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Down Syndrome

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Syed Intisar Hussain

Overview

Down syndrome or Down&rsquo;s syndrome is a condition in which a child is born with an extra chromosome 21. For centuries, both science and art have hinted at Down syndrome. It was not until 1866 that English physician, John Langdon Down published an accurate description of the syndrome in his scholarly work. Since he was the first to present it as a separate and distinct entity, the condition came to be known as Down syndrome.

Then, in 1959, French physician J&eacute;r&ocirc;me Lejeune observed that there were 47 cells instead of 46 chromosomes in an individual with Down syndrome. He identified it as a chromosomal condition. Fast forward, to 2000, an international team of scientists identified each of 329 genes on chromosome 21, paving the way for further research in Down syndrome.

To date, what&rsquo;s known is that every cell in the human body consists of a nucleus that stores the genetic material or genes. The genes carry codes that are grouped as rod-like structures known as chromosomes. The chromosomes are responsible for all our inherited traits and determine how a baby&rsquo;s body forms as it grows during pregnancy and after birth.

Each nucleus typically contains 23 pairs of chromosomes or 46 chromosomes, half of which are inherited from each parent. Down syndrome occurs when there is an extra copy of chromosome 21. In medical terminology, this is referred to as &ldquo;Trisomy 21&rdquo;, the additional genetic material that alters the course of development, thereby causing mental and physical challenges for the baby.&nbsp;

Down syndrome is characterized by some common physical traits such as small stature, low muscle tone, upward-slanted eyes, and a single deep crease across the center of the palm. However, each person with Down syndrome is unique and the genetic material abnormality may manifest with characteristics of varying degrees.&nbsp;

The Centers for Disease Control and Prevention states that one in every 772 babies in the United States is born with Down syndrome. Each year, approximately 5,100 babies are born with Down syndrome in the United States<a href="#accordion">[1]</a>. Closer to home, the overall incidence of Down syndrome in Pakistan is reported as 1 in 700 live births<a href="#accordion">[2]</a>.

While Down syndrome is not specific to any gender, race, or age, older women are at a greater risk of having a child with Down syndrome. A cytogenetic analysis of the prevalence of chromosomal defects with advancing age indicates the risk of Down syndrome is fairly higher in pregnancies where the maternal age is more than 35 years these women have a 1 in 350 chance of conceiving a child with Down syndrome<a href="#accordion">[2][3]</a>.&nbsp;The probability increases to 1 in 100 by the time a woman turns 40 and 1 in 30 when she is 45 years of age<a href="#accordion">[3]</a>.

&nbsp;

These include:

&nbsp;

<ul>
	<li>
	<h5>Trisomy 21 (Nondisjunction)&nbsp;</h5>
	</li>
</ul>

An error in cell division is called &ldquo;nondisjunction&rdquo;. Instead of the usual 2, there are 3 copies of chromosome 21 in nondisjunction. That is, a pair of chromosome 21 in the sperm or the egg fails to separate either prior to or at conception.&nbsp;

The extra chromosome is then replicated in every cell of the body as the embryo develops. 95% of the cases of Down syndrome are a result of nondisjunction<a href="#accordion">[3]</a>. 
&nbsp;

<ul>
	<li>
	<h5>Mosaicism&nbsp;</h5>
	</li>
</ul>

Mosaicism or mosaic Down syndrome is characterized by a combination of two types of cells, some contain the usual 46 chromosomes, and some 47. The cells that have the extra chromosomes contain a copy of chromosome 21.&nbsp;

This type of Down syndrome is the rarest type of the condition and accounts for only 2% of the cases<a href="#accordion">[3]</a>.&nbsp;Studies have further shown that individuals with mosaicism have fewer characteristics of Down syndrome in contrast to those with other types.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Translocation&nbsp;</h5>
	</li>
</ul>

Translocation accounts for 3% of the cases of Down syndrome<a href="#accordion">[3]</a>. While the total number of chromosomes remains the same in this type, there is an additional full or partial copy of chromosome 21 which attaches to another chromosome &ndash; usually chromosome 14. This extra chromosome is responsible for the characteristic features of Down syndrome.

&nbsp;

Signs And Symptoms

Down syndrome can be identified by its symptoms. It affects the physical, cognitive, and behavioral abilities of an individual. For instance, infants with Down syndrome have an average size at birth but they typically grow slower and remain smaller than children of the same age.&nbsp;

&nbsp;

<h5>Physical Signs</h5>

<ul>
	<li>Short height with a short neck&nbsp;</li>
	<li>Poor muscle tone&nbsp;</li>
	<li>Flattened face&nbsp;</li>
	<li>Small head</li>
	<li>Small or unusually shaped ears&nbsp;</li>
	<li>Protruding tongue&nbsp;</li>
	<li>Palpebral fissures or upward-slanting eyelids</li>
	<li>Broad and small hands with a single crease in the palm&nbsp;</li>
	<li>Small feet&nbsp;</li>
	<li>Relatively shorter fingers&nbsp;</li>
	<li>Excessive flexibility&nbsp;</li>
	<li>Brushfield&#39;s spots or tiny white spots on the iris (colored part of the eye) 
	&nbsp;</li>
</ul>

<h5>Cognitive Impairment</h5>

<ul>
	<li>Delayed speech and language development&nbsp;</li>
	<li>Short attention span</li>
	<li>Slow learning 
	&nbsp;</li>
</ul>

<h5>Behavioral Problems</h5>

<ul>
	<li>Impulsive behavior, like restlessness&nbsp;</li>
	<li>Sleep issues, such as insomnia and excessive daytime sleepiness&nbsp; 
	&nbsp;</li>
</ul>

Note: The severity of the signs and symptoms varies from person to person and not all people with the syndrome have these signs and symptoms.&nbsp;

&nbsp;

Causes

All cells in the body contain genes that have a set of instructions. Each chromosome present in the nucleus of the cell has many genes. Now, we know that each cell typically contains 46 chromosomes &ndash; 23 chromosomes from each parent. But, when there is an extra partial or full copy of chromosome 21, the baby is born with Down syndrome.&nbsp;

At this stage, it&rsquo;s important to remember that in most cases, this condition is not inherited, even though the syndrome comes from genes themselves. It occurs because of errors between sperm and an egg when the genetic information combines and copies. 
&nbsp;

<h5>How Genetics Work&nbsp;</h5>

<ul>
	<li>Chances are higher if the mother is over 35 years.</li>
	<li>The likelihood of Down syndrome increases if the parents of a person have translocation Down syndrome<a href="#accordion">[4]</a>.</li>
	<li>There may be an increased chance of Down syndrome in future pregnancies if a parent has balanced translocation. But this does not occur in every case.&nbsp;</li>
	<li>Down syndrome is caused because of an error in cell division (nondisjunction). Typically, when cells divide in two, the pairs of chromosomes also split, and each split chromosome goes into one cell. In nondisjunction, both chromosomes from one pair go into one cell. The error is mostly random and occurs during the formation of an egg or sperm; no behavioral activity of the parents or environmental factors have any control over it.&nbsp; 
	&nbsp;</li>
</ul>

<h5>What Are The Odds Of Having A Baby With Down Syndrome?</h5>

Research shows that:&nbsp;

<ul>
	<li>The extra copy of the chromosome in a majority of the cases comes from the mother through the egg.&nbsp;</li>
	<li>In less than 5% of cases, the extra copy of chromosome 21 comes from the father through the sperm.&nbsp;</li>
	<li>A third possibility is that the error may occur after fertilization as the embryo grows. 
	&nbsp;</li>
</ul>

<h5>What Does It Mean For The Child?</h5>

Three types of chromosomal changes can lead to Down syndrome. Understanding what it specifies for the child can help the parent(s) or caregiver(s) address it and ensure the young ones can lead a quality life:

&nbsp;

<ul>
	<li>Complete Trisomy 21:&nbsp;An error occurs in the formation of the egg or the sperm, which results in either of the two having an extra chromosome. Therefore, after the cells unite, the resultant copy also has three copies of chromosome 21. In other words, the new copy of the chromosome or complete trisomy is in every cell of the person&rsquo;s body.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Mosaic Trisomy 21:&nbsp;Most of the cells in the body have an extra chromosome. This is known as mosaic trisomy 21. This type of trisomy occurs when there is an error early in cell division after a normal egg and sperm unite.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Translocation Trisomy 21:&nbsp;There is only part of an extra chromosome 21 copy in the cells. The extra part gets &ldquo;stuck&rdquo; to another chromosome and transmits into other cells during cell division.&nbsp;</li>
</ul>

&nbsp;

In some cases, a parent who does not have Down syndrome may carry a translocation in chromosome 21 that can be passed on to children. Studying the chromosomes of the parents can delineate whether this is the cause of the condition.&nbsp;

&nbsp;

Routine tests during pregnancy give a heads-up to the family if the baby will be born with Down&rsquo;s syndrome.&nbsp; 
&nbsp;

<h5>First Trimester</h5>

The tests advised in the first trimester include:&nbsp;

&nbsp;

<ul>
	<li>Blood Tests: The blood tests will measure the levels of protein PAPP-A and hormone hCG in the blood. If the test results are deranged, it could mean a problem with the baby.&nbsp; 
	&nbsp;</li>
</ul>

If there is a high risk for Down syndrome, DNA from the baby in the blood may also be examined for chromosome abnormalities.

&nbsp;

<ul>
	<li>Ultrasound: The ultrasound will measure the folds of tissue at the back of the baby&rsquo;s neck. Babies with Down syndrome have extra fluid there.&nbsp; 
	&nbsp;</li>
</ul>

<h5>Second Trimester</h5>

The tests advised in the second trimester include:&nbsp;

&nbsp;

<ul>
	<li>Blood Tests: Triple or quad screen tests are advised to measure the substances in the blood including hormone estriol and protein AFP. The levels will give a good estimate of whether the baby is at risk of having Down syndrome.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Ultrasound: An enhanced ultrasound can show the physical features of Down syndrome.&nbsp; 
	&nbsp;</li>
</ul>

<h5>Other Tests</h5>

Other tests that can diagnose Down syndrome by checking a sample of the DNA for chromosome 21 include:&nbsp;

&nbsp;

<ul>
	<li>Chorionic Villus Sampling (CVS): This test is performed during the first trimester using cells that are taken from the placenta.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Amniocentesis: This test is usually performed in the second trimester and fluid is taken from the amniotic sac surrounding the baby.&nbsp;</li>
</ul>

&nbsp;

<ul>
	<li>Percutaneous Umbilical Blood Sampling (PUBS): This test is also performed during the second trimester using blood from the umbilical cord.&nbsp;</li>
</ul>

&nbsp;

Diagnosis

Down syndrome is identified at birth by the presence of physical traits. For example, flattened facial features, an upward slant to the eyes, low muscle tone, and a single deep crease across the palms. However, the same features may also be present in babies without Down syndrome. Therefore, a chromosomal analysis is carried out to confirm the diagnosis.&nbsp;

To begin with, a blood sample is taken to obtain a karyotype to examine the baby&rsquo;s cells. The chromosomes are photographed and then grouped according to the size, number, and shape.&nbsp;

Another genetic test called fluorescence in situ hybridization can be used for confirming the diagnosis of Down syndrome in a shorter time by mapping genetic material in the cells.&nbsp;

&nbsp;

Treatment

There is no treatment for Down syndrome. Nevertheless, services early in life can help improve physical and intellectual abilities in children with the condition. These services typically include speech therapy, occupational therapy, and physical therapy to help children develop to their full potential.&nbsp;

The good news is that with a little extra help, children with Down syndrome are admitted to mainstream schools. They are also widely accepted in society, in social or recreational activities, in healthcare systems, and in other workforces.&nbsp;

In the early 1900s, children with Down syndrome were only expected to live till age 9, but with advancements in medicine, they are living to 19 or 20 years.&nbsp; Similarly, with clinical treatments and corrective heart surgeries, 80% of adults with Down syndrome reach the age of 60 or may even live longer<a href="#accordion">[5]</a>.

&nbsp;

People with Down syndrome may present with an array of complications.&nbsp; 
&nbsp;

<ul>
	<li>Heart Defects: Nearly half of all these children are born with a congenital heart defect that require surgical correction.&nbsp; 
	&nbsp;</li>
	<li>Gastrointestinal Defects: They may have GI abnormalities of the trachea, esophagus, intestines, and anus. Moreover, individuals with Down syndrome are at an increased risk of developing celiac disease, heartburn, and GI blockage.&nbsp; 
	&nbsp;</li>
	<li><a href="https://www.merisehat.pk/disease/sleep-apnea-91" target="_blank">Sleep Apnea</a>: Children with Down syndrome are at a higher risk of developing sleep apnea because of soft tissue and skeletal changes that may obstruct the airways. 
	&nbsp;</li>
	<li>Immune Disorders: Abnormalities in their immune systems mean they often develop infections. For example, pneumonia, cancers, and autoimmune disorders. 
	&nbsp;</li>
	<li><a href="https://www.merisehat.pk/disease/obesity" target="_blank">Obesity</a>: People with Down syndrome are typically more obese than the general population. 
	&nbsp;</li>
	<li>Spinal Defects: In some cases, the top two vertebrae in the neck may be misaligned, which puts them at risk of spinal injuries. 
	&nbsp;</li>
	<li>Leukemia: Having leukemia, a cancer of the white blood cells, bone marrow, and lymphatic system is a possibility, too. 
	&nbsp;</li>
	<li>Early Onset Dementia: Symptoms of dementia begin to appear when they&rsquo;re around the age of 50. They are also at an increased risk of developing Alzheimer&rsquo;s.&nbsp; 
	&nbsp;</li>
	<li>Other Health Conditions: Other issues associated with Down syndrome include endocrine problems, vision and hearing problems, ear infections, seizures, and dental problems. However, medical care and treatment can help those with Down syndrome maintain a healthy lifestyle.</li>
</ul>

&nbsp;

There are some factors that increase the risk of having a baby with Down syndrome:&nbsp;

<ul>
	<li>Advanced maternal age&nbsp;</li>
	<li>Either of the parents are carriers of genetic translocation&nbsp;</li>
	<li>Already have a child with Down syndrome</li>
</ul>

&nbsp;

There is currently no prevention for Down syndrome. However, a couple risks having a baby with Down syndrome if they already have a child or children with this condition. A genetic counseling session before planning a pregnancy can help understand the chances of having another kid with Down syndrome.

&nbsp;

<ul>
	<li>People with Down syndrome are people first and should be referred to as &ldquo;people&rdquo; instead of a &ldquo;Down syndrome child&rdquo; or &ldquo;Down&rsquo;s child&rdquo;.&nbsp;</li>
	<li>Down syndrome is not a disease and should not be described as &ldquo;Down&rsquo;s&rdquo; or &ldquo;he/she has Down&rsquo;s&rdquo;.&nbsp;</li>
	<li>Individuals with Down syndrome do not &ldquo;suffer from&rdquo; it; they &ldquo;have&rdquo; it. So, the correct way to talk about them is as &ldquo;a child/person with Down syndrome&rdquo;.</li>
	<li>The Down syndrome society condemns the use of the word &ldquo;retarded&rdquo; and has replaced &ldquo;mental retardation&rdquo; with &ldquo;intellectual disability&rdquo; or &ldquo;cognitive disability&rdquo;.&nbsp;</li>
</ul>

&nbsp;

Key Points

<ul>
	<li>Down syndrome&nbsp;(also referred to as &ldquo;Down&rsquo;s syndrome&rdquo; and not as &ldquo;Down&rsquo;s&rdquo;) is a condition in which a child is born with an extra chromosome.&nbsp;</li>
	<li>The Centers for Disease Control and Prevention elucidates that one in every 772 babies in the United States is born with Down syndrome. Comparatively, the overall incidence of Down syndrome in Pakistan is reported as 1 in 700 live births.</li>
	<li>While there are several factors that contribute to Down syndrome, the mother being over 35 years at the time of pregnancy remains the most significant reason for giving birth to a baby with Down syndrome.</li>
	<li>Down syndrome is generally identified at birth by the presence of physical traits, like flattened facial features, an upward slant to the eyes, low muscle tone and a single deep crease across the palms.</li>
	<li>There is currently no prevention or treatment for Down syndrome. However, services early in life can help improve physical and intellectual abilities in children with the condition.</li>
</ul>

&nbsp;

[1] De Graaf, G., Buckley, F. and Skotko, B.G., 2017. Estimation of the number of people with Down syndrome in the United States. Genetics in Medicine, 19(4), pp.439-447.

[2] Jameel, T., Rashid, Y., Anwar, M., Sultana, N., Waqar, M.A. and Saleem, M., 1999. Down's syndrome: prospects for prevention by antenatal diagnosis. JOURNAL-PAKISTAN MEDICAL ASSOCIATION, 49, pp.60-62.