Category : Health and you
A healthy human cell contains 46 number of chromosomes existing in 23 pairs. Chromosomes carry the genetic information of a living organism in the form of a hereditary material called Deoxyribose nucleic acid (DNA). Any deviation in chromosome number results in health conditions, collectively referred to as chromosomal abnormalities or aneuploidies. Down Syndrome (DS) is one of the most prevalent live-birth aneuploidies in humans. It is also referred to as Trisomy 21 for being characterized by the presence of an extra, full or partial copy of chromosome 21. Therefore, an individual with DS has 47 chromosomes in their cells instead of 46. Because of the gene-dosage effect, the overexpressed Down syndrome critical region (DSCR; on 21q21.22) of Hsa21 may alter the course of body and brain development, and results in a wide spectrum of clinical manifestations.
Individuals with DS experience numerous challenges. However, today they have a far brighter future than ever before, owing to advancements in prenatal screening, early intervention, and multidisciplinary care. In recent decades, the global outlook on DS has undergone a profound transformation, shifting from a purely medical condition to a social and human rights discourse centered on inclusion, empowerment, and equality. By exploring the genetic, clinical, and psychosocial dimensions of DS, this article aims to promote a comprehensive understanding of the condition.
History: Down Syndrome is named after an English physician John Langdon Down, who described the characteristic features of the condition in the late 19th century.
Clinical Features:
The physical signs of DS are typically evident at birth and become increasingly apparent as the child develops. These signs include the following:
- distinct facial features (including flat nasal bridge, upward slanting eyes, small ears)
- other unique dysmorphic traits (including small hands and feet, palmar crease or single deep crease across the palm, small little finger that points inward towards the thumb, broad neck, short stature)
- weak muscle tone (hypotonia), and
- developmental delays (particularly in speech and motor skills)
- intellectual disabilities (cognitive delays and impaired cognition; typically ranging from very mild to severe)
- behavioral problems (such as stubbornness and tantrums, attention deficits, obsessive or compulsive behaviors)
- deficits in social and emotional skills.
Healthcare providers will routinely monitor for these clinical features and any other conditions that may cause additional symptoms throughout the child’s life.
Epidemiology:
DS represents the most frequently diagnosed chromosomal condition in newborns and is also one of the leading causes of intellectual disability worldwide. Its incidence varies across different populations (1 in 319-1000 live births). In the United States (US), an estimated 5,000 infants with DS are born each year, equating to approximately 1 in 700 births. Currently, there are about 200,000 individuals in the US living with DS. Nevertheless, there is a lack of data regarding gender- and ethnicity-related disparities in its demographics. DS can affect individuals irrespective of their gender and ethnicity. Both genders can be affected almost equally, with cases of DS reported across all the global races.
In India, it is estimated that about 30,000-35,000 children are born with DS annually, with a survival rate of merely 44%. However, the estimated annual prevalence rate of DS in India is between 0.81 to 1.2 in 1,000 live births. The scenario is particularly concerning and dire in India, attributed to negligence, a lack of awareness, and obsolete medical and technological facilities, particularly in rural and underserved regions.
Etiology: Down Syndrome can manifest in any of the three genetic forms described below:
- Trisomy 21: This form primarily arises due to the non-disjunction of Chromosome 21 during parental gametogenesis, leading to an additional copy of chromosome 21 in every cell of a developing embryo. Approximately 95% of all DS cases are attributed to Trisomy 21.
- Translocation: It accounts for about 3-4% of DS cases. In this, a full or partial copy of chromosome 21 becomes attached to another chromosome, rendering the normal chromosome number of 46. However, the presence of additional genetic components may cause the manifestation of DS. The most frequently observed translocations include 13/21, 14/21, 21/21 or 22/21 translocations.
- Mosaicism (or mosaic DS): This variant is characterized by the presence of two different cell types – some cells possess three copies of chromosome 21, while others possess the normal chromosome number of 46. It is the least frequent form of DS, accounting about 1-2% of all the known cases. The condition results from a post-zygotic event, resulting from a trisomic zygote undergoing mitotic loss of one chromosome. Individuals with this DS form may exhibit fewer but variable characteristic features of DS, ranging from nearly normal to the classic Trisomy 21 phenotype.
Most of the DS cases are sporadic in occurrence (occurs by chance), with only 1% having a hereditary origin. Heredity factors are acknowledged in about one-third of DS cases associated with translocation.
Health Complications:
DS is highly acknowledged in decreased prenatal viability and increased prenatal and postnatal morbidity. Individuals with DS may have a higher risk of developing various medical conditions that can either be present at birth or manifest over time. Commonly observed conditions include:
- congenital heart defects (in approximately 50% of DS cases),
- hearing and vision impairments, endocrine disorders (such as hypothyroidism and increased risk of diabetes),
- frequent infections due to impaired immune system,
- dental problems,
- obstructive sleep apnea,
- a higher predisposition to leukemia (10-20 times higher than the general population),
- autism (characterized by challenges in social skills and communication, and repetitive behaviors), and
- neurological disorders (including epilepsy, and early-onset Alzheimer’s disease (in about 30% of individuals in their 50s and 50% in their 60s).
Risk Factors:
Studies have linked an elevated likelihood of having a child with DS to advanced parental age. In approximately 95% of cases, the underpinning cause is maternal non-disjunction, with errors in meiosis I occurring three times more than those in meiosis II. A woman aged 35 has about a 1 in 350 chance of conceiving a child with DS, a risk that gradually escalates to 1 in 100 by the age 40. By age 45, the incidental risk raises to approximately 1 in 50. Nevertheless, parental age does not appear to influence the risk of translocation. Approximately 5% of DS cases are attributed to paternal origin, with errors occurring predominantly in meiosis II.
The likelihood of bearing a child with DS is significantly higher for couples who already have a child diagnosed with Trisomy 21 or translocation. It is estimated that the probability of having another baby with Trisomy 21 is 1 in 100 until the age 40. The recurrence risk for translocation is about 3% if the father is the carrier and ranges from 10-15% if the mother is the carrier.
About 35-50% of females with Trisomy 21 are fertile, with a 50% chance of giving birth to a child with Trisomy 21. On the contrary, males with DS are typically infertile, with the exception of those with mosaicism.
Furthermore, there are no available reports suggesting that environmental factors or parental activities before or during pregnancy contribute to the occurrence of DS.
Diagnosis:
A healthcare provider can suspect DS during pregnancy via prenatal screening and diagnostic tests. While prenatal screening tests assess for the risk of having a child with DS rather than providing a definitive diagnosis, diagnostic tests conducted during pregnancy can confirm the presence of DS.
Prenatal screening tests typically involve a blood test to assess blood biomarkers for DS in women classified as having a high-risk pregnancy. This screening is often performed in conjunction with a comprehensive ultrasonogram. When conducted between 11 and 14 weeks of gestation, the ultrasound may facilitate the detection of nuchal translucency (NT screening) which is caused by the accumulation of excess fluid beneath the skin at the back of the fetal neck. While ultrasonogram performed between 14 and 24 weeks of gestation may assist in detecting soft markers such as an increased nuchal fold, small or absent nasal bone, and large ventricles. It is possible that a screening test may remain unremarkable even if the condition is present.
Diagnostic tests are generally performed following a positive screening test. These tests can detect chromosomal alteration that result in a DS diagnosis. These tests include amniocentesis (performed between 15 and 20 weeks of gestation), chorionic villus sampling (CVS; performed between 11 and 14 weeks) and percutaneous umbilical blood sampling (PUBS). Although these diagnostic procedures offer a higher risk for both the mother and the developing fetus (with a 0.5% to 1% risk of causing a miscarriage), these are highly accurate in confirming the diagnosis. Furthermore, non-invasive prenatal testing (NIPT) has recently been utilized to identify the presence of Trisomy 21 in cell-free fetal DNA (cfDNA) in the maternal blood with high sensitivity and specificity.
Down syndrome is typically diagnosed at birth by the healthcare provider during baby’s physical evaluation. The presence of characteristic traits and a positive karyotype result (indicating the existence of specific chromosomal aberration) can confirm the diagnosis of DS.
The Hsa21-specific probe-based Fluorescence In Situ Hybridization (FISH) test is most commonly performed for the rapid detection of Trisomy 21 by mapping and visualizing the genetic material present in the cells of a fetus and suspected newborn. Another method named multiplex quantitative fluorescent polymerase chain reaction (QF-PCR) is also employed for the detection of chromosomal aneuploidies. Another PCR-based approach called paralogue sequence quantification (PSQ) is also used for diagnosing this condition. This method leverages the paralogue sequence on the Hsa21 to identify the chromosomal aberrations or copy number variations of chromosome 21.
Therapeutic interventions and Management: Building Capability and Confidence
The individuals with DS may require lifelong assistance and care. While there is currently no cure for DS, various symptomatic treatments are available to assist children with DS in achieving their maximum potential. Treatment programs are designed to support their physical and mental well-being, enabling them to lead fulfilling and productive lives. Early intervention programs encompass physiotherapy, occupational therapy, speech therapy, behavioral therapy, inclusive educational programs in schools (where supportive teaching methods are adopted), management of underlying medical conditions (such as cardiac, thyroid, vision, and hearing issues), vocational training and community integration initiatives.
Molecular therapies, such as chromosome silencing and RNA interference strategies designed to mitigate the overexpression of certain genes that contribute to DS, are under investigation. In a recent breakthrough, scientists in Japan were able to perform trisomic rescue in Trisomy 21 cells via CRISPR-Cas9 gene editing tool. While such interventions are still in early stages, these hold immense potential to redefine the therapeutic management of DS in the coming decades.
The management of DS cases is indeed multidisciplinary, with parental education being the foremost aspect. When a suspicion for DS arises, healthcare providers would direct the parents to educational resources, genetic counselling and local support groups for additional information and assistance regarding the baby’s birth, care, education, employment and living standards. An array of organizations offers resources aimed at educating and empowering those affected, along with their families and caregivers.
Prognosis:
About 75% of conceptions with Trisomy 21 become non-viable during the embryonic or fetal stages. Between 50 to 75% of affected fetuses are lost spontaneously before reaching term, and 25-30% individuals with DS don not survive past their first year-of-life due to complications secondary to the condition, including respiratory infections and congenital heart disease. However, the life-expectancy of individuals with DS has significantly improved owing to advancements in modern healthcare, with many living into their 60s and beyond.
What to expect living with DS?
Individuals with DS can lead happy and fulfilling lives when provided with adequate supportive care. Therapeutic interventions can assist them in achieving developmental milestones, obtaining education along with their peers, forming relationships and pursuing successful careers. Many of them are capable of learning, working, and living either semi-independently or independently with the right assistance. Due to their strong social, emotional, and adaptive abilities, they are increasingly integrated into society and community organizations, including educational institutions, healthcare systems, workplaces, and social and recreational activities. With appropriate support, they can excel in areas such as arts, athletics, public speaking and advocacy.
Awareness and Advocacy: From Stigma to Social Integration
Individuals with DS experience severe social marginalization because of societal unawareness about their medical condition. They may face challenges with regards to obtaining education, finances, and inclusion in the societal norms due to prejudices and misconceptions. With several initiatives in place, it is anticipated that more and more people will come to know about such medical conditions. In this regard, World Down Syndrome Day is celebrated on March 21 (3/21 symbolizes Trisomy 21) to raise awareness and support for those affected with DS. The month of October is designated as the National Down Syndrome Awareness month. It is observed every year to raise awareness, promote understanding, foster acceptance and inclusion for individuals with DS, and celebrate their achievements. Awareness campaigns like “Lots of Socks” encourage inclusion of individuals with DS. Several global and local organizations advocate for their healthcare, education, and fundamental rights. The National Down Syndrome Society and the National Association for Down Syndrome are two of the most commonly used resources for information and support. In India, several organizations (such as Down Syndrome Federation of India (DSFI)) and local support groups offer support to individuals with Down syndrome and their families via multiple institutions across India.
Bottom line:
With the recent progress in healthcare, genetic understanding, early interventions, and growing societal awareness, individuals with DS are able to live healthy, longer, fulfilling and independent lives. It is our shared responsibility to create an informed and compassionate world – the one that begins with awareness, grow through advocacy, blossoms through love and respect, celebrates ability over difference, and ensures that every child, regardless of their clinical condition, has the opportunity to thrive. Beyond the realms of medicine and therapy, what truly transforms lives is acceptance, understanding, and opportunity. Families, healthcare professionals, educators, and policymakers must collectively foster an ecosystem that empowers individuals with DS to learn, work, and live with dignity. It is essential to remember that DS is not a limitation but rather a testament to human diversity, resilience and the strength of inclusion. When we unite as an informed and empathetic society, every individual with DS can live not just a life of dignity, but also one filled with pride, purpose and joy.
By,
Dr. Arshia Angural, M.Sc., Ph.D.
Assistant Professor,
DBT-BUILDER,
Department of Medical Genetics,
JSS Medical College & Hospital