VERIFIED CONTENTAuthor: Krzysztof Bialazite

Down syndrome (trisomy 21) is not a disease, but a gene defect caused by an extra chromosome 21. It is not known why these chromosomes do not separate during cell division in some fetuses. What is the genetic basis of Down syndrome? Can the band perform in family? What are the common he alth problems of patients with this condition?

Down syndrome( trisomy 21 ) is a genetic disorder belonging to the group of aneuploidy. Aneuploidy is an abnormal number of copies of chromosomes that contain genetic material.

In Down's syndrome we are dealing with a triple copy of the 21st chromosome instead of a double. The excessive amount of genetic material located on this chromosome is the cause of the characteristics of this syndrome. These include:

  • typical appearance changes
  • lower IQ
  • many accompanying flaws

Medical advances today make it possible to treat the most serious effects of Down syndrome. As a result, the life expectancy of patients under proper care has been extended to around 50-60 years.

Down syndrome - causes

Before getting to know the nature of the disorders underlying Down's syndrome, it is worth understanding a few basic concepts in genetics. Every cell in our body contains genetic material - a code in which all our features are written.

From a chemical point of view, genes are stored in the form of a double strand of DNA. This thread is very long and its arrangement in the cell nucleus is not random. Special proteins called histones oversee the tight twist of the DNA. Such "packed" threads form chromosomes.

Correctly, each cell contains 23 pairs of chromosomes. Each pair has one chromosome inherited from the mother and father. The last, 23rd pair is the so-called sex chromosomes - XX for women or XY for men.

The set of chromosomes in a given cell is called a karyotype. The schematic representation of the normal human karyotype is 46, XX or 46, XY. It includes 23 pairs of all chromosomes (46 in total), taking into account the type of sex chromosomes (XX or XY).

Down syndrome belongs to a group of numerical chromosomal abnormalities called aneuploidy. The most commonA form of aneuploidy istrisomy , i.e. the presence of three copies of a given chromosome (there should be only two copies in a correct cell).

The additional genetic material results in very serious disorders - only some children with trisomy have a chance to be born alive. The most common is trisomy of the 21st chromosome, i.e.Down's syndrome .

The karyotype of a child with Down syndrome is schematically written as:

  • 47, XX, + 21 (girls)
  • 47, XY, + 21 (boys)

Children with trisomy 18 (Edwards' syndrome) or 13 (Patau's syndrome) are born much less frequently.

It is also possible to have a sex chromosome trisomy.

Trisomy of other chromosomes is a lethal feature - a child with such a defect has no chance of being born.

So where does the extra chromosome come from in patients with Down's syndrome?

It is most often the result of their improper separation during the formation of the sex cells of the child's parents.

Correctly, a sperm and an egg should contain only one copy of each chromosome - so that after they are combined, a cell containing a complete set (23 pairs) is formed.

Unfortunately, during the separation of chromosomes, they may not separate - then the child receives two chromosomes from one parent and one chromosome from the other. This is how a trisomy is formed.

Interestingly, the extra chromosome comes from the mother in 80% of cases - although the cause of this phenomenon has not yet been clarified.

It may also happen that the trisomy of the 21st chromosome will occur despite proper cell division of the parents.

The primary cell from which the daughter cells that build the whole organism arise, has the appropriate number of chromosomes. Unfortunately, when it divides, it goes wrong and some of its daughter cells contain an extra copy of the chromosome. Others, on the other hand, have the correct genetic material.

One organism is then composed of two types of cell lines. We call such a situation mosaicism.

The fact that some cells in the body are completely normal determines in many cases a slightly milder course of the disease, less intellectual impairment and a better prognosis for patients.

The last mechanism of the trisomy of the 21st chromosome lies at the base of the so-called family Down's syndrome (2-4% of cases). This mechanism is called translocation, i.e. the transfer of a fragment of genetic material from one chromosome to another.

Translocation may be asymptomatic and may appear in a perfectly he althy person. We call her thenbalanced translocation. However, during the formation of a germ cell, a double copy of the genetic material may be transferred to it - both the translocated and the normal 21 chromosome

A balanced translocation can be a trait inherited in the family. Its presence increases the risk of Down's syndrome in offspring. The percentage estimate ranges from 2 to 100% and depends on the type of translocation, which is determined by appropriate genetic testing.

Risk of Down's syndrome

Down's syndromeis the most common chromosomal abnormality. The incidence of chromosome 21 trisomy is estimated at 1/700 - 1/900 liveborn babies.

Other trisomes are less frequent - Edwards' syndrome (trisomy 18) occurs at a frequency of 1/3500 and Patau's syndrome (trisomy 13) occurs at 1 / 5000.

Not all babies with Down's syndrome have a chance of being born alive - more than half of trisomy 21 pregnancies end in spontaneous miscarriage.

The most important risk factor identified ismother's age.Among women in their 20s, the risk of having a baby with Down's syndrome is 0.067%. In the case of women in their 40s, the risk is 15 times greater, amounting to 1%.

Parents of children with Down syndrome usually want to know how high the risk of their offspring reoccurring.

To estimate it, it is necessary to perform a genetic test - karyotype, which will determine the cause of chromosomal abnormalities in the child.

If it is a lack of parental chromosome separation, resulting intrisomy 21 , the risk is relatively small - around 1%.

The risk assessment is different in the case of a balanced translocation occurring in one of the parents. It then depends on where the genetic material has been transferred (translocated).

Certain types of translocations give 100% certainty that the next offspring will develop Down's syndrome (the so-called 21/21 translocation). Regardless of the genetic risk factors, the likelihood of developing the disease always increases with the mother's age.

Characteristics of Down syndrome. Course of the disease

Down syndromeis associated with the presence of characteristic clinical symptoms, patient appearance, and possible organ dysfunction.

SomeDown syndrome symptomsdo not have serious consequences, while others may be a real threat to he alth and life. The influence of the disease on the functioning of the organism is as follows:

  • Features of dysmorphia

Dysmorphic features are characteristic changes in the appearance of the body through which a clinical diagnosis of Down's syndrome is possible - even before genetic testing is performed. They are not dangerous and are only a cosmetic defect. Most of them concern the face area as well as hands and feet.

It is worth emphasizing that there is no pathognomonic feature of the Down syndrome. This means that none of them occurs only in this disease. Moreover, it happens that single dysmorphic features occur in completely he althy people.

Typical changes in the appearance of patients with Down syndrome are:

  • Mongoloid eye positioning
  • flattening the nose and face
  • tongue enlargement
  • beard reduction
  • low-set ears
  • single palmar furrow
  • finger shortening

and many more.

  • Psychomotor development

The development of a baby with Down syndrome is slowed down - the baby later starts to sit up, crawl, stand up and walk. A typical feature of newborns with this condition is hypotension - a significant reduction in muscle tone.

Later, mobility usually reaches a fairly good level. Patients typically have speech difficulties - they are able to understand more than to express themselves. They usually use simple phrases, speak slurred, and some people lose this skill completely.

  • Intellectual disability

Down's syndromeis one of the most common causes of moderate intellectual disability. All patients suffer from decreased intelligence, although to a different extent. Most often, however, the IQ does not exceed 50. A lower degree of disability usually occurs in cases of mosaicism - when only some of the body's cells have abnormal genetic material.

  • Cardiovascular

The most serious complications of Down syndrome are congenital heart defects. Until recently, they were the leading cause of early patient mortality. Currently, thanks to the development of pediatric cardiac surgery, many of them can be operated quickly and effectively.

It is estimated that approximately 40% of patients with Down's syndrome have an accompanying heart defect. The most common are the defects related to the disturbance in the development of partitions separating the heart cavities:

  • common atrioventricular canal
  • defect in the interventricular septum

Treatment of serious heart defects often involves several steps and requires severaloperation.

Down syndromeis associated with a reduced risk of developing hypertension, however, the causes of this phenomenon have not yet been fully understood.

  • Digestive tract

Congenital defects of the gastrointestinal tract are the second most common cause of surgical interventions in children with Down syndrome. The most common of them are:

  • atresia of the anus or duodenum
  • hypertrophic pyloric stenosis
  • Hirschprung's disease, related to the underdevelopment of the nerve plexuses in the intestinal wall

In addition to birth defects, there is also a greater likelihood of other gastrointestinal diseases:

  • celiakii
  • gastroesophageal reflux

The early onset of reflux may make it difficult to feed your baby and a slow pace of weight gain.

  • The organs of sight and hearing

The visual impairment may involve various structures of the eyeball:

  • lenses (congenital cataracts)
  • corneas (keratoconus)
  • oculomotor muscles (strabismus)

People with Down's syndrome also often have hearing problems: many experience gradual hearing loss with age.

Another common complaint is the form of chronic "glue ear" otitis media.

  • Cancer

Down syndromeis associated with an increased risk of childhood leukemia (AML, ALL).

  • Neurological disorders

The most common dysfunction of the nervous system in patients with Down syndrome is decreased intellectual performance.

They also have an increased risk of developing epilepsy (both in childhood and in adulthood).

The neurological status of patients over 40 years of age often deteriorates due to the high prevalence of premature dementia.

In turn, the psychosocial development of patients, the ability to establish relationships and emotional maturity are usually of a good level.

  • Hormonal disorders

The most common endocrine problem is hypothyroidism (20-40% of patients).

  • Immune system

The functions of the immune system of patients with Down syndrome are reduced, which results in high susceptibility to various types of infections (most often of the respiratory tract, gastrointestinal tract and within the oral cavity).oral).

An increased tendency to develop autoimmune diseases (e.g. autoimmune thyroiditis, celiac disease) has also been observed.

  • Reproductive system

Down's syndromecauses delayed puberty. Most of the men affected by this condition are infertile, although individual cases of having offspring have been reported in the scientific literature.

Female reproductive functions are less often disturbed - it is estimated that 30-50% of patients retain fertility.

Patients with the mosaic variant of Down's syndrome have a greater chance of maintaining their reproductive potential.

Medical care for a patient with Down syndrome

The organization of medical care for a patient with Down syndrome changes with the course of his / her life.

The postnatal period should focus on searching for and possible treatment of serious birth defects (heart, gastrointestinal tract). Throughout childhood, the patient should undergo regular ophthalmological and ENT checkups.

Due to the increased susceptibility to infections, it is very important to follow the recommendations regarding preventive vaccinations. It is currently believed that (unless there are exceptional contraindications), children with Down's syndrome should be vaccinated according to the generally accepted immunization schedule.

The remaining activities are usually aimed at the prevention and treatment of the most common disorders associated with Down's syndrome. These include regular tests of thyroid hormone levels and blood counts, obesity prevention as well as dental prophylaxis.

It is also very important to advise the child's parents about psychosocial, developmental and educational issues.

Diagnostics for Down's syndrome

  • Prenatal testing

Nowadays, most cases of Down's syndrome are diagnosed before the baby is born thanks to widespread prenatal diagnosis.

Screening tests for genetic diseases include both an ultrasound examination and the determination of the so-called biochemical markers - substances whose abnormal concentrations may indicate serious malformations of the fetus.

An abnormal result of screening tests is never the basis for diagnosing a disease, but only an indication for additional diagnostic tests. Each of them carries the risk of a false-positive result - that is, demonstrating the presence of the disease in a completely he althy fetus. For the most important non-invasive testsduring pregnancy include:

  • nuchal translucency test (NT), performed during ultrasound examination at 11-13 weeks of pregnancy. Thickening of the space between the skin and the spine of the fetus near the nape of the neck can be one of the signs of Down's syndrome, but it can also accompany other genetic diseases, birth defects or infections. Increasing the nuchal translucency is also recognized in he althy fetuses.
  • assessment of fetal morphology in ultrasound of the fetus. In addition to measuring the nuchal translucency, in screening ultrasound examinations, the doctor looks for additional features that may indicate genetic defects. The appearance of the hands and feet, the nasal bone and the development of internal organs are assessed. The dysmorphic features typical of Down's syndrome may unfortunately remain invisible on ultrasound.
  • measurement of biochemical markers, including the concentration of PAPPA protein (in the first trimester) and the so-called triple test (after the 14th week of pregnancy). The triple test includes the determination of free estriol, human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP). In the so-called In addition, the quadruple test measures the level of inhibin A. Increased likelihood of Down's syndrome is indicated by increased levels of beta-hCG and inhibin A, as well as decreased levels of other markers. Abnormal levels of markers are not specific to Down's syndrome - just like increased cervical translucency, they may accompany other conditions.
  • free fetal DNA (cffDNA, NIPT test), which is the examination of the fetal DNA in the mother's bloodstream. It is one of the most modern methods of non-invasive prenatal diagnosis. The test is highly sensitive, but it should be remembered that it should be considered a screening test. It allows you to recognize an increased risk of Down's syndrome, but it is not a basis for confirming the disease.

The results of all the above tests should always be interpreted together - the combination of several types of screening tests gives a greater chance of avoiding diagnostic errors.

If prenatal tests indicate a risk of disease, parents are offered to extend diagnosis and perform invasive tests.

Another indication for their implementation may be the mother's age over 35. The most commonly used invasive diagnostic methods are:

  • amniocentesis- collection of a small volume of amniotic fluid with a special needle
  • chorionic villus sampling- taking a small sample from the placenta

The material obtained in this way gives upgenetic research. Invasive tests are much more accurate and allow you to confirm the diagnosis - on the other hand, unfortunately, they are at risk of complications, including miscarriage.

  • Postnatal diagnosis

The confirmation of Down syndrome requires a genetic test to determine the child's karyotype. Its conduct is also important from the point of view of estimating the risk of recurrence of the disease in the family.

If a translocation is detected in genetic testing, the child's parents may also be tested. You can then check whether the translocation was inherited from them - in such a situation the risk of Down syndrome in subsequent children is higher.

Confirmation of Down syndrome is also an indication for further diagnostic steps - for example echocardiographic examination to exclude a heart defect.

Krzysztof BialaziteA medical student at Collegium Medicum in Krakow, slowly entering the world of constant challenges of the doctor's work. She is particularly interested in gynecology and obstetrics, paediatrics and lifestyle medicine. A lover of foreign languages, travel and mountain hiking.

Category:

Genetic diseases