Down syndrome and genetics

ALSO KNOWN AS: Trisomy 21

DEFINITION: Down syndrome is one of the most common chromosomal defects in human beings. According to the Centers for Disease Control and Prevention (CDC) in 2022, it occurs in one in about 772 live births in the United States.

This syndrome (a pattern of characteristic abnormalities) was first described in 1866 by the English physician John Langdon Down. While in charge of an institution housing the profoundly intellectually disabled, he noticed that almost one in ten of his patients had a flat face and slanted eyes, causing Down to use the term mongolism to describe the syndrome; this term, however, is misleading. Males and females of every race and ethnicity can and do have this syndrome. To eliminate the unintentionally racist implications of the term mongolism, Lionel Penrose and his colleagues changed the name to Down syndrome. Although Down syndrome was observed and reported in the 1860s, it was almost one hundred years before the cause was discovered.

Risk Factors

A woman’s chance of having a child with Down syndrome increases with age because older egg cells are at greater risk of having improperly divided chromosomes. According to the National Down Syndrome Society, a pregnant woman who has given birth to one child with Down syndrome has about a 1 percent chance of having another child with the condition until the age of forty. In addition, both women and men who have the genetic for Down syndrome can pass it on to their children.

Etiology and Genetics

In 1959, the French physician Jérôme Lejeune and his associates realized that the presence of an extra chromosome 21 was the apparent cause of Down syndrome. This fact places the syndrome in the broader category of aneuploid conditions. All human cells have forty-six chromosomes, or strands, made up of a chemical called deoxyribonucleic acid (DNA). The sections or subdivisions along these forty-six strands, called genes, are responsible for producing all the proteins that determine specific human characteristics. An aneuploid is a cell with forty-five, forty-seven, or more chromosomes, with the missing or extra strands of DNA leaving the individual with too few or too many genes. This aneuploid condition then results in significant alterations in one’s traits and a great number of potential abnormalities.

The forty-six strands of standard DNA are actually twenty-three pairs of chromosomes that are referred to as homologous because each pair is the same size and contains the same genes. In most cases of Down syndrome, there are three copies of chromosome 21. An aneuploid with three of a particular chromosome is called trisomic; thus, Down syndrome is often called trisomy 21. The extra chromosome is gained because either the egg or sperm that came together at fertilization contained an extra one. This error in gamete (egg or sperm) production is called nondisjunction and occurs during the process of meiosis. When meiosis proceeds normally, the homologous chromosome pairs are separated from each other, forming gametes with twenty-three chromosomes, one from each pair. If nondisjunction occurs, a pair fails to separate, producing a gamete type with twenty-two chromosomes and a second gamete type with twenty-four chromosomes. If the pair that has failed to separate is chromosome 21, then the potential exists for twenty-three chromosomes in a normal gamete to combine with a gamete containing twenty-four, creating a trisomic individual with forty-seven chromosomes.

Although this syndrome was recognized by Down in 1866, true understanding of it dates from the work that Lejeune began in 1953. The seemingly innocuous characteristic of unconventional palm prints and fingerprints fostered an important insight for him. Since those prints are laid down very early in the child’s prenatal development, they suggest a profoundly altered embryological course of events. His intuition told him that not one or two altered genes but rather a whole chromosome’s genes must be at fault. In 1957, he discovered, by culturing cells from children with Down syndrome in dishes in the laboratory, that those cells contained forty-seven chromosomes. This work eventually resulted in his 1959 publication, which was soon followed by the discovery that the extra chromosome present was a third copy of chromosome 21.

The subsequent development of more sophisticated methods of identifying individual parts of chromosomes has shed much light on the possible mechanisms by which the symptoms are caused. Some affected individuals do not have a whole extra chromosome 21; rather, they possess a third copy of some part of that chromosome. A very tiny strand of DNA, chromosome 21 contains only about fifteen hundred genes. Of these fifteen hundred, only a few hundred are consistently present in those who have Down syndrome, namely the genes in the bottom one-third of the chromosome. Among those genes are several that could very likely cause certain symptoms associated with Down syndrome. A leukemia-causing gene and a gene for a protein in the lens of the eye that could trigger cataract formation have both been identified. A gene for the production of the chemicals called purines has been located. The overabundance of purines produced when three copies of this gene are present has been linked to the intellectual disability usually seen.

Even the fact that individuals with Down syndrome have a greatly reduced life expectancy is validated by the presence of an extra gene for the superoxide dismutase, which seems involved in the normal aging process. Like Alzheimer’s disease patients, Down syndrome patients who live past forty years of age have gummy tangles of protein strands called amyloid fibers in their brains. Since one form of inherited Alzheimer’s is caused by a gene on chromosome 21, scientists continue to search for links between the impaired mental functioning characteristic of both diseases.

Other research has shed light on the long-recognized relationship between the age of the mother and an increased risk of having a child with Down syndrome. Using more and more elaborate methods of chromosome banding, geneticists can determine whether the extra chromosome 21 came from the mother or the father. In 94 percent of children, the egg brings the extra chromosome. Since the first steps of meiosis to produce her future eggs occur before the mother’s own birth, the older the mother, the longer these egg cells have been exposed to potentially harmful chemicals or radiation. On the other hand, paternal age is not a factor because all the steps of meiosis in males occur in cells produced in the few weeks before conception. The continued study of the age factor, as well as new insights from genomics, are leading to a greater understanding for all those affected by Down syndrome.

The relationship between Down syndrome and age may not be limited to just the age of the mother who gives birth to a baby with the condition. One study published in Cell Stem Cell in 2022 found that the underlying genetic problem that leads to Down syndrome may be specifically tied to senescent cells. Researchers discovered that these cells, which are linked to many diseases related to aging, may play a direct role in the neuropathology of Down syndrome.

Symptoms

The slanted appearance of the eyes first reported by Down is caused by a prominent fold of skin called an epicanthic fold (a fold in the upper eyelid near the corner of the eye). This fold of skin is accompanied by excess skin on the back of the neck and unconventional creases in the skin of the palm. In addition, the skull is wide, with a flat back and a flat face. The hair on the skull is sparse and straight.

The rather benign physical characteristics are minor compared to the defects in internal organ systems. About 50 percent of Down syndrome patients have heart defects at birth, according to data from the US Centers for Disease Control and Prevention (CDC). They are very prone to cancer of the white blood cells (acute leukemia), the formation of cataracts, and serious recurring respiratory infections. Short of stature with poorly formed joints, they often have poor reflexes, weak muscle tone, and an unstable gait. The furrowed, protruding tongue that often holds the mouth partially open is an external sign of the serious internal digestive blockages frequently present. These blockages must often be surgically repaired before the individual’s first birthday. Many have major kidney defects that are often irreparable. Furthermore, a suppressed immune system can easily lead to death from an infectious disease such as influenza or pneumonia.

With all these potential physical problems, it is not surprising that a significant portion of Down syndrome patients die before the age of one. For those who live, there are enormous physical, behavioral, and mental challenges. The intellectual disability that always accompanies Down syndrome ranges from quite mild to profound. This intellectual disability makes all learning difficult, and speech acquisition in particular very slow. Yet most individuals with Down syndrome have warm, loving personalities and enjoy art and music.

Screening and Diagnosis

The American College of Obstetricians and Gynecologists recommends that all pregnant women, regardless of their age, be screened for Down syndrome. Various prenatal screening tests can help detect whether the mother has a high risk of having a baby with this condition. A blood test usually is conducted around the sixteenth week of pregnancy to screen for Down syndrome and other disorders. Women who want an earlier assessment can receive a first-trimester combined test, which is conducted in two phases from week eleven to week thirteen of pregnancy. However, about 5 percent of women who undergo this test have a false-positive result, which means that they are incorrectly identified as being at risk for having a baby with Down syndrome. This first-trimester test consists of an ultrasound and blood tests.

Women who opt to wait for a later assessment can have full integrated testing, which is conducted in two phases during their first two trimesters of pregnancy. Only about 1 percent of women receive a false-positive result from this test. The first part of the integrated test, performed during the first trimester, includes an ultrasound and blood test; additional blood tests are performed during the second trimester, at fifteen to twenty weeks of pregnancy. If this test indicates a high risk of Down syndrome, a woman may receive a more invasive test to confirm whether her baby has the condition.

Women who do not want to have screening tests can choose to have diagnostic tests, such as amniocentesis, in which a sample of is used to analyze the fetus’s chromosomes; chorionic villus sampling (CVS), which uses cells from the mother’s placenta to analyze fetal chromosomes; and percutaneous umbilical blood sampling (PUBS), in which blood is taken from a vein in the umbilical cord and examined for chromosomal defects.

In certain cases of high-risk pregnancies, women may have the option of noninvasive prenatal testing (NIPT). At around ten weeks, a blood sample can be taken from the mother to look at the baby's DNA in the mother's blood. NIPT testing, which can screen for several conditions, including trisomy 18 and trisomy 13, is about 99 percent accurate in detecting Down syndrome.

After a child is born, an initial diagnosis of Down syndrome can be made at birth based upon the baby’s appearance. The physician, using a stethoscope, may also hear a heart murmur in the baby’s chest. Blood tests can then be conducted to locate the extra chromosome and confirm the diagnosis. Other diagnostic tests include an echocardiogram (the use of ultrasound to check for heart defects), an electrocardiogram (ECG) of the heart, and X-rays of the chest and the gastrointestinal tract.

Individuals with Down syndrome must be closely screened for certain medical conditions. Children should have an eye exam every year during infancy and X-rays of the upper or cervical spine between the ages of three and five. Patients with the syndrome also need to have a hearing test every six to twelve months, depending on age; dental exams every six months; and Pap smears and pelvic exams beginning in puberty or by the age of twenty-one.

Treatment and Therapy

There is no specific treatment for Down syndrome. Babies who are born with a gastrointestinal blockage may need major surgery immediately after birth, and some heart defects may also require surgery. The mother should be sure that the baby is well supported and fully awake during breast-feeding. Although poor tongue control could cause a baby to experience some milk leakage during feeding, many infants with Down syndrome can be successfully breastfed.

Older children and adults with Down syndrome may have a problem with obesity. They should get plenty of exercise and avoid eating high-calorie foods. In addition, their necks and hips should be examined before they begin sports activities.

People with Down syndrome can benefit from behavioral training to help them cope with their anger, frustration, and compulsive behavior. Parents and caregivers should encourage a child with Down syndrome to be independent, and they should learn how to help the child deal with frustration.

Both males and females with Down syndrome are at risk of being abused sexually or in some other way. Adolescent girls and women with Down syndrome are usually able to become pregnant. For these reasons, it is important that individuals with Down syndrome learn about pregnancy and know how to take the proper precautions. They should also be taught how to take care of themselves in difficult situations.

A variety of social and educational services are available in many communities to help those with Down syndrome, including special education programs to address delayed mental development. Speech, physical, and occupational therapies can help with language and movement skills, feeding, and performing other tasks. In addition, children and their parents can receive mental health care in order to manage their moods or behaviors.

Prevention and Outcomes

Down syndrome cannot be prevented. However, women at risk of giving birth to a child with this condition may seek genetic counseling before becoming pregnant. At the same time, by 2015 the advancement in screening tests had led to a debate over the information given in genetic counseling and the rate of abortions regarding disabilities such as Down syndrome. Some commentators were concerned that the information given may be negatively swaying mothers toward choosing abortion, leading to action such as the passing of the Down Syndrome Prenatal Education Act in the state of Pennsylvania in 2014, which requires healthcare workers to ensure that women making the prenatal decision about whether to abort a baby with Down syndrome will receive a thorough range of supportive information through the state's health department. In 2022, after the US Supreme Court struck down the legal right to seek an abortion, many states enacted laws that severely limited or outlawed the procedure. The situation left many couples without options and led to more discussion about when and whether to provide genetic screening for these and other genetic conditions.

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