersuchung einer Schwangeren (iStock / gorodenkoff)

Ultraschall (Sonografie)

An indication of trisomy 21 may be a thickened nuchal fold in the fetus (nuchal edema), which is visible on ultrasound. This is a temporary swelling in the 11th and 14th week of pregnancy, which suggests a chromosomal disorder. Ultrasound may also reveal other external malformations and abnormalities that are due to excess chromosome 21 (small head, short hands and feet, and sandal gap and shortened nasal bone).

First trimester screening

From this screening, a statistical value for the risk of trisomy 21 is obtained. This is done on the basis of certain measurement results from ultrasound examination, blood test with the determination of two values (HCG and Papp-A) and the survey of individual risks, which include the age of the mother and family history.

Triple test

In this test, certain parameters in the maternal blood serum are collected: the fetal protein alpha-fetoprotein (AFP) and the maternal hormones estriol and HCG. Through these parameters, as well as the mother's age and the time of pregnancy, it is often possible to tell how high the risk is that a child is affected by trisomy 21.

Chorionic villus sampling

The chorionic villi are a part of the placenta from which a tissue sample is obtained for chromosomal analysis. These chorionic villi originate from the fertilized egg and therefore have the same genetic material. This examination can be performed from the 11th week of pregnancy.

Amniocentesis (amniocentesis)

A sample of amniotic fluid contains isolated fetal cells whose genetic material can be examined for genetic disorders. This examination method is only possible from the 15th - 16th week of pregnancy.

Fetal blood collection

In this procedure, some blood is taken from the umbilical cord (cord puncture). The cells in the blood are then checked for their chromosome count. This examination is usually performed from the 19th week of pregnancy at the earliest.

Therapy

Since the excess chromosome 21 cannot be blocked or eliminated, Down syndrome cannot be cured. However, with care and support, which should begin as early as possible, the limitations can be reduced and individual talents can also be promoted.

Surgery & physiotherapy

If affected persons suffer from a heart defect or other malformations in the intestinal tract, these can often be corrected by surgery in childhood. Weakened muscles or loose connective tissue can be strengthened and built up through physiotherapy. Success depends on the therapist, whom the child should trust, and the therapy plan. However, the child should never be put under pressure to perform - rather, it is advisable to approach the exercises in a playful manner.

Language support

Children with trisomy 21 can significantly improve their ability to communicate and express themselves with the help of speech and language exercises. Slow and clear speech, as well as sign language, also help to understand what is being said. It is also important to treat a hearing disorder at an early stage, as it can otherwise impair language learning. Misaligned teeth and the typical high, pointed palate can be a hindrance to speech understanding, which is why they should be corrected by a dentist or orthodontist if possible.

Mental and social development

To learn and practice social behaviors, it is important for Down syndrome children to be around family and friends a lot. For this purpose, attendance in an integrative kindergarten and later in an integrative class or school for the learning disabled is also advisable.

Forecast

Appropriate individual support and the best possible medical care are crucial for the child's development. About 15% of children with trisomy 21 die in the first year of life as a result of heart defects or severe gastrointestinal malformations. Also, chromosome 21 trisomies lead to a large number of miscarriages in early pregnancy.

The life expectancy of people with Down syndrome is about 60 years and has increased steadily in recent years. Many affected individuals achieve a certain degree of independence with optimal school and social support.

Down syndrome (trisomy 21)