Down Syndrome

Down syndrome is a common genetic condition associated with intellectual disability and characterized by a variety of additional clinical findings. The syndrome is caused by the presence of all or a part of a third copy of Chromosome 21, mainly an extra chromosome. Chromosomes are bundles of genes which regulate the body. The syndrome is known also under the term of Trisomy 21. That extra chromosome leads to a range of issues that affect the one who carry it, both mentally and physically. This entity is mainly associated with growth delays, intellectual disability over a characteristic facial feature. Most young adult with Down syndrome will also demonstrate an average IQ around 50, representing the mental ability of a 9-year-old child but there may be variations. It is a lifelong condition which can’t be cured but the children can enjoy a full and meaningful life when proper care are provided.

The parents of the affected child are genetically normal. The younger the mother the lesser chance in having a child with the Down syndrome. In a young woman of 20 years there is a less than 0.1% of probability to encounter such condition but in an, older mother of 45 years old the chances triple. Advances in medicine has allowed us to screen during the prenatal period, individuals at risk. Then genetic testing can be performed as well although nowadays regular screening for health problems is recommended through a person’s life. This extra chromosome is believed to occur by chance and once the diagnosis is made, the mother has the choice to terminate the pregnancy through abortion.

Special education and exercises programs has rendered these kids more functional in coping with their daily living activities. Many graduate from high school but rarely they can attend collegial schools while others will require specialized education. Less than a quarter of these children in the United States are able to perform in special work activities like being a helper at a grocery store or working at a desk with proper training, but they will require financial help or will remain dependent of their parents for life. Their life expectancy is around the fifties.

Let us define a little this condition. In the human body, every cell has a nucleus where a genetic material is stored under the forms of “Genes” carrying our inherited traits. They are grouped along rod-like structures called “Chromosomes” Each cell has a nucleus containing 23 pairs of chromosomes, half of which are inherited from each parent. Down syndrome occurs when an individual has a full or a partial extra copy of the “Chromosome 21”. This additional chromosome alters the course of development and causes the unique characteristics found in individual with Down Syndrome.

Down syndrome is the most common chromosomal abnormality in humans due to this anomaly of the chromosome 21 (Trisomy 21). The syndrome is seen in one on 700 to 800 births worldwide while in the USA, approximatively 500 live births annually while more than 300,000 are living with the syndrome. It was estimated that around 5.4 million individuals in 2015 were found to live with the syndrome around the world, resulting in 27,000 deaths but in 1990 the number of death was estimated to 43,000 The risk in having the syndrome increase with the maternal age. We owe to John Langdon Down, a physician from Cornwall, England, the original description of this syndrome in 1862 but later published his essay in 1896.although two previous French physicians, a psychiatrist Jean-Etienne Domonique Esquirol in 1838 and a generalist Edouard Seguin in 1844 reported earlier some aspects of the clinical features in describing it as a form of “Cretinism”. This will be only in 1959 that the genetic cause of the disease was demonstrated and the condition was named “Down Syndrome”, the most recognizable form of mental disability. Patients presenting with Down syndrome, have physical and intellectual disabilities, and once they become adult, their mental abilities are comparable to the one of an 8-year-old child. They have poor immune function and demonstrate problems reaching developmental maturity at a later age. They exhibit major health problems including congenital heart defect, epilepsy, leukemia, thyroid diseases and even mental problems especially at an early age through a form of Alzheimer, in less than 50% of the cases. Down syndrome is associated with multiple musculoskeletal problems related to ligamentous laxity, joint hypermobility and hypotonia. A common physical trait among these children suffering of Down Syndrome is a low muscle tone and a short stature. Some may have an abdominal wall defect or present with an umbilical hernia.

In the ancient times, such children were killed or abandoned. A recent discovery found an infant who was believed to have been buried in 3200 BC at Poulnabrone dolmen in Ireland with the fascies. Many potteries were discovered in the pre Columbian era, depicting faces of Down Syndrome kids especially in Ecuador. In the 16-century a painting representing The Adoration of Christ child represented a down syndrome child. During the 20th century, many individuals with the syndrome were institutionalized with no chances in having their medical conditions treated properly. They died certainly in their early adulthood. Some of them were even sterilized as we have seen during the second war in the Nazi camps, with a systematic involuntary Euthanization (Act of ending the life of a person for a medical reason). It is only in 1950 that the karyotype was discovered and in 1958 Jerome Lejeune reported the discovery of the extra chromosome. After scientific disputes between scientists, recognition was given to Marthe Gautier by the awarding of the “Grand Prize”. Similarly, old maternal age was found to play a role in the transmission of the disease.

Characteristic features like a flat and wide face, flat nasal bridge, small chin, upward slanting of palpebral fissures, giving the eyes a unique perception that children with Down Syndrome shares on a distinctive fascies, similar to the features found in the Mongolian race. This was the reason why John Langdon termed these characteristics as “mongoloid”. The World Health Organization (WHO) dropped the term in 1965 after a delegation from the People Republic of China (Mongolian’s people), requested it but the term Mongolism was still used as criteria for idiocy or imbecility until the early 1980’s. It became unacceptable to use the term “Mongoloid”. More these children will exhibit poor muscle tone, a flat nasal bridge, a single deep crease in the palm of the hands (reminding a simian hand), a protruding large tongue and a short neck, certainly facilitating sleep apnea in almost half of the cases. Down syndrome patients enjoy an excessive joint laxity. The feet present typical deformity with a wide first web space coupled with abnormal pattern involving the second toes or Plano valgus deformities. The hands similarly may also demonstrate an abnormal pattern at the fingertips and short fingers. Around 20% of the Down syndrome patients have an atlanto-axial instability which may lead to instability. As orthopedist we get involved often with the care of such athletes. Any athlete with Down Syndrome willing to participate in competitive sport activities, needs to have a cervical spine series and a medical clearance. This abnormality may result in spinal cord injury in 2% of the cases. They exhibit a short stature and may have spine deformities like scoliosis. A third of patients will have signs of hips dysplasia or dislocations. Others may develop unilateral or bilateral slipped capital femoral epiphysis often associated with hormonal problems due to a hypo-functioning thyroid…Knee problems are also frequent (20%) mainly demonstrating a patellofemoral instability with often a deficient medial retinaculum forcing a lateral subluxation or dislocation of the patella. Patients tend to become obese in their short stature and physicians will carry special growth charts for such children.

About one third of patients with Down syndrome exhibit intellectual instability. Delay in crawling (8-9 months) is typically seen as well as an inability to ambulate (20 months). Most individual with the syndrome will have a mild (IQ=60) to severe (IQ=30) intellectual disability. The one presenting the mosaic form of Down syndrome may perform better. They understand better that they can speak. Generally, they express themselves in a “stutter” or an irregular speech, difficult to understand at time. After reaching the age 30, they generally lose their ability to talk. Down syndrome can do well in social activities. Mental illness occurs in 30% with autism (5%). They are generally happy but can express variation in their emotions. Anxiety and Depression can also be seen during early adulthood. All individuals exhibiting the syndrome are at risk for epileptic seizures like infantile spasms more often in the adults (50%) than the children (10%). By the age of 40 and older, there is higher incidence for developing Alzheimer disease (15% to 70%}. I will refer all to the previous AMHE Newsletter dealing with Alzheimer disease (AMHE Newsletter # 262 and reference # 21).

Down syndrome patients have a display of vision and hearing problems. Strabismus (20-50%), Cataracts (15%) may be present at birth with cloudiness of the lens, others may present a thinning of the cornea called “keratoconus” or even an increase in the pressure in the eye (Glaucoma). Some may require glasses or contact lens to correct the refractive errors while others may present small white or grayish-brown spots around the Iris, in almost 80% of cases: they are called Brushfield spots. Up to 90% of children with Down Syndrome exhibit hearing problems. An otitis media (80%) with an effusion can be discovered with chronic subsequent ear infections (50%). during the first year of life because mal functioning of the Eustachian tube. Excessive ear wax can become a cause of hearing loss after the obstruction at the external canal. It is important for a kid to assure fine hearing because any degree of hearing loss brings a negative effect on speeches, language understanding and academics. Hearing problems may deteriorate also social communication. In 60% of Down syndrome patients, a sensorineural type of hearing loss is expected.

40% of patients with Down Syndrome will suffer from congenital heart disease. The majority will demonstrate an atrioventricular septal defect more often than a ventricular septal defect. The older they become, the more they may develop valvar problem. A tetralogy of Fallot (Ventricular septal defect, stenotic pulmonary valve, thickening of the right ventricular wall) or a persistent ductus arteriosus is occasionally seen.

There is no predilection for malignancy in Down syndrome but the risks of testicular cancer or blood cancer like leukemia can increase as reported by Caird (2006) and Alman (2014). A simple example is with the Leukemia’s: Acute Lymphoblastic leukemia (ALL) and Acute Megakaryoblastic Leukemia (AMKL) have high incidence among Down Syndrome patients while other non-blood cancers are seldom seen although cancers deriving from stem cells has demonstrated a higher risk. Leukemia’s are believed to be 15 times more often in children with the syndrome. The Acute Lymphoblastic leukemia is 20 times more common but the megalokaryoblastic form is even 500 times more common. The megakaryocytes are precursors of blood platelets. Acute Lymphoblastic Leukemia accounts for a little less than 3^ of all childhood cases but more often seen in the older children or the one with a white blood cell greater than 50,000. The outcome is poor. AMKL is a disorder of blood cell production (Transient myeloproliferative disease) in which the non-cancerous megakarioblasts sustain a mutation in the GATAT gene during the late period of pregnancy affecting 3% of the babies with Down Syndrome and spontaneously resolving within three months to 5 years after birth. In such cases, serious blood or liver complications can be seen.

Major solid cancers of the lungs, breast, cervix present with a lower risk because of the “Tumor Suppressor Gene” present in the chromosome 21 in the oldest patient after the 50’s while a low thyroid hormone level is generally seen in more than half of patients on Down Syndrome. Often a non-functioning thyroid is noted at birth or discovered later through an immunosuppressive mechanism resulting in Graves ‘disease. Finally, a type I Diabetes Mellitus is commonly seen.

More than half of Down Syndrome patients will suffer of constipation with a potential to develop Hirschsprung’s disease in 15% of the cases due to a lack of nerve cells controlling the colon. Duodenal Atresia, Meckel Diverticulum, Imperforate anus and Celiac disease can be seen in 15% of cases. These individual tend to be susceptible to gingivitis with periodontal disease and loss of the lower front teeth because of a lack of hygiene and the presence of plaques contributing to an increase incidence in yeast infection especially with “Candida Albicans”. Their saliva is scanty but tend to be alkaline in nature and providing a greater resistance to tooth decay but” Bruxim” (Teeth grinding or clenching) is common. A hypotonic lip with a narrow palate can exhibit crowded teeth and a delay in eruption of adult teeth generally missing but often presenting shorter roots. Rarely, they may have other congenital malformation like cleft lip and palate with enamel opacification (20%).

Male Down Syndrome generally are sterile because of a poor sperm development while 50% of female may exhibit a lower rate of fertility compared to a normal population. Women will reach menopause at an earlier age. Since 2006, it is reported that 3 males have fathered children while 26 women have given birth and it was found that half of the children were carrying the syndrome. We have already discussed the way such individuals are born with three copies of the gene on the chromosome 21 rather than two. Often the parents are genetically normal. It is important to know that a couple who bought to this world a child with the syndrome, carry a 1% chance in having a second child with the syndrome even if both parents have normal karyotypes.

The extra chromosome may arise through different mechanisms. the most common is a complete extra copy of chromosome 21 (trisomy 21) found in 95% of cases but other cases may represent a mosaic pattern, the least common form of Down Syndrome, in which 1 % of cases. This is the Mosaicism” or “Mosaic Down Syndrome” where the there is a mixture of the two types of cells, some containing the usual 46 chromosomes and some containing 47 carrying the chromosome 21. Individuals with the mosaic pattern appears to have fewer characteristics of the syndrome. Finally, a third mechanism will present with a” ring chromosome” or “isochromosome” called the “Robertsonian translocation in another 4% of the cases. This “isochromososme” originates from the separation of two long arms of the chromosome 21, during the egg or sperm development. The total number of chromosomes in the cells remains 46 and an additional full or partial copy of the chromosome 21 attaches to another chromosome, generally the chromosome 14. This is the translocation phenomenon in Down Syndrome. Regardless the type of Down Syndrome a person may have all will carry the extra chromosome 21 in their genetic baggage. All 3 types of Down Syndrome are related to genetic conditions. but  1% of all cases may have an hereditary component from parent to a child. Heredity is not a factor in Trisomy 21 (non-disjunction) or in the Mosaicism but there is a hereditary component in the translocated cases where maybe 1/3 of cases may have received the gene from one of the parents. A mother who has given birth to a baby with trisomy 21 or translocation has increased her chances in having another baby with the syndrome by 1/100. The risk in translocation is around 3% if the father is a carrier but 15% if the mother is at the origin of the translocation. Genetic counseling can determine the origin of the translocated gene.

A Trisomy 21 (Karyotype 47, XX, + 21 and 47, XY, +21) is caused by the failure of the 21th chromosome to separate (Non-Disjunction) during the sperm or egg development resulting in the formation of a sperm or an egg carrying an extra copy of the chromosome 21 giving them 24 chromosomes. Then when combined with a normal cell from the other parent, the baby will have 47 chromosomes with three (3) copies of the chromosome 21. Almost 90% of this trisomy 21 results from the non-separation in the mother, around 8% from the non-separation in the father and in the remaining 3%, the non-separation is noted after the sperm emergence. With this extra material, called the “Robertsonian translocation”, the long arm of the chromosome 21 is attached to another chromosome, often the chromosome 14. There is no relation with the old age of the mother but if the mother is affected, there will be a 15% chance of having a child with the syndrome and a less than 5% chance when the father is affected. In the family, normal children may also inherit the translocation and carry a higher probability in transmitting the gene to their children. This is called “Familial Down Syndrome”. Some researchers have suggested that the Down Syndrome critical region is located at bands 21q22.1-q22.3 in the area including the genes for amyloid, superoxide dismutase and this is why the dementia that occurs with these patients is due to an excess of amyloid beta peptide in the brain. That amyloid beta is processed from the amyloid precursor protein located on the chromosome 21. I will refer the lector to the article on Alzheimer published in the Newsletter of the AMHE # 262. We have already described the way senile plaques and neurofibrillary tangles are present in the down syndrome patient by the age of 35. They also lack in lymphocytes and produce less antibodies rendering them prone to infection. The changes seen with Alzheimer disease among the young Down syndrome patients, may represent an “epigenetic clock” in the trisomy 21.

How do we screen for Down Syndrome? Amniocentesis or chorionic villus sampling is a good way to confirm the risk of Down syndrome. They are reliable tests but they increase the risk for miscarriage (1%). The risks for limb problems may be increased if the test on the chorionic villus sampling is carried before 10 weeks of gestation. The earlier the test performed the riskier it becomes and this is the reason an amniocentesis is not recommended before 15 weeks of gestation. 92% of pregnancies in Europe are generally terminated. Countries like Iceland or Denmark have no children with the syndrome. In the United States, the termination rate is around 75 % depending on the population involved in the survey. One third of American women would request for a termination of the pregnancy if the test confirm the syndrome. Once the baby born, the diagnosis can be also suspected on the child’s appearance at birth. Nowadays, it is recommended to screen for Down syndrome all pregnant women. A number of tests are available: Amniocentesis or Chorionic Villus Sampling in the first and second trimester capable of picking up to 95% of cases. There may be a small 2% chance of false positivity. Many other tests can allow us to find blood markers during the first and the second trimester of the pregnancy. Testing in both trimesters is often recommended with the addition of an ultrasound. Most tests will look for alpha fetoproteins, estradiol total hCG and free beta hCG which can be detected in around 65% of the cases especially during the second trimester. The mother’s blood can be tested for fetal DNA during the first trimester is considered a good screening option in pregnancies at risk for trisomy 21. There is an accuracy reaching more than 95% reported in the third trimester of the pregnancy. Confirmatory studies are still necessary to asset the diagnosis with invasive techniques of amniocentesis. examples like ultrasound and nuchal transparency with blood samples for hCG. Quad screen before 20 weeks to obtain alpha fetoproteins or a cell-free fetal DNA around 10 weeks via a blood sample taken from the mother to analyze the DNA.

Some parents still chose to avoid an abortion. Once the baby is born, an early childhood intervention to screen the common problems, medical treatment as needed, a good family environment and work training can improve the development of such affected children. Special education and training can improve the quality of life. I know personally for having participated to the life of my beautiful niece Stephanie with the syndrome. It took a family effort to help her reach a functional level. I dedicated this page to her and to all around the world who have acquired this extra chromosome 21. Raising such a kid is a lot of work for the parents and the family. All childhood vaccinations are recommended and the devotion of a pediatric physician has to be encouraged while ongoing problems will present regularly during her development. Early hearing and Vision problems in the first 6 months, hormonal imbalance with the thyroid, Gastrointestinal and musculoskeletal problems, obstructive sleep apnea etc. EKG’s and ultrasounds of the heart, radiographic studies neck, knees, hips, hearing aids and other devices to enhance their learning capabilities. Sign language… Behavior problems… Speech therapies… Special education programs and medications… physical therapy and conditioning have imposed on congress the need to create a Disability Act in 1975 requiring schools to facilitate attendance to such students.

Many procedures have become routine in the care of such patients. Multiple throat infections have imposed Tonsillectomies to help with the sleep apnea. Tympanostomy tubes may be needed because of multiple ear infections. A continuous positive airway pressure machine (CPAP) is useful as well as physical therapy and educations to improve skills.  It is important to prevent respiratory syncytial viral infections (RSV) in using human monoclonal antibodies especially when they have heart problems. or monoclonal infections. In the early cases of dementia, medications like donepezil, galantamine and memantine and other drugs have been used’ Plastic surgery has been tried to change the physiognomy of the down syndrome patient but it remains controversial. Societies has learned to have a better acceptance. Chiropractic treatment, massage therapies, animal therapy or even the use of naturopathy have failed to improve the quality of life of such patients.

Many children with the syndrome attend regular school in Sweden and many have graduated from high school. In the United States as well 40% of the children who attended high school graduated to a point that they may be able perform in paid jobs and 30% reach the goal. The one presenting the mosaic form of Down Syndrome exhibit better outcomes. They all have a higher chance of early death because of heart problems or infections. With better care now, their life expectancy has increased tremendously to a point that almost 80% will survive past 30 years of age. Rarely, they will reach the 70’s.

This syndrome is the most common chromosomal abnormality in humans. If at the beginning of the new millennium, Down Syndrome was seen in one in 1000 births, now in most countries, parents have accepted early abortion to prevent suffering. The multiple prenatal screening and testing as discussed earlier, have also convinced many parents to terminate the pregnancy. We have seen also spontaneous abortions. The maternal age affects the probability. After the age 50, it is believed that one in 44 mother will deliver a baby with Down Syndrome while the father’s old age may be as well a risk factor. Most obstetricians will argue that the screening for Down Syndrome and the results should be discussed with the pregnant mother and it will become her choice or the family choice to terminate or keep the pregnancy, based on their personal and religious beliefs. Others in the United States may consider testing and abortion discriminatory, and if they are anti-abortionist they may consider it only if the fetus is disabled. 50% of women over the age of 50 in the USA have agreed to screening if they become pregnant.

The religion has often a part to play in the mother or parent decision to keep the baby or abort. Some Protestant denominations have accepted the abortion when the fetus has Down Syndrome but the Roman Catholics or the Orthodox see it with different eyes and do not accept it. Disagreement exists also within Islam regarding the acceptability of an abortion. Women may face stigmatization if they chose to abort. Similarly, many organizations have fought for the admission of Down Syndrome kids into the general school to allow a greater understanding of the condition and better support to the families involved especially when too many of these kids were placed in mental institutions or asylums. Many societies like the Royal Society for Handicapped Children in UK (1945), The National Down Syndrome Congress in the USA (1973) were founded to support the cause. The little sisters Disciples of the lamb in France (1985) were all placing their efforts for the well-being of these children. A world Down Syndrome Day was initiated in 2006 and recognized by the United Nations General Assembly in 2011. Hope is on the way because the chromosome 21 in still being studied to improve the intelligence among the one suffering from it, by the use of stem cells or gene therapies on animal model (Ts65Cn mouse). It is believed that other animals may have an equivalent of Down Syndrome especially among the great Apes, a trisomy 22 was discovered, very common among the chimpanzees (1969) and a Bornean Orangutan (1979). A chimpanzee named “Kanako” born in 1883 in Japan, has become the longest lived animal with common features similar to the one found in humans with the syndrome.

Maxime J-M Coles MD

Boca Raton FL 11-21-2020


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