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genetic pattern of trisomy 21

Image: “Trisomía” by UPO649 1112 mreycor1. License: CC BY-SA 3.0


Down syndrome as a mental and physical handicap

genetic pattern of trisomy 21

Image: Trisomia. By: UPO649 1112 mreycor1. License: CC BY-SA 3.0

Trisomy 21, also known as Down syndrome, is a chromosomal aberration that leads to the presence of 3 copies of chromosome 21.

In trisomy 21, patients show delayed or impaired mental and physical development. The syndrome is named after the English physician J. Langdon Down who first described the disease in 1866.


Down syndrome in the population

A graph of data showing the risk of down syndrome

Image: Graph showing the risk (as a percentage of live births) of Down syndrome, along with other trisomies, by age of the mother (at delivery). By: Tdadamemd. License: CC BY-SA 3.0

With a prevalence of 1 in 700, trisomy 21 is the most common autosomal chromosome aberration. It is also the most frequent genetic cause of mental retardation in humans. Life expectancy in those with this condition is currently about 50 years and tends to increase due to improved therapeutic options.

The older the mother, the higher the risk of Down syndrome. The risk of Down syndrome in children born to women below 30 years of age is less than 1 in 1000. In 40 to 44-year-old mothers, 10–20 in 1000 children are affected, and for mothers over 44 years, 20–40 in 1000 children are affected.

Note: The older the mother, the higher the risk of trisomy 21!


Causes of Down syndrome

The underlying cause of the condition is a trisomy — a triple set of chromosomes. In Down syndrome, there is an extra chromosome 21, resulting in 3 instead of 2 chromosomes. On a cytogenetic level, the following possibilities could lead to trisomy 21.

Free trisomy 21: In >90% of all cases, the surplus chromosome 21 is free. This is caused by non-separation and is usually of maternal origin (dependent on the age of the mother; chromosome number: 47).

Scheme of a genetic mutation, in this case Trissomy 21

Image: Schema of a genetic mutation, in this case, trisomy 21. By: National Human Genome Research Institute. License: Public Domain

Trisomy 21 due to translocation: In approx. 2–4% of all cases, the surplus chromosome 21 is attached to another acrocentric chromosome (often 14) (Robertsonian translocation). The age of the mother does not have any influence in this scenario (chromosome number: 46).

Down Syndrome translocation

Image: Down syndrome translocation. By: National Human Genome Research Institute. License: Public Domain

Trisomy 21 in mosaic: In 1–2% of all cases, there is the simultaneous existence of a normal cell line and another with trisomy; the phenotype depends on the distribution pattern in the brain.

Partial trisomy 21: Very rare, duplication of one segment of chromosome 21.

Trisomy 21 due to translocation occurs de novo (by mutation) or is inherited. Here, it is possible that the parents are carriers of a balanced translocation, with a well-balanced genotype and without any clinical symptoms. If the father is a carrier of the translocation, the empirical risk of recurrence (likelihood of an ill child) is approx. 1–2%. If the mother is a carrier, the risk increases to 10–15%. With a translocation of chromosome 14, the maternal karyotype is 46, XX, t(14;21).

If there is a 21/21 translocation, the risk of trisomy 21 is 100%.

Hereditary Down Syndrome Translocation

Image: Robertsonian translocation of Down syndrome in families. By: UPO649 1112 mreycor1. License: CC BY-SA 3.0

Clinical Picture

Symptoms of Down syndrome

Image: A cropped photo of the eyes of a baby with Down syndrome. Brushfield spots are visible between the inner and outer circle of the iris. By: Szymon Tomczak. License: CC0 1.0

While there is no difference between the symptoms of a free trisomy and those of a trisomy due to translocation, the degree of manifestation of a mosaic trisomy depends on the number of cells with trisomy.

Affected persons show increased susceptibility to infections and a more frequent occurrence of leukemia.

Phenotype of Down syndrome

Patients with Down syndrome have a characteristic outer appearance with the following dysmorphic features that can occasionally be found in the normal population.

Craniofacial: Brachycephaly, flattened and broad nasal bridge, oblique lid axis in the superior and lateral direction, epicanthus, small mouth and chin, macroglossia, furrows in the lips and tongue, high roof of the mouth, abnormal teeth, abnormal auricles, Brushfield spots (whitish concentration of the iris), cataract, strabismus, nuchal fold, and short neck.

Feet of a 10 year old boy with Down Syndrome, with the typical large space between the large toe and second toe

Image: Feet of a 10-year-old boy with Down syndrome, with the typical large space between the large toe and second toe. By: Loranchet. License: CC BY 3.0

Acral: Shortened and broad hands and feet, clinodactyly, brachydactyly, single transverse palmar crease, and separation of the 1st and 2nd toes (sandal gap).

Musculoskeletal system: Hypotension of the muscles, hypermobility of the joints, umbilical/inguinal hernia, diastasis recti, surplus ribs, abnormal vertebral bodies, leveled angle of the acetabulum and ilium, and stunted growth.

Skin: Rough, dry, mottled.

Note: The mentioned abnormalities can also be found in the normal population and are hence not specific for Down syndrome!

Organic malformations in Down syndrome

Cryptorchidism, undescended testis

Image: Cryptorchidism, undescended testis. By: Nevit Dilmen. License: CC BY-SA 3.0

In addition to changes in the exterior, the organs can also be malformed. Patients with Down syndrome can have hypothyroidism. Furthermore, males, unlike females, are mostly infertile and exhibit cryptorchidism.

However, the most common (up to 50%) malformations are congenital heart diseases. They include, mostly, an atrioventricular septal defect, in addition to other heart diseases like a ventricular septal defect, patent ductus arteriosus, and isolated atrial septal defects.

Concerning the intestinal tract, duodenal atresia and Hirschsprung’s disease are common. Other possibilities include atresia of the esophagus or anus as well as malformation of the bile duct and pancreas.

Mental retardation in Down syndrome

The IQ of patients with trisomy 21 lies between 20 and 50. The mental retardation can, however, vary considerably in its severity. Usually, it is possible for patients to learn how to read and write so that in some cases, the possibility of an autonomous life exists.


Postnatal diagnosis of Down syndrome

The diagnosis of trisomy 21 is often suspected postnatally based on the clinical picture. Since many symptoms of Down syndrome can also be found in the normal population, Jackson et al. (1976) created an index that aids in the visual diagnosis. The index lists the following 25 symptoms of Down syndrome:

  1. Brachycephaly
  2. Oblique lid axis in the superior and lateral directions
  3. Nystagmus
  4. Flattened nasal bridge
  5. Narrow roof of the mouth
  6. Clinodactyly of the 5th finger
  7. Hypotension of the muscles
  8. Sandal gap
  9. Folded auricle
  10. Short neck
  11. Epicanthus
  12. Blepharitis, conjunctivitis
  13. Brushfield spots
  14. Constantly open mouth
  15. Abnormal teeth
  16. Protruding tongue
  17. Scrotal tongue
  18. High roof of the mouth
  19. Nuchal fold
  20. Shortened and broad hands
  21. Brachydactyly of the 5th finger
  22. Single transverse palmar crease
  23. Congenital heart diseases
  24. Cardiac murmur
  25. Hyperflexible ligaments

If at least 13 of these symptoms are noticed in a child, the child has a 100% probability of trisomy 21. The occurrence of 10–12 characteristics indicates a probability of 85%; 7–9 characteristics indicate a 75% probability of the condition; 5–6, a probability of 23%, and if less than 5 characteristics are found, the probability is 0%.

It is, however, necessary to confirm the diagnosis via cytogenetic examinations (analysis of the karyotype) in order to diagnose or rule out Down syndrome. It is also important to determine the underlying type of trisomy 21 in order to assess the risk of recurrence (see above), among other things.

Prenatal diagnosis of Down syndrome

Triple test

The triple test is used between the 16th and 20th weeks of pregnancy. The triple test measures the blood serum levels of the mother and compares them to reference values of other pregnant women in the same week of pregnancy. The test includes β-hCG, α-fetoprotein, and estriol. If those values differ from the standard (β-hCG high, α-fetoprotein, and estriol low), trisomy 21 can be suspected. This test is, however, not specific for Down syndrome and is susceptible to errors. It is also necessary to calculate the exact gestational age for a conclusive comparison.


Atrioventricular septal defect. Four-chamber view

Image: Atrioventricular septal defect. The four-chamber view shows the absent crux (arrow). RA – right atrium, LA – left atrium, RV – right ventricle, LV – left ventricle. By: openi. License: CC BY 2.0

Sonography could be used to detect malformations like a flat face, macroglossia, shortened femur, lack of ossification of the nasal bone, shortened fingers, dilated renal pelvis, or heart defects. These malformations are associated with trisomy 21 but cannot always be interpreted as a manifestation of a disease. Sonography can thus yield false-positive or false-negative results.

Sonography of fetal nuchal translucency (subcutaneous tissue between the neck and cervical spine) in the 11–14th weeks of pregnancy is also indicative of Down syndrome. However, this finding is also not specific to trisomy 21.

Ultrasound image of measurements of fetal nuchal translucency, and absent nasal bone at 11 weeks of pregnancy. CVS demontrated a trisomy 21 of the fetus

Image: Ultrasound image of measurements of fetal nuchal translucency, and absent nasal bone at 11 weeks of pregnancy. CVS demonstrated trisomy 21 of the fetus. By: Wolfgang Moroder. License: CC BY-SA 3.0

Amniocentesis and chorionic villus sampling

If non-invasive examinations like sonography or the triple test show noticeable findings, invasive examinations like amniocentesis and chorionic villus sampling should be considered. For this procedure, the fetal or placental cellular material is extracted and chromosomal analysis is performed. Both methods can diagnose trisomy 21 with a high degree of certainty. They are, however, known to be associated with an increased risk of miscarriage.

Treatment of Down syndrome

Organic malformations have to be treated symptomatically. For example, hypothyroidism can be treated by substituting thyroxinecongenital heart diseases can be treated surgically in order to considerably increase the quality of life. Physiotherapy (as early as possible) can mitigate the extent of muscular hypotension.

It is also essential to encourage the affected children and to treat them with adequate care. Hence, they need a loving environment as well as medical and psychosocial care. Caring for a child with Down syndrome is often a special challenge for the parents, so it can be helpful for such parents to join self-help groups. The accessibility of a social pediatric center is also useful.

Medical check-ups are important for patients with trisomy 21. It is crucial to watch out for abnormalities of the gastrointestinal tract and heart in newborn babies and infants. It is also necessary to detect eye diseases like cataract and strabismus as early as possible in order to prevent additional handicaps due to visual impairment.

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