Introduction
Risk Factors
Epidemiology
Pathophysiology
Clinical Manifestations
Diagnosis
Treatment, Habilitation and Support
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Introducation:
The most common disorders that alter the number of chromosomes in cells are trisomies, i.e., increased genetic mass in the body. This change causes an imbalance in the genotype, leading to an abnormal phenotype. Down syndrome (DS) is the most common chromosomal anomaly that leads to mental retardation or intellectual disability.
DS is an unbalanced overdose of genetic material, meaning that genetic capacity is expressed at 150% of normal levels. The imbalance is due to the presence of three chromosome 21s in each cell instead of the usual two. There are four different types of chromosomal anomalies associated with DS. The most common is an extra chromosome 21 in all cells (94%). The second most common type is translocation trisomy 21 (4%). Translocation can occur between chromosome 21 and other chromosomes, such as 9, 13, 14, 15, and 22. Translocation can also occur between the two parts of chromosome 21. The third type is trisomy 21 mosaicism (2-3%), which means a mixture of cells with a normal chromosome complement and cells with an extra chromosome 21. The fourth and rarest type is partial trisomy 21 (0.1%). In partial trisomy 21, a small segment of chromosome 21 has been duplicated.
Risk Factors:
Epidemiology:
Down syndrome is one of the most common chromosomal abnormalities. The prevalence varies somewhat depending on the population and region, but generally, it is estimated that: Down syndrome occurs in approximately 1 in 700 births globally, which means that about 6,000 children with Down syndrome are born each year in the United States alone. The prevalence increases significantly with the mother's age: at ages 20-25, the risk is about 1 in 1,500, while it rises to 1 in 270 by age 35 and to 1 in 100 by age 40. Epidemiological studies have shown that males and females are born with Down syndrome in roughly equal numbers, but boys are more commonly diagnosed with certain associated medical conditions. Pathophysiology: DS is a well-known disability both medically and psychosocially.
However, there are no studies that clarify how the presence of an extra chromosome 21 can lead to widespread stigma. Therefore, children with DS have both medical and non-medical impairments.
Clinical Manifestations:
The most common medical manifestations are congenital heart defects, gastrointestinal atresia, hearing impairment, and intellectual disability, among others. Additionally, these children have a higher risk of developing gluten intolerance, thyroid disorders, thrombosis, and cancers such as leukemia. Mental health issues, dementia, and depression are two major symptoms in children with DS that have increased over the past decade.
Congenital heart defects are one of the most significant medical challenges in infants with DS. Various types of heart defects of varying severity may occur. Some of these anomalies may be considered clinically insignificant, meaning that the child's health and development are not significantly affected. On the other hand, there can be life-threatening and complex heart diseases that require special treatments and surgeries, such as AV canal defects.
Complicated heart conditions can cause issues like hypoxia, recurrent pneumonia, cyanosis, pulmonary hypertension, and impaired growth. Studies show that children with DS and congenital heart defects also have significantly higher mortality rates than heart-healthy children with DS. Sometimes these malformations can be fatal, resulting in the child dying shortly after birth.
However, there are studies showing promising results, such as a 10-year survival rate of 88.6% for children with DS and an increased life expectancy from 12 years to 60 years over the past two generations. This increased life expectancy is likely due to various advanced treatment options for children with DS (both surgical and non-surgical) as well as preventive measures performed before and after birth. For example, prophylactic treatment with anticoagulant medications or antibiotics in children with specific heart defects dramatically reduces the risk of thrombosis or severe infections.
The mechanism by which the chromosomal abnormality causes structural heart defects, as well as other malformations in the body associated with DS, is unclear. However, congenital heart defects may be more common in girls than in boys with DS.
The gastrointestinal tract is another organ system that can be affected in children with DS. Various studies have reported the following anomalies: duodenal obstruction (the most common gastrointestinal malformation in children with DS), anal atresia, tracheoesophageal fistula, diaphragmatic hernia, gastroesophageal reflux, and Hirschsprung's disease. In addition to the mentioned malformations, delayed bowel motility may also occur, which can contribute to constipation and other gastrointestinal issues.
Many children with DS also experience difficulties with feeding and swallowing, which may be related to both anatomical factors and hypotonia (decreased muscle tone) in the gastrointestinal tract. This can lead to nutritional deficiencies and affect the children's growth and development.
Children with DS also have a higher risk of various non-infectious inflammations. Celiac disease and Graves' disease are two examples of such autoimmune diseases. The autoimmune reaction leads to various symptoms and issues (e.g., diarrhea, abdominal pain, malabsorption, and weight loss in children with celiac disease).
In addition to celiac disease and Graves' disease, children with Down syndrome are at an increased risk for other autoimmune conditions, such as type 1 diabetes and autoimmune hypothyroidism. Type 1 diabetes occurs when the body's immune system attacks the insulin-producing cells in the pancreas, leading to insulin deficiency and high blood sugar levels. This can cause symptoms such as increased thirst, weight loss, and fatigue.
Autoimmune hypothyroidism, where the thyroid gland is attacked by the immune system, leads to a deficiency of thyroid hormone and can cause fatigue, weight gain, constipation, and impaired growth in children. Since these diseases can have a subtle onset and affect the child's development, regular check-ups and early detection are important to provide the right treatment and support.
The increased risk of various infections is another concern for children with DS. The risk of otitis media, pneumonia, hepatitis B, and viral infections (such as RSV in children with heart disease) justifies preventive care in the form of both passive and active vaccination.
Today, there is the opportunity for children to be vaccinated against Streptococcus pneumoniae, hepatitis B, and RSV. Hearing impairment in the form of conductive, sensorineural, or mixed types is common in children with DS.
Hearing loss can range from mild to moderate and is primarily due to otitis media, earwax buildup, and skeletal malformations. Purely neurological or sensorineural forms are rare and require specific diagnoses, such as brainstem audiometry. Delays in diagnosis and adequate care can lead to a pronounced deterioration in the child's psychomotor development.
Studies have shown that the metabolism of individuals with DS deviates from the norm. Metabolic deviations indicate that endocrine disorders in DS are more common than in the general population. For example, thyroid disorders, obesity, and diabetes are more prevalent in individuals with DS than in those without DS. Hypothyroidism, for instance, contributes to the increased risk of obesity.
Reports also indicate the occurrence of hyperthyroidism in children with DS. Other hormonal imbalances are common in individuals with Down syndrome, such as low levels of growth hormone, which can affect both growth and body composition.
Obesity in individuals with DS is not solely due to hormonal disorders but is also influenced by hypotonia (decreased muscle tone), which can make physical activity more challenging, and a lower metabolism that contributes to quicker weight gain. Nutritional status, exercise, and lifestyle are other important factors in this context.
Visual impairments and other eye diseases are relatively common in children with Down syndrome and can affect their development and quality of life. Visual impairment is one of the most frequent visual problems, but there are also several specific conditions that require monitoring. For instance, myopia (nearsightedness) and hyperopia (farsightedness) are common, which can lead to blurred vision and difficulties focusing on objects.
Other conditions include strabismus (crossed eyes) and nystagmus (involuntary eye movements), which can affect the child's visual acuity and perception. Amblyopia (often referred to as "lazy eye") is another risk factor that, if untreated, can lead to permanent vision impairment in the affected eye. Cataracts (clouding of the lens) can also develop at an early age in children with DS, leading to decreased vision.
Retinal abnormalities and nasolacrimal duct obstruction (blockage of the tear duct), which can cause increased tear production and infections, are also relatively common. Given the increased risk of these eye problems, regular eye examinations are essential for children with Down syndrome. Early detection and treatment can help improve vision and prevent further complications.
As mentioned above, there is a slightly increased risk for children with DS to develop various types of cancer, with a higher risk particularly for leukemia and testicular cancer. Cancer thus poses a risk factor leading to increased mortality among children and adults with DS. One study shows that the overall prevalence of cancer among children with DS is approximately the same as in the general population.
However, there is a remarkable increase in the incidence of leukemia (about ten times the expected risk, SIR 10.5 and CI 95%) and testicular cancer (about five times the expected risk, SIR 4.8 and CI 95%) among these children. Although the total incidence of cancer among children with DS is roughly the same as in the general population, with the exceptions of the aforementioned types of cancer, cancer remains a significant risk factor affecting the survival of both children and adults with DS.
The increased risk of leukemia and testicular cancer underscores the importance of early diagnosis and monitoring, especially for symptoms that may signal malignancy. In addition to leukemia and testicular cancer, some studies have also shown an increased risk of other cancers in adults with DS, such as lymphoma, making regular health check-ups important throughout life.
Cognitive impairment is a complex aspect of Down syndrome that affects the child's development from an early age. The intellectual ability of children with DS varies but tends to gradually decline over the years, with a significant proportion developing dementia-like symptoms early in adulthood.
In particular, the risk of Alzheimer's disease is significantly higher in individuals with DS, with as many as 100% potentially developing Alzheimer’s-like changes in the brain by their 40s. Studies estimate a risk of 13.3% for dementia among individuals with DS at an average age of approximately 54.7 years. The underlying genetic mechanism behind this increased vulnerability to dementia has not yet been fully clarified.
A possible connection has been identified with trisomy 21, where the amyloid precursor protein (APP) is coded, which may increase the formation of amyloid plaques in the brain, one of the main factors in Alzheimer's disease. However, the genetic variant that is crucial in Alzheimer's disease in the general population, such as APOE-ε4, has not yet shown the same significance in the development of dementia among individuals with DS.
Studies have also shown a higher risk of Alzheimer's disease in mothers of children with DS, suggesting that hereditary or predisposing factors may play a role. In addition to genetic factors, untreated hearing and vision impairments can further exacerbate cognitive function in children and adults with DS, affecting their learning, social interaction, and overall mental health.
Children and adults with Down syndrome may experience a range of other medical conditions that further complicate the clinical picture and require multidisciplinary care.
The higher risk of deep vein thrombosis (DVT) can be explained by both circulatory disorders and possible anatomical abnormalities, making it important to be aware of signs of blood clots and to prevent risk factors early.
Difficult-to-treat epilepsy, including infantile spasms, can lead to neurological complications that affect development and quality of life. These types of seizures often require specialized treatment and frequent follow-ups to minimize harmful effects on the brain and support the child’s development.
Sleep apnea, caused by narrow airways, hypotonia in the pharyngeal muscles, and possibly obesity, is a common issue and can lead to chronic fatigue, concentration difficulties, and, in some cases, cardiovascular problems if left untreated. Treatment with CPAP (continuous positive airway pressure) or surgical interventions may be indicated depending on severity.
Joint hypermobility, often associated with muscular hypotonia, can cause joint pain, instability, and increase the risk of joint injuries. This can sometimes affect the children's mobility and balance, which may require tailored physical therapy and training to strengthen muscles and support the joints.
Diagnosis:
The diagnosis of Down syndrome is based on both clinical suspicion and genetic confirmation, which can occur both prenatally and postnatally. Prenatal screening offers the opportunity to identify an increased likelihood of Down syndrome early, allowing parents to prepare for any needs the child may have.
Common prenatal screening methods include blood tests and ultrasounds, where the measurement of nuchal translucency is a central part of assessing the risk for chromosomal abnormalities. Parents need access to reliable information about the screening process and its implications in order to make informed decisions about further investigations. If the screening results show an elevated risk, diagnostic tests such as amniocentesis or chorionic villus sampling (CVS) can be offered to genetically verify the diagnosis. These tests analyze the fetus's DNA and can provide a definitive diagnosis, although they carry a small risk of complications.
Postnatally, the diagnosis is usually made through the observation of physical characteristics, such as hypotonia (low muscle tone), specific facial features, and other physical signs. In cases of clinical suspicion, a genetic test, typically through karyotyping, is performed to confirm the presence of an extra copy of chromosome 21, which is characteristic of Down syndrome.
Treatment, Rehabilitation, and Support:
Unfortunately, there is no curative treatment for children with Down syndrome; however, symptomatic treatments are available. Treatments and interventions focus on managing and alleviating symptoms as well as supporting the individual’s development and quality of life.
To support children with Down syndrome in their overall development, a wide range of specialized interventions across multiple areas is required. In special education, adapted learning environments and educational strategies are crucial to meet their individual cognitive needs. This includes structured learning methods, clear routines, and visual support, which help them understand and retain information.
Additionally, inclusive classroom environments and small student groups can be beneficial in promoting social interaction and communication. Employment support, often in the form of job preparation programs and transition planning, is central to preparing individuals with Down syndrome for active participation in the workforce. Such programs may include skill training, social skills support, and practical work tasks in real-world environments, contributing to a higher degree of independence and self-worth.
Physical therapy plays an important role in improving muscle strength, balance, and coordination in children with Down syndrome, especially given the hypotonia and hypermobility that may affect their mobility. Regular exercise and individually tailored exercises help develop motor skills, which in turn facilitate participation in daily activities and leisure pursuits.
Occupational therapy is another important resource that focuses on enhancing skills for independent living. By training in daily activities, such as eating independently, dressing, and personal hygiene, children can develop practical skills that boost their confidence and independence.
Dental health is often a particular focus area, as children with Down syndrome may have an increased incidence of dental issues, such as crowded teeth and gum inflammation. Regular dental care and preventive measures, including basic dental hygiene routines and adapted dental visits, are therefore essential to avoid complications.
By offering these comprehensive resources and services within an integrated and individualized care model, children with Down syndrome can be supported in reaching their full potential and achieving a meaningful and active life.
Parents going through the screening and diagnosis process often need both medical and psychological support to cope with the information and decision-making regarding the various tests. It is important for healthcare professionals to provide support and guidance throughout the process to help parents understand the results and what a potential diagnosis means for their family.
By AmirHossein Mahdavian MD,
Pediatric neurologist
