Down syndrome

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Down syndrome
Other namesDown's syndrome, Down's, trisomy 21
Boy with Down Syndrome.JPG
An eight-year-old boy displaying characteristic facial features of Down syndrome
Specialty Medical genetics, pediatrics
Symptoms Delayed development, characteristic physical features, mild to moderate intellectual disability [1]
Usual onsetMostly at conception, rarely after fertilization [2]
DurationLifelong
CausesThird copy of chromosome 21 [3]
Risk factors Older age of mother, prior affected child [4] [5]
Diagnostic method Prenatal screening, genetic testing [6]
TreatmentPhysical therapy, Occupational therapy, Speech therapy, Educational support, Supported work environment [7] [8]
Prognosis Life expectancy 50 to 60 years (developed world) [9] [10]
Frequency5.4 million (0.1%) [1] [11]
Named after John Langdon Down

Down syndrome or Down's syndrome, [12] also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. [3] It is usually associated with developmental delays, mild to moderate intellectual disability, and characteristic physical features. [1] [13]

Contents

The parents of the affected individual are usually genetically normal. [14] The incidence of the syndrome increases with the age of the mother, from less than 0.1% for 20-year-old mothers to 3% for those of age 45. [4] It is believed to occur by chance, with no known behavioral activity or environmental factor that changes the probability. [2] Usually, babies get 23 chromosomes from each parent for a total of 46, whereas in Down syndrome, a third 21st chromosome is attached. [15] The extra chromosome is provided at conception as the egg and sperm combine. [16] In 1–2% of cases, the additional chromosome is added in the embryo stage and only impacts some of the cells in the body; this is known as Mosaic Down syndrome. [17] [15] Translocation Down syndrome is another rare type. [18] [19] Down syndrome can be identified during pregnancy by prenatal screening, followed by diagnostic testing, or after birth by direct observation and genetic testing. [6] Since the introduction of screening, Down syndrome pregnancies are often aborted (rates varying from 50 to 85% depending on maternal age, gestational age, and maternal race/ethnicity). [20] [21] [22]

As of 2024, there is no known cure for Down syndrome. [23] Education and proper care have been shown to provide better quality of life. [7] Some children with Down syndrome are educated in typical school classes, while others require more specialized education. [8] Some individuals with Down syndrome graduate from high school, and a few attend post-secondary education. [24] In adulthood, about 20% in the United States do some paid work, [25] with many requiring a sheltered work environment. [8] Caretaker support in financial and legal matters is often needed. [10] Life expectancy is around 50 to 60 years in the developed world, with proper health care. [9] [10] Regular screening for health issues common in Down syndrome is recommended throughout the person's life. [9]

Down syndrome is the most common chromosomal abnormality, [26] occurring in about 1 in 1,000 babies born worldwide, [1] and one in 700 in the US. [18] In 2015, there were 5.4 million people with Down syndrome globally, of whom 27,000 died, down from 43,000 deaths in 1990. [11] [27] [28] The syndrome is named after British physician John Langdon Down, who fully described it in 1866. [29] Some aspects were described earlier by French psychiatrist Jean-Étienne Dominique Esquirol in 1838 and French physician Édouard Séguin in 1844. [30] The genetic cause was discovered in 1959. [29]

Signs and symptoms

A boy from Somalia with Down syndrome Autism somali Center 01.jpg
A boy from Somalia with Down syndrome

Those with Down syndrome nearly always have physical and intellectual disabilities. [31] As adults, their mental abilities are typically similar to those of an 8- or 9-year-old. [9] At the same time, their emotional and social awareness is very high. [32] They can have poor immune function [14] and generally reach developmental milestones at a later age. [10] They have an increased risk of a number of health concerns, such as congenital heart defect, epilepsy, leukemia, and thyroid diseases. [29]

CharacteristicsPercentageCharacteristicsPercentage
Mental impairment99% [33] Abnormal teeth60% [34]
Stunted growth90% [35] Slanted eyes 60% [14]
Umbilical hernia 90% [36] Shortened hands60% [34]
Increased skin on back of neck80% [29] Short neck60% [34]
Low muscle tone 80% [37] Obstructive sleep apnea 60% [29]
Narrow roof of mouth 76% [34] Bent fifth finger tip 57% [14]
Flat head 75% [14] Brushfield spots in the iris 56% [14]
Flexible ligaments75% [14] Single transverse palmar crease 53% [14]
Proportionally large tongue [38] 75% [37] Protruding tongue47% [34]
Abnormal outer ears 70% [29] Congenital heart disease 40% [34]
Flattened nose68% [14] Strabismus ≈35% [1]
Separation of first and second toes68% [34] Undescended testicles 20% [39]

Physical

Feet of a boy with Down syndrome, showing the deviated first toes Feet of a boy with Down Syndrome.JPG
Feet of a boy with Down syndrome, showing the deviated first toes

People with Down syndrome may have these physical characteristics: a small chin, epicanthic folds, low muscle tone, a flat nasal bridge, and a protruding tongue. A protruding tongue is caused by low tone and weak facial muscles, and often corrected with myofunctional exercises. [40] Some characteristic airway features can lead to obstructive sleep apnea in around half of those with Down syndrome. [29] Other common features include: excessive joint flexibility, extra space between big toe and second toe, a single crease of the palm, and short fingers. [34] [37]

Instability of the atlantoaxial joint occurs in about 1–2%. [41] Atlantoaxial instability may cause myelopathy due to cervical spinal cord compression later in life, this often manifests as new onset weakness, problems with coordination, bowel or bladder incontinence, and gait dysfunction. [42] Serial imaging cannot reliably predict future cervical cord compression, but changes can be seen on neurological exam. The condition is surgically corrected with spine surgery. [42]

Growth in height is slower, resulting in adults who tend to have short stature—the average height for men is 154 centimetres (5 feet 1 inch), and for women is 142 centimetres (4 feet 8 inches). [43] Individuals with Down syndrome are at increased risk for obesity as they age due to hypothyroidism, other medical issues and lifestyle. [29] [44] Growth charts have been developed specifically for children with Down syndrome. [29]

Neurological

A boy with Down syndrome using a cordless drill to assemble a book case A boy with Down syndrome using cordless drill to assemble a book case.jpg
A boy with Down syndrome using a cordless drill to assemble a book case

This syndrome causes about a third of cases of intellectual disability. [14] Many developmental milestones are delayed with the ability to crawl typically occurring around 8–22 months rather than 6–12 months, and the ability to walk independently typically occurring around 1–4 years rather than 9–18 months. [45] Walking is acquired in 50% of children after 24 months. [46]

Most individuals with Down syndrome have mild (IQ: 50–69) or moderate (IQ: 35–50) intellectual disability with some cases having severe (IQ: 20–35) difficulties. [1] [47] Those with mosaic Down syndrome typically have IQ scores 10–30 points higher than that. [48] As they age, the gap tends to widen between people with Down syndrome and their same-age peers. [47] [49]

Commonly, individuals with Down syndrome have better language understanding than ability to speak. [29] [47] Babbling typically emerges around 15 months on average. [50] 10–45% of those with Down syndrome have either a stutter or rapid and irregular speech, making it difficult to understand them. [51] After reaching 30 years of age, some may lose their ability to speak. [9]

They typically do fairly well with social skills. [29] Behavior problems are not generally as great an issue as in other syndromes associated with intellectual disability. [47] In children with Down syndrome, mental illness occurs in nearly 30% with autism occurring in 5–10%. [10] People with Down syndrome experience a wide range of emotions. [52] While people with Down syndrome are generally happy, [53] symptoms of depression and anxiety may develop in early adulthood. [9]

Children and adults with Down syndrome are at increased risk of epileptic seizures, which occur in 5–10% of children and up to 50% of adults. [9] This includes an increased risk of a specific type of seizure called infantile spasms. [29] Many (15%) who live 40 years or longer develop Alzheimer's disease. [54] In those who reach 60 years of age, 50–70% have the disease. [9]

Down syndrome regression disorder is a sudden regression with neuropsychiatric symptoms such as catatonia, possibly caused by an autoimmune disease. [55] It primarily appears in teenagers and younger adults. [56]

Senses

Brushfield spots, visible in the irises of a baby with Down syndrome Brushfield eye crop.jpg
Brushfield spots, visible in the irises of a baby with Down syndrome

Hearing and vision disorders occur in more than half of people with Down syndrome. [29]

Ocular findings

Brushfield spots (small white or grayish/brown spots on the periphery of the iris), upward slanting palpebral fissures (the opening between the upper and lower lids) and epicanthal folds (folds of skin between the upper eyelid and the nose) are clinical signs at birth suggesting the diagnosis of Down syndrome [57] [58] especially in the Western World. [58] None of these requires treatment.[ citation needed ]

Visually significant congenital cataracts (clouding of the lens of the eye) occur more frequently with Down syndrome. [58] Neonates with Down syndrome should be screened for cataract because early recognition and referral reduce the risk of vision loss from amblyopia. [59] Dot-like opacities in the cortex of the lens (cerulean cataract) are present in up to 50% of people with Down syndrome, but may be followed without treatment if they are not visually significant. [58]

Strabismus, nystagmus and nasolacrimal duct obstruction occur more frequently in children with Down syndrome. [58] Screening for these diagnoses should begin within six months of birth. [58] [59] Strabismus is more often acquired than congenital. [58] Early diagnosis and treatment of strabismus reduces the risk of vision loss from amblyopia. [60] In Down syndrome, the presence of epicanthal folds may give the false impression of strabismus, referred to as pseudostrabismus. Nasolacrimal duct obstruction, which causes tearing (epiphora), is more frequently bilateral and multifactorial than in children without Down syndrome. [58]

Refractive error is more common with Down syndrome, though the rate may not differ until after twelve months of age compared to children without Down syndrome. [58] Early screening is recommended to identify and treat significant refractive error with glasses or contact lenses. Poor accommodation (ability to focus on close objects) is associated with Down syndrome, which may mean bifocals are indicated. [58]

In keratoconus, the cornea progressively thins and bulges into a cone shape, [61] causing visual blurring or distortion. Keratoconus first presents in the teen years and progresses into the thirties. [61] [62] Down syndrome is a strong risk factor for developing keratoconus, and onset may be occur at a younger age than in those without Down syndrome. [58] Eye rubbing is also a risk factor for developing keratoconus. [62] It is speculated that chronic eye irritation from blepharitis may increase eye rubbing in Down syndrome, [58] contributing to the increased prevalence of keratoconus.

An association between glaucoma and Down syndrome is often cited. [57] Glaucoma in children with Down syndrome is uncommon, with a prevalence of less than 1%. [57] [58] It is currently unclear if the prevalence of glaucoma in those with Down syndrome differs from that in the absence of Down syndrome. [58]

Estimates of prevalence of ocular findings in Down Syndrome vary widely depending on the study. [58] Some prevalence estimates follow. Vision problems have been observed in 38–80% of cases. [57] Brushfield spots are present in 38–85% of individuals. [57] Between 20 and 50% have strabismus. [57] Cataracts occur in 15%, [63] and may be present at birth. [57] Keratoconus may occur in as many as 21–30%. [58]

Hearing Loss

Hearing problems are found in 50–90% of children with Down syndrome. [64] This is often the result of otitis media with effusion which occurs in 50–70% [10] and chronic ear infections which occur in 40–60%. [65] Ear infections often begin in the first year of life and are partly due to poor eustachian tube function. [66] [67] Excessive ear wax can also cause hearing loss due to obstruction of the outer ear canal. [9] Even a mild degree of hearing loss can have negative consequences for speech, language understanding, and academics. [1] [67] It is important to rule out hearing loss as a factor in social and cognitive deterioration. [68] Age-related hearing loss of the sensorineural type occurs at a much earlier age and affects 10–70% of people with Down syndrome. [9]

Heart

The rate of congenital heart disease in newborns with Down syndrome is around 40%. [34] Of those with heart disease, about 80% have an atrial septal defect or ventricular septal defect with the former being more common. [9] Congenital heart disease can also put individuals at a higher risk of pulmonary hypertension, where arteries in the lungs narrow and cause inadequate blood oxygenation. [69] Some of the genetic contributions to pulmonary hypertension in individuals with Down Syndrome are abnormal lung development, endothelial dysfunction, and proinflammatory genes. [69] Mitral valve problems become common as people age, even in those without heart problems at birth. [9] Other problems that may occur include tetralogy of Fallot and patent ductus arteriosus. [66] People with Down syndrome have a lower risk of hardening of the arteries. [9]

Cancer

Although the overall risk of cancer in Down syndrome is not changed, [70] the risk of testicular cancer and certain blood cancers, including acute lymphoblastic leukemia (ALL) and acute megakaryoblastic leukemia (AMKL) is increased while the risk of other non-blood cancers is decreased. [9] People with Down syndrome are believed to have an increased risk of developing cancers derived from germ cells whether these cancers are blood- or non-blood-related. [71] In 2008, the World Health Organization (WHO) introduced a distinct classification for myeloid proliferation in individuals with Down syndrome. [72]

Blood cancers

Leukemia is 10 to 15 times more common in children with Down syndrome. [29] In particular, acute lymphoblastic leukemia is 20 times more common and the megakaryoblastic form of acute myeloid leukemia (acute megakaryoblastic leukemia), is 500 times more common. [73] Acute megakaryoblastic leukemia (AMKL) is a leukemia of megakaryoblasts, the precursors cells to megakaryocytes which form blood platelets. [73] Acute lymphoblastic leukemia in Down syndrome accounts for 1–3% of all childhood cases of ALL. It occurs most often in those older than nine years or having a white blood cell count greater than 50,000 per microliter and is rare in those younger than one year old. ALL in Down syndrome tends to have poorer outcomes than other cases of ALL in people without Down syndrome. [73] [74] In short, the likelihood of developing acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is higher in children with Down syndrome compared to those without Down syndrome. [75]

Myeloid leukemia typically precedes Down syndrome and is accompanied by a condition known as transient abnormal myelopoiesis (TAM), which generally disrupts the differentiation of megakaryocytes and erythrocytes. [76] In Down syndrome, AMKL is typically preceded by transient myeloproliferative disease (TMD), a disorder of blood cell production in which non-cancerous megakaryoblasts with a mutation in the GATA1 gene rapidly divide during the later period of pregnancy. [73] [77] GATA1 mutations combined with trisomy 21 contribute to a predisposition to TAM. [78] In trisomy 21, the process of leukemogenesis starts in early fetal life, with genetic factors, including GATA1 mutations, contributing to the development of TAM on the preleukemic pathway. [76] The condition affects 3–10% of babies with Down. [73] While it often spontaneously resolves within three months of birth, it can cause serious blood, liver, or other complications. [79] In about 10% of cases, TMD progresses to AMKL during the three months to five years following its resolution. [73] [79] [78]

Non-blood cancers

People with Down syndrome have a lower risk of all major solid cancers, including those of lung, breast, and cervix, with the lowest relative rates occurring in those aged 50 years or older. [71] This low risk is thought to be due to an increase in the expression of tumor suppressor genes present on chromosome 21. [80] [71] One exception is testicular germ cell cancer which occurs at a higher rate in Down syndrome. [71]

Endocrine

Problems of the thyroid gland occur in 20–50% of individuals with Down syndrome. [9] [29] Low thyroid is the most common form, occurring in almost half of all individuals. [9] Thyroid problems can be due to a poorly or nonfunctioning thyroid at birth (known as congenital hypothyroidism) which occurs in 1% [10] or can develop later due to an attack on the thyroid by the immune system resulting in Graves' disease or autoimmune hypothyroidism. [81] Type 1 diabetes mellitus is also more common. [9]

Gastrointestinal

Constipation occurs in nearly half of people with Down syndrome and may result in changes in behavior. [29] One potential cause is Hirschsprung's disease, occurring in 2–15%, which is due to a lack of nerve cells controlling the colon. [82] Other congenital problems can include duodenal atresia, imperforate anus and gastroesophageal reflux disease. [66] Celiac disease affects about 7–20%. [9] [29]

Teeth

People with Down syndrome tend to be more susceptible to gingivitis as well as early, severe periodontal disease, necrotising ulcerative gingivitis, and early tooth loss, especially in the lower front teeth. [83] [84] While plaque and poor oral hygiene are contributing factors, the severity of these periodontal diseases cannot be explained solely by external factors. [84] Research suggests that the severity is likely a result of a weakened immune system. [84] [85] The weakened immune system also contributes to increased incidence of yeast infections in the mouth (from Candida albicans ). [85]

People with Down syndrome also tend to have a more alkaline saliva resulting in a greater resistance to tooth decay, despite decreased quantities of saliva, [86] less effective oral hygiene habits, and higher plaque indexes. [83] [85] [86] [87]

Higher rates of tooth wear and bruxism are also common. [85] Other common oral manifestations of Down syndrome include enlarged hypotonic tongue, crusted and hypotonic lips, mouth breathing, narrow palate with crowded teeth, class III malocclusion with an underdeveloped maxilla and posterior crossbite, delayed exfoliation of baby teeth and delayed eruption of adult teeth, shorter roots on teeth, and often missing and malformed (usually smaller) teeth. [83] [85] [86] [87] Less common manifestations include cleft lip and palate and enamel hypocalcification (20% prevalence). [87]

Taurodontism, an elongation of the pulp chamber, has a high prevalence in people with DS. [88] [89]

Fertility

Males with Down syndrome usually do not father children, while females have lower rates of fertility relative to those who are unaffected. [90] Fertility is estimated to be present in 30–50% of females. [91] Menopause usually occurs at an earlier age. [9] The poor fertility in males is thought to be due to problems with sperm development; however, it may also be related to not being sexually active. [90] As of 2006, three instances of males with Down syndrome fathering children and 26 cases of females having children have been reported. [90] Without assisted reproductive technologies, around half of the children of someone with Down syndrome will also have the syndrome. [90] [92]

Cause

The cause of the extra full or partial chromosome is still unknown. [93] Most of the time, Down syndrome is caused by a random mistake in cell division during early development of the fetus, but not inherited, [94] and there is no scientific research which shows that environmental factors or the parents' activities contribute to Down syndrome. The only factor that has been linked to the increased chance of having a baby with Down syndrome is advanced parental age. This is mostly associated with advanced maternal age but about 10 per cent of cases are associated with advanced paternal age. [95]

Karyotype for Down syndrome (trisomy 21) showing the three copies of chromosome 21 Down Syndrome Karyotype.png
Karyotype for Down syndrome (trisomy 21) showing the three copies of chromosome 21

Down syndrome is caused by having three copies of the genes on chromosome 21, rather than the usual two. [3] [96] The parents of the affected individual are typically genetically normal. [14] Those who have one child with Down syndrome have about a 1% possibility of having a second child with the syndrome, if both parents are found to have normal karyotypes. [91]

The extra chromosome content can arise through several different ways. The most common cause (about 92–95% of cases) is a complete extra copy of chromosome 21, resulting in trisomy 21. [92] [97] In 1–2.5% of cases, some of the cells in the body are normal and others have trisomy 21, known as mosaic Down syndrome. [91] [98] The other common mechanisms that can give rise to Down syndrome include: a Robertsonian translocation, isochromosome, or ring chromosome. These contain additional material from chromosome 21 and occur in about 2.5% of cases. [29] [91] An isochromosome results when the two long arms of a chromosome separate together rather than the long and short arm separating together during egg or sperm development. [92]

Trisomy 21

Down syndrome (also known by the karyotype 47,XX,+21 for females and 47,XY,+21 for males) [99] is mostly caused by a failure of the 21st chromosome to separate during egg or sperm development, known as nondisjunction. [92] As a result, a sperm or egg cell is produced with an extra copy of chromosome 21; this cell thus has 24 chromosomes. When combined with a normal cell from the other parent, the baby has 47 chromosomes, with three copies of chromosome 21. [3] [92] About 88% of cases of trisomy 21 result from nonseparation of the chromosomes in the mother, 8% from nonseparation in the father, and 3% after the egg and sperm have merged. [100]

Mosaic Down syndrome

Mosaic Down syndrome is diagnosed when there is a mixture of two types of cells: some cells have three copies of chromosome 21 but some cells have the typical two copies of chromosome 21. [18] This type is the least common form of Down syndrome and accounts for only about 1% of all cases. [93] Children with mosaic Down syndrome may have the same features as other children with Down syndrome. However, they may have fewer characteristics of the condition due to the presence of some (or many) cells with a typical number of chromosomes. [18]

Translocation Down syndrome

The extra chromosome 21 material may also occur due to a Robertsonian translocation in 2–4% of cases. [91] [101] In this translocation Down syndrome, the long arm of chromosome 21 is attached to another chromosome, often chromosome 14. [102] In a male affected with Down syndrome, it results in a karyotype of 46XY,t(14q21q). [102] [103] This may be a new mutation or previously present in one of the parents. [104] The parent with such a translocation is usually normal physically and mentally; [102] however, during production of egg or sperm cells, a higher chance of creating reproductive cells with extra chromosome 21 material exists. [101] This results in a 15% chance of having a child with Down syndrome when the mother is affected and a less than 5% probability if the father is affected. [104] The probability of this type of Down syndrome is not related to the mother's age. [102] Some children without Down syndrome may inherit the translocation and have a higher probability of having children of their own with Down syndrome. [102] In this case it is sometimes known as familial Down syndrome. [105]

Mechanism

The extra genetic material present in Down syndrome results in overexpression of a portion of the 310 genes located on chromosome 21. [96] This overexpression has been estimated at 50%, due to the third copy of the chromosome present. [91] Some research has suggested the Down syndrome critical region is located at bands 21q22.1–q22.3, [106] with this area including genes for the amyloid precursor protein, superoxide dismutase, and likely the ETS2 proto oncogene. [107] Other research, however, has not confirmed these findings. [96] MicroRNAs are also proposed to be involved. [108]

The dementia that occurs in Down syndrome is due to an excess of amyloid beta peptide produced in the brain and is similar to Alzheimer's disease, which also involves amyloid beta build-up. [109] Amyloid beta is processed from amyloid precursor protein, the gene for which is located on chromosome 21. [109] Senile plaques and neurofibrillary tangles are present in nearly all by 35 years of age, though dementia may not be present. [14] It is hypothesized that those with Down syndrome lack a normal number of lymphocytes and produce less antibodies which is said to present an increased risk of infection. [29]

Epigenetics

Down syndrome is associated with an increased risk of some chronic diseases that are typically associated with older age such as Alzheimer's disease. It is believed that accelerated aging occurs and increases the biological age of tissues, but molecular evidence for this hypothesis is sparse. According to a biomarker of tissue age known as epigenetic clock, it is hypothesized that trisomy 21 increases the age of blood and brain tissue (on average by 6.6 years). [110]

Diagnosis

Screening before birth

Guidelines recommend screening for Down syndrome to be offered to all pregnant women, regardless of age. [111] [112] A number of tests are used, with varying levels of accuracy. They are typically used in combination to increase the detection rate. [29] None can be definitive; thus, if screening predicts a high possibility of Down syndrome, either amniocentesis or chorionic villus sampling is required to confirm the diagnosis. [111]

Ultrasound

Prenatal ultrasound can be used to screen for Down syndrome. Findings that indicate increased chances when seen at 14 to 24 weeks of gestation include a small or no nasal bone, large ventricles, nuchal fold thickness, and an abnormal right subclavian artery, among others. [113] The presence or absence of many markers is more accurate. [113] Increased fetal nuchal translucency (NT) indicates an increased possibility of Down syndrome picking up 75–80% of cases and being falsely positive in 6%. [114]

Blood tests

Several blood markers can be measured to predict the chances of Down syndrome during the first or second trimester. [115] [116] Testing in both trimesters is sometimes recommended and test results are often combined with ultrasound results. [115] In the second trimester, often two or three tests are used in combination with two or three of: α-fetoprotein, unconjugated estriol, total hCG, and free βhCG detecting about 60–70% of cases. [116]

Testing of the mother's blood for fetal DNA is being studied and appears promising in the first trimester. [117] [118] The International Society for Prenatal Diagnosis considers it a reasonable screening option for those women whose pregnancies are at a high likelihood of trisomy 21. [119] Accuracy has been reported at 98.6% in the first trimester of pregnancy. [29] Confirmatory testing by invasive techniques (amniocentesis, CVS) is still required to confirm the screening result. [119]

Combinations

First- and second-trimester screening [111]
Screen Week of pregnancy when performedDetection rateFalse positiveDescription
Combined test10–13.5 wks82–87%5%Uses ultrasound to measure nuchal translucency in addition to blood tests for free or total beta-hCG and PAPP-A
Quad screen 15–20 wks81%5%Measures the maternal serum alpha-fetoprotein, unconjugated estriol, hCG, and inhibin-A
Integrated test15–20 wks94–96%5%Is a combination of the quad screen, PAPP-A, and NT
Cell-free fetal DNA From 10 wks [120] 96–100% [117] 0.3% [121] A blood sample is taken from the mother by venipuncture and is sent for DNA analysis.

Efficacy

For combinations of ultrasonography and non-genetic blood tests, screening in both the first and second trimesters is better than just screening in the first trimester. [111] The different screening techniques in use are able to pick up 90–95% of cases, with a false-positive rate of 2–5%. [115] If Down syndrome occurs in one in 500 pregnancies with a 90% detection rate and the test used has a 5% false-positive rate, this means, of 20 women who test positive on screening, only one will not have a fetus with Down syndrome confirmed. [115] If the screening test has a 2% false-positive rate, this means, of 50 women who test positive on screening, one will not have a fetus with Down syndrome. [115]

Invasive genetic testing

Amniocentesis and chorionic villus sampling are more reliable tests, but they increase the risk of miscarriage by between 0.5–1%. [122] The risk of limb problems may be increased in the offspring if chorionic villus sampling is performed before 10 weeks. [122]

An example of an algorithm for determining the indication for prenatal genetic testing of Down syndrome Prenatal Down syndrome screening algorithm.png
An example of an algorithm for determining the indication for prenatal genetic testing of Down syndrome

The risk from the procedure is greater the earlier it is performed, thus amniocentesis is not recommended before 15 weeks gestational age and chorionic villus sampling before 10 weeks gestational age. [122]

Abortion rates

About 92% of pregnancies in Europe with a diagnosis of Down syndrome are terminated. [22] As a result, there is almost no one with Down syndrome in Iceland and Denmark, where screening is commonplace. [124] In the United States, the termination rate after diagnosis is around 75%, [124] but varies from 61 to 93%, depending on the population surveyed. [21] Rates are lower among women who are younger and have decreased over time. [21] When asked if they would have a termination if their fetus tested positive, 23–33% said yes, when high-risk pregnant women were asked, 46–86% said yes, and when women who screened positive are asked, 89–97% say yes. [125]

After birth

A diagnosis can often be suspected based on the child's physical appearance at birth. [10] An analysis of the child's chromosomes is needed to confirm the diagnosis, and to determine if a translocation is present, as this may help determine the chances of the child's parents having further children with Down syndrome. [10]

Management

Efforts such as early childhood intervention, therapies, screening for common medical issues, a good family environment, and work-related training can improve the development of children with Down syndrome and provide good quality of life. Common therapies utilized include physical therapy, occupational therapy and speech therapy. [126] Education and proper care can provide a positive quality of life. [7] Typical childhood vaccinations are recommended. [29]

Health screening

Recommended screening
TestingChildren [127] Adults [9]
Hearing6 months, 12 months, then yearly3–5 years
T4 and TSH 6 months, then yearly
Eyes6 months, then yearly3–5 years
Teeth2 years, then every 6 months
Celiac diseaseBetween 2 and 3 years of age,
or earlier if symptoms occur
Sleep study 3 to 4 years, or earlier if symptoms
of obstructive sleep apnea occur
Neck X-raysBetween 3 and 5 years of age

A number of health organizations have issued recommendations for screening those with Down syndrome for particular diseases. [127] This is recommended to be done systematically. [29]

At birth, all children should get an electrocardiogram and ultrasound of the heart. [29] Surgical repair of heart problems may be required as early as three months of age. [29] Heart valve problems may occur in young adults, and further ultrasound evaluation may be needed in adolescents and in early adulthood. [29] Due to the elevated risk of testicular cancer, some recommend checking the person's testicles yearly. [9]

Cognitive development

Some people with Down syndrome experience hearing loss. In this instance, hearing aids or other amplification devices can be useful for language learning. [29] Speech therapy may be useful and is recommended to be started around nine months of age. [29] As those with Down syndrome typically have good hand-eye coordination, learning sign language is a helpful communication tool. [47] Augmentative and alternative communication methods, such as pointing, body language, objects, or pictures, are often used to help with communication. [128] Behavioral issues and mental illness are typically managed with counseling or medications. [10]

Education programs before reaching school age may be useful. [1] School-age children with Down syndrome may benefit from inclusive education (whereby students of differing abilities are placed in classes with their peers of the same age), provided some adjustments are made to the curriculum. [129] In the United States, the Individuals with Disabilities Education Act of 1975 requires public schools generally to allow attendance by students with Down syndrome. [130]

Individuals with Down syndrome may learn better visually. Drawing may help with language, speech, and reading skills. Children with Down syndrome still often have difficulty with sentence structure and grammar, as well as developing the ability to speak clearly. [131] Several types of early intervention can help with cognitive development. Efforts to develop motor skills include physical therapy, speech and language therapy, and occupational therapy. Physical therapy focuses specifically on motor development and teaching children to interact with their environment. Speech and language therapy can help prepare for later language. Lastly, occupational therapy can help with skills needed for later independence. [132]

Other

Tympanostomy tubes are often needed [29] and often more than one set during the person's childhood. [64] Tonsillectomy is also often done to help with sleep apnea and throat infections. [29] Surgery does not correct every instance of sleep apnea and a continuous positive airway pressure (CPAP) machine may be useful in those cases. [64]

Efforts to prevent respiratory syncytial virus (RSV) infection with human monoclonal antibodies should be considered, especially in those with heart problems. [1] In those who develop dementia there is no evidence for memantine, [133] donepezil, [134] rivastigmine, [135] or galantamine. [136]

Prognosis

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Deaths due to Down syndrome per million persons in 2012
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Between 5–15% of children with Down syndrome in Sweden attend regular school. [137] Some graduate from high school; however, most do not. [24] Of those with intellectual disability in the United States who attended high school about 40% graduated. [138] Many learn to read and write and some are able to do paid work. [24] In adulthood about 20% in the United States do paid work in some capacity. [25] [139] In Sweden, however, less than 1% have regular jobs. [137] Many are able to live semi-independently, [14] but they often require help with financial, medical, and legal matters. [10] Those with mosaic Down syndrome usually have better outcomes. [91]

Individuals with Down syndrome have a higher risk of early death than the general population. [29] This is most often from heart problems or infections. [1] [9] Following improved medical care, particularly for heart and gastrointestinal problems, the life expectancy has increased. [1] This increase has been from 12 years in 1912, [140] to 25 years in the 1980s, [1] to 50 to 60 years in the developed world in the 2000s. [9] [10] Data collected between the 1985–2003 showed between 4–12% infants with Down syndrome die in the first year of life. [79] The probability of long-term survival is partly determined by the presence of heart problems. From research at the turn of the century, it tracked those with congenital heart problems, showing 60% survived to at least 10 years and 50% survived to at least 30 years of age. The research failed to track further aging beyond 30 years. [14] In those without heart problems, 85% studied survived to at least 10 years and 80% survived to at least 30 years of age. [14] It is estimated that 10% lived to 70 years of age in the early 2000s. [92] Much of this data is outdated and life expectancy has drastically improved with more equitable healthcare and continuous advancement of surgical practice. [141] The National Down Syndrome Society provides information regarding raising a child with Down syndrome. [142]

Epidemiology

The risk of having a Down syndrome pregnancy in relation to a mother's age Down risk by maternal age from jk morris.png
The risk of having a Down syndrome pregnancy in relation to a mother's age

Down syndrome is the most common chromosomal abnormality in humans. [9] Globally, as of 2010, Down syndrome occurs in about 1 per 1,000 births [1] and results in about 17,000 deaths. [143] More children are born with Down syndrome in countries where abortion is not allowed and in countries where pregnancy more commonly occurs at a later age. [1] About 1.4 per 1,000 live births in the United States [144] and 1.1 per 1,000 live births in Norway are affected. [9] In the 1950s, in the United States, it occurred in 2 per 1,000 live births with the decrease since then due to prenatal screening and abortions. [104] The number of pregnancies with Down syndrome is more than two times greater with many spontaneously aborting. [10] It is the cause of 8% of all congenital disorders. [1]

Maternal age affects the chances of having a pregnancy with Down syndrome. [4] At age 20, the chance is 1 in 1,441; at age 30, it is 1 in 959; at age 40, it is 1 in 84; and at age 50 it is 1 in 44. [4] Although the probability increases with maternal age, 70% of children with Down syndrome are born to women 35 years of age and younger, because younger people have more children. [4] The father's older age is also a risk factor in women older than 35, but not in women younger than 35, and may partly explain the increase in risk as women age. [145]

History

Levitas and Reid have suggested that this early Netherlandish painting, The Adoration of the Christ Child, depicts a person with Down syndrome as one of the angels. The Adoration of the Christ Child MET DT8852.jpg
Levitas and Reid have suggested that this early Netherlandish painting, The Adoration of the Christ Child, depicts a person with Down syndrome as one of the angels.
John Langdon Haydon Down -- first described Down syndrome Portrait of John Langdon Down (c 1870) by Sydney Hodges.jpg
John Langdon Haydon Down — first described Down syndrome

English physician John Langdon Down first described Down syndrome in 1862, recognizing it as a distinct type of mental disability, and again in a more widely published report in 1866. [29] [147] [148] Édouard Séguin described it as separate from cretinism in 1844. [30] [149] By the 20th century, Down syndrome had become the most recognizable form of mental disability.

Due to his perception that children with Down syndrome shared facial similarities with those of Blumenbach's Mongoloid race, John Langdon Down used the term "mongoloid". [150] He felt that the existence of Down syndrome confirmed that all peoples were genetically related. [151] In the 1950s with discovery of the underlying cause as being related to chromosomes, concerns about the race-based nature of the name increased. [152]

In 1961, a group of nineteen scientists suggested that "mongolism" had "misleading connotations" and had become "an embarrassing term". [153] The World Health Organization (WHO) dropped the term in 1965 after a request by the delegation from the Mongolian People's Republic. [154] While this terminology continued to be used until the late twentieth century, [155] : 21  it is now considered unacceptable and is no longer in common use.

In antiquity, many infants with disabilities were either killed or abandoned. [30] In June 2020, the earliest incidence of Down syndrome was found in genomic evidence from an infant that was buried before 3200 BC at Poulnabrone dolmen in Ireland. [156] Researchers believe that a number of historical pieces of art portray Down syndrome, including pottery from the pre-Columbian Tumaco-La Tolita culture in present-day Colombia and Ecuador, [157] and the 16th-century painting The Adoration of the Christ Child. [158] [159]

In the 20th century, many individuals with Down syndrome were institutionalized, few of the associated medical problems were treated, and most people died in infancy or early adulthood. With the rise of the eugenics movement, 33 of the then 48 U.S. states and several countries began programs of forced sterilization of individuals with Down syndrome and comparable degrees of disability. Action T4 in Nazi Germany saw the systematic murder of people with Down syndrome made public policy. [160]

With the discovery of karyotype techniques in the 1950s it became possible to identify abnormalities of chromosomal number or shape. [149] In 1959 Jérôme Lejeune reported the discovery that Down syndrome resulted from an extra chromosome. [29] However, Lejeune's claim to the discovery has been disputed, [161] and in 2014 the Scientific Council of the French Federation of Human Genetics unanimously awarded its Grand Prize to his colleague Marthe Gautier for her role in this discovery. [162] The discovery took place in the laboratory of Raymond Turpin at the Hôpital Trousseau in Paris, France. [163] Jérôme Lejeune and Marthe Gautier were both his students. [164]

As a result of this discovery, the condition became known as trisomy 21. [165] Even before the discovery of its cause, the presence of the syndrome in all races, its association with older maternal age, and its rarity of recurrence had been noticed. Medical texts had assumed it was caused by a combination of inheritable factors that had not been identified. Other theories had focused on injuries sustained during birth. [166]

Society and culture

Name

Down syndrome is named after John Langdon Down. He was the first person to provide an accurate description of the syndrome. His research that was published in 1866 earned him the recognition as the Father of the syndrome. [167] While others had previously recognized components of the condition, John Langdon Down described the syndrome as a distinct, unique medical condition. [19]

In 1975, the United States National Institutes of Health (NIH) convened a conference to standardize the naming and recommended replacing the possessive form, "Down's syndrome", with "Down syndrome". [168] However, both the possessive and nonpossessive forms remain in use by the general population. [12] The term "trisomy 21" is also commonly used. [153] [169]

Ethics

Father with son who has Down syndrome Vater und Sohn mit Down-Syndrom.jpg
Father with son who has Down syndrome

Obstetricians routinely offer antenatal screenings for various conditions, including Down syndrome. [170] [171] When results from testing become available, it is considered an ethical requirement to share the results with the patient. [170] [172]

Some bioethicists deem it reasonable for parents to select a child who would have the highest well-being. [173] One criticism of this reasoning is that it often values those with disabilities less. [174] Some parents argue that Down syndrome should not be prevented or cured and that eliminating Down syndrome amounts to genocide. [175] [176] The disability rights movement does not have a position on screening, [177] although some members consider testing and abortion discriminatory. [177] Some in the United States who are anti-abortion support abortion if the fetus is disabled, while others do not. [178] Of a group of 40 mothers in the United States who have had one child with Down syndrome, half agreed to screening in the next pregnancy. [178]

Within the US, some Protestant denominations see abortion as acceptable when a fetus has Down syndrome while Orthodox Christianity and Roman Catholicism do not. [179] Some of those against screening refer to it as a form of eugenics. [179] Parents may be stigmatized whichever decision they make. [180]

Advocacy groups

Advocacy groups for individuals with Down syndrome began to be formed after the Second World War. [181] These were organizations advocating for the inclusion of people with Down syndrome into the general school system and for a greater understanding of the condition among the general population, [181] as well as groups providing support for families with children living with Down syndrome. [181] Before this individuals with Down syndrome were often placed in mental hospitals or asylums. Organizations included the Royal Society for Handicapped Children and Adults founded in the UK in 1946 by Judy Fryd, [181] [182] Kobato Kai founded in Japan in 1964, [181] the National Down Syndrome Congress founded in the United States in 1973 by Kathryn McGee and others, [181] [183] and the National Down Syndrome Society founded in 1979 in the United States. [181] The first Roman Catholic order of nuns for women with Down Syndrome, Little Sisters Disciples of the Lamb, was founded in 1985 in France. [184]

The first World Down Syndrome Day was held on 21 March 2006. [185] The day and month were chosen to correspond with 21 and trisomy, respectively. [186] It was recognized by the United Nations General Assembly in 2011. [185]

Special21.org, founded in 2015, advocates the need for a specific classification category to enable Down syndrome swimmers the opportunity to qualify and compete at the Paralympic Games. [187] The project began when International Down syndrome swimmer Filipe Santos broke the world record in the 50m butterfly event, but was unable to compete at the Paralympic Games. [188] [189]

Paralympic Swimming

International Paralympic Committee Para-swimming classification codes are based upon single impairment only, whereas Down syndrome individuals have both physical and intellectual impairments.

Although Down syndrome swimmers are able to compete in the Paralympic Swimming S14 intellectual impairment category (provided they score low in IQ tests), they are often outmatched by the superior physicality of their opponents. [190] [191]

At present there is no designated Paralympic category for swimmers with Down syndrome, meaning they have to compete as intellectually disadvantaged athletes. This disregards their physical disabilities. [192] [193]

A number of advocacy groups globally have been lobbying for the inclusion of a distinct classification category for Down syndrome swimmers within the IPC Classification Codes framework. [194]

Despite ongoing advocacy, the issue remains unresolved, and swimmers with Down syndrome continue to face challenges in accessing appropriate classification pathways. [195] [196]

Research

Efforts are underway to determine how the extra chromosome 21 material causes Down syndrome, as currently this is unknown, [197] and to develop treatments to improve intelligence in those with the syndrome. [198] Two efforts being studied are the use stem cells [197] and gene therapy. [199] [200] Other methods being studied include the use of antioxidants, gamma secretase inhibition, adrenergic agonists, and memantine. [201] Research is often carried out on an animal model, the Ts65Dn mouse. [202]

Other hominids

Down syndrome may also occur in hominids other than humans. In great apes chromosome 22 corresponds to the human chromosome 21 [a] and thus trisomy 22 causes Down syndrome in apes. The condition was observed in a common chimpanzee in 1969 and a Bornean orangutan in 1979, but neither lived very long. The common chimpanzee Kanako (born around 1993, in Japan) has become the longest-lived known example of this condition. Kanako has some of the same symptoms that are common in human Down syndrome. It is unknown how common this condition is in chimps, but it is plausible it could be roughly as common as Down syndrome is in humans. [204] [205]

Fossilized remains of a Neanderthal aged approximately 6 at death were described in 2024. The child, nicknamed Tina, suffered from a malformation of the inner ear that only occurs in people with Down syndrome, and would have caused hearing loss and disabling vertigo. The fact that a Neanderthal with such a condition survived to such an age was taken as evidence of compassion and extra-maternal care among Neanderthals. [206] [207]

Chris Burke, an actor with Down syndrome, born in 1965 Chris Burke.jpg
Chris Burke, an actor with Down syndrome, born in 1965

Individuals

Television and film

Music

Toys

See also

Notes

  1. ↑ Using the traditional numbering; the current numbering scheme retains human chromosome numbers, using 2A and 2B instead of 2 and 3 to refer to the two chromosomes that fused into chromosome 2 in humans. [203]

Related Research Articles

<span class="mw-page-title-main">Autosome</span> Any chromosome other than a sex chromosome

An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal pairs, which may have different structures. The DNA in autosomes is collectively known as atDNA or auDNA.

<span class="mw-page-title-main">Amniocentesis</span> Sampling of amniotic fluid done mainly to detect fetal chromosomal abnormalities

Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is necessary to conclusively diagnose the majority of genetic disorders, with amniocentesis being the gold-standard procedure after 15 weeks' gestation.

<span class="mw-page-title-main">Patau syndrome</span> Chromosomal disorder in which there are three copies of chromosome 13

Patau syndrome is a syndrome caused by a chromosomal abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13. The extra genetic material disrupts normal development, causing multiple and complex organ defects.

<span class="mw-page-title-main">Trisomy 18</span> Chromosomal disorder in which there are three copies of chromosome 18

Trisomy 18, also known as Edwards syndrome, is a genetic disorder caused by the presence of a third copy of all or part of chromosome 18. Many parts of the body are affected. Babies are often born small and have heart defects. Other features include a small head, small jaw, clenched fists with overlapping fingers, and severe intellectual disability.

<span class="mw-page-title-main">Chromosomal translocation</span> Phenomenon that results in unusual rearrangement of chromosomes

In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal, and Robertsonian translocation. Reciprocal translocation is a chromosome abnormality caused by exchange of parts between non-homologous chromosomes. Two detached fragments of two different chromosomes are switched. Robertsonian translocation occurs when two non-homologous chromosomes get attached, meaning that given two healthy pairs of chromosomes, one of each pair "sticks" and blends together homogeneously.

<span class="mw-page-title-main">Prenatal testing</span> Testing for diseases or conditions in a fetus

Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects, such as spina bifida, cleft palate, Down syndrome, trisomy 18, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.

The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy in the second trimester to classify a patient as either high-risk or low-risk for chromosomal abnormalities.

<span class="mw-page-title-main">Polysomy</span> Abnormal multiples of one or more chromosomes

Polysomy is a condition found in many species, including fungi, plants, insects, and mammals, in which an organism has at least one more chromosome than normal, i.e., there may be three or more copies of the chromosome rather than the expected two copies. Most eukaryotic species are diploid, meaning they have two sets of chromosomes, whereas prokaryotes are haploid, containing a single chromosome in each cell. Aneuploids possess chromosome numbers that are not exact multiples of the haploid number and polysomy is a type of aneuploidy. A karyotype is the set of chromosomes in an organism and the suffix -somy is used to name aneuploid karyotypes. This is not to be confused with the suffix -ploidy, referring to the number of complete sets of chromosomes.

The Pallister–Killian syndrome (PKS), also termed tetrasomy 12p mosaicism or the Pallister mosaic aneuploidy syndrome, is an extremely rare and severe genetic disorder. PKS is due to the presence of an extra and abnormal chromosome termed a small supernumerary marker chromosome (sSMC). sSMCs contain copies of genetic material from parts of virtually any other chromosome and, depending on the genetic material they carry, can cause various genetic disorders and neoplasms. The sSMC in PKS consists of multiple copies of the short arm of chromosome 12. Consequently, the multiple copies of the genetic material in the sSMC plus the two copies of this genetic material in the two normal chromosome 12's are overexpressed and thereby cause the syndrome. Due to a form of genetic mosaicism, however, individuals with PKS differ in the tissue distributions of their sSMC and therefore show different syndrome-related birth defects and disease severities. For example, individuals with the sSMC in their heart tissue are likely to have cardiac structural abnormalities while those without this sSMC localization have a structurally normal heart.

<span class="mw-page-title-main">Nuchal scan</span> Routine ultrasound done between 11 and 14 weeks pregnancy

A nuchal scan or nuchal translucency (NT) scan/procedure is a sonographic prenatal screening scan (ultrasound) to detect chromosomal abnormalities in a fetus, though altered extracellular matrix composition and limited lymphatic drainage can also be detected.

A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where there is an atypical number of chromosomes, or as structural abnormalities, where one or more individual chromosomes are altered. Chromosome mutation was formerly used in a strict sense to mean a change in a chromosomal segment, involving more than one gene. Chromosome anomalies usually occur when there is an error in cell division following meiosis or mitosis. Chromosome abnormalities may be detected or confirmed by comparing an individual's karyotype, or full set of chromosomes, to a typical karyotype for the species via genetic testing.

The genetics and abortion issue is an extension of the abortion debate and the disability rights movement. Since the advent of forms of prenatal diagnosis, such as amniocentesis and ultrasound, it has become possible to detect the presence of congenital disorders in the fetus before birth. Specifically, disability-selective abortion is the abortion of fetuses that are found to have non-fatal mental or physical defects detected through prenatal testing. Many prenatal tests are now considered routine, such as testing for Down syndrome. Women who are discovered to be carrying fetuses with disabilities are often faced with the decision of whether to abort or to prepare to parent a child with disabilities.

<span class="mw-page-title-main">Trisomy 16</span> Partial or complete triplication of chromosome 16

Trisomy 16 is a chromosomal abnormality in which there are 3 copies of chromosome 16 rather than two. It is the most common autosomal trisomy leading to miscarriage, and the second most common chromosomal cause. About 6% of miscarriages have trisomy 16. Those mostly occur between 8 and 15 weeks after the last menstrual period.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Blood marrow cancer originating in megakaryoblast cells

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

Cell-free fetal DNA (cffDNA) is fetal DNA that circulates freely in the maternal blood. Maternal blood is sampled by venipuncture. Analysis of cffDNA is a method of non-invasive prenatal diagnosis frequently ordered for pregnant women of advanced maternal age. Two hours after delivery, cffDNA is no longer detectable in maternal blood.

<span class="mw-page-title-main">Tetrasomy X</span> Chromosomal disorder with 4 X chromosomes

Tetrasomy X, also known as 48,XXXX, is a chromosomal disorder in which a female has four, rather than two, copies of the X chromosome. It is associated with intellectual disability of varying severity, characteristic "coarse" facial features, heart defects, and skeletal anomalies such as increased height, clinodactyly, and radioulnar synostosis. Tetrasomy X is a rare condition, with few medically recognized cases; it is estimated to occur in approximately 1 in 50,000 females.

<span class="mw-page-title-main">Pentasomy X</span> Chromosomal disorder

Pentasomy X, also known as 49,XXXXX, is a chromosomal disorder in which a female has five, rather than two, copies of the X chromosome. Pentasomy X is associated with short stature, intellectual disability, characteristic facial features, heart defects, skeletal anomalies, and pubertal and reproductive abnormalities. The condition is exceptionally rare, with an estimated prevalence between 1 in 85,000 and 1 in 250,000.

<span class="mw-page-title-main">Trisomy X</span> Chromosome disorder in women

Trisomy X, also known as triple X syndrome and characterized by the karyotype 47,XXX, is a chromosome disorder in which a female has an extra copy of the X chromosome. It is relatively common and occurs in 1 in 1,000 females, but is rarely diagnosed; fewer than 10% of those with the condition know they have it.

Noninvasive prenatal testing (NIPT) is a method used to determine the risk for the fetus being born with certain chromosomal abnormalities, such as trisomy 21, trisomy 18 and trisomy 13. This testing analyzes small DNA fragments that circulate in the blood of a pregnant woman. Unlike most DNA found in the nucleus of a cell, these fragments are not found within the cells, instead they are free-floating, and so are called cell free fetal DNA (cffDNA). These fragments usually contain less than 200 DNA building blocks and arise when cells die, and their contents, including DNA, are released into the bloodstream. cffDNA derives from placental cells and is usually identical to fetal DNA. Analysis of cffDNA from placenta provides the opportunity for early detection of certain chromosomal abnormalities without harming the fetus.

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.

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