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Down syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2] Dildar Hussain, MBBS [3]

Synonyms and keywords: Trisomy 21, trisomy 21 syndrome, mongolianism, mongolism, Down’s syndrome baby

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Dildar Hussain, MBBS [3]

Overview

Down syndrome is a genetic disorder caused by the presence of all or part of an extra 21st chromosome. Often Down syndrome is associated with some impairment of cognitive ability and physical growth as well as facial appearance. Down syndrome can be identified during pregnancy or at birth. John Langdon Down, a British doctor described it first in 1866. JĂ©rĂŽme Lejeune in 1959 ascribed the features associated with Down’s syndrome to the presence of an extra 21st chromosome (trisomy 21). Based on anthropometric measurements and photographic appearance, John Landdon Down delineated a well-defined group of mentally disabled individuals, whose members all resembled the little girl very well. He called them, in concordance with the ethnical insights of the then famous dr. Blumenbach, mongoloid “idiots”. Today they are known by his own, more ethically correct name: Down’s syndrome. Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome. Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle. Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.Immaturity of the feto–placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Down’s syndrome pregnancies. The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination. Second quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. Pre-natal differentials of low AFP include Down syndrome, Edwards syndrome and Patau syndrome. In the newborn, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include isolated hypotonia, congenital hypothyroidism and Zellweger syndrome. Down syndrome is the most common chromosomal abnormality. Each year approximately 3,000 to 5,000 children are born with this chromosome disorder and it is believed there are about 250,000 families in the United States of America who are affected by Down syndrome. Birth rates are highest among mothers of advanced maternal age however 80% of all children with Down syndrome are born to mothers younger than 35 years. Down syndrome occurs in people of all races and economic levels. Common risk factors involved in the development of Down syndrome include maternal smoking, increased maternal age, impaired recombination of chromosome 21, impaired folate metabolism and oral contraceptive pills (OCPs). Less common risk factors leading to the development of Down syndrome include genomic instability in mothers, radiation exposure, low socioeconomic status and maternal obesity. During the first trimester of pregnancy, increased nuchal translucency in the fetus on ultrasound and decreased levels of pregnancy associated protein- A (PAPP-A) suggest the diagnosis of a chromosomal abnormality. Quad screen results during the second trimester of pregnancy may show increased beta-hCG, increased inhibin A, decreased alfa-fetoprotein (AFP) and decreased estriol. 3% of fetuses with Down’s syndrome diagnosed in utero at 16 weeks’ gestation would be lost spontaneously if termination of pregnancy was not performed. At birth, 50% of newborns with Down’s syndrome have one or more additional serious congenital abnormalities (in addition to intellectual disability). 96% without and 80% with heart defects survive the first year. At age 21 mean IQ is 42 (range 8–67) and mental age is 5 years (range 1–8 years). 11% develop Alzheimer’s disease by age 50 and 77% by age 70 (mean age of onset age 56). Common complication that may arise in patients suffering from Down syndrome include, congenital heart defects (ASD, VSD, PDA), hearing loss, diabetes, celiac disease, cataracts, endocarditis, atlantoaxial subluxation, hypo and hyperthyroidism, duodenal atresia, Hirschprung disease. Life expectancy is 50–55 years. Down syndrome is confirmed through cytogenetic studies which confirm trisomy 21. In addition complete blood count with differentials is performed to rule out leukemia, TSH and T4 are performed at birth, 6 months, 1 year and then annually to rule out hypothyroidism. Low level of IgG subclass 4 are correlated with bacterial infections. The mosaic trisomy 21 includes lymphocyte preparations, FISH, buccal mucosa cellular preparations and scoring frequency of trisomic cells. An x-ray may be helpful in the diagnosis of complications of Down syndrome which include atrial septal defect, ventricular septal defect,atrioventricular septal defect, patent ductus arteriosus, 11 ribs, omphalocoele, mickey mouse pelvis, flaring of iliac wings, hyper-segmented sternum, joint laxity or dislocations, Developmental dysplasia of the hip, atlanto-axial subluxation, atlanto-occipital instability and hypoplastic posterior arch of C1. On X-ray of hands short hands with shortened phalanges and clinodactyly because of hypoplastic middle phalanx of the fifth finger can also be present. Treatment of individuals with Down Syndrome depends on the particular manifestations of the disease. For instance, individuals with congenital heart disease may need to undergo major corrective surgery soon after birth. Other individuals may have relatively minor health problems requiring no therapy. Patients suffering from Down syndrome require rigorous follow-up in order to prevent the complications associated with the syndrome. Close monitoring of growth, hearing evaluation, ophthalmologic evaluation, thyroid profile, cardiac evaluation, dental care and close monitoring of complete blood counts in order to identify hematological maliganancies should be a part of care for a Down syndrome patient.

Historical Perspective

Down syndrome (Trisomey 21 or Dow’s syndrome) is a genetic disorder is characterized by the presence of all or part of an extra 21st chromosome. John Langdon Down, a British doctor described it first in 1866. JĂ©rĂŽme Lejeune in 1959 ascribed the features associated with Down’s syndrome to the presence of an extra 21st chromosome (trisomy 21). Based on anthropometric measurements and photographic appearance, John Landdon Down delineated a well-defined group of mentally disabled individuals, whose members all resembled the little girl very well. He called them, in concordance with the ethnical insights of the then famous dr. Blumenbach, mongoloid “idiots”. Today they are known by his own, more ethically correct name: Down’s syndrome. Until the middle of the 20th century, the cause of Down syndrome was largely. However, was known that it affected humans of all races, was associated with older maternal age and was rare. Standard medical texts assumed it was caused by a combination of inheritable factors which had not been identified. Other theories focused on injuries sustained during birth. In 1886 Shuttleworth referred to Langdon Down’s ethnic classification and he included the “Mongol type” in his publication. Beginning in 1888, John Langdon Down’s work became widely accepted and was consistently being referred to by scientists and physicians, beginning with Goodheart in 1888. By the 20th century, Mongolism had become a widely used descriptive term. This was the title used by Bertram Hill in 1908 and by Penrose as late as 1961. With the discovery of karyotype techniques in the 1950s, it became possible to identify abnormalities of chromosomal number or shape. In 1959, Professor JĂ©rĂŽme Lejeune discovered that Down syndrome resulted from an extra chromosome. The extra chromosome was subsequently labeled as the 21st, and the condition as trisomy 21.

Pathophysiology

Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome. Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle. Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.Immaturity of the feto–placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Down’s syndrome pregnancies. Reduced synthesis of AFP by the fetal liver is also thought to contribute to low AFP in Down’s syndrome pregnancies. Robertsonian translocation occurrs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromeres and the 2 short arms are lost. Mosaicism does not have any maternal association and it is a post-fertilization mitotic error. Disbilities found in Down syndrome patients are thought to arise secondary to varied genetic expression associated with the presence an extra 21st chromosome. 

Causes

Down’s syndrome (DS) is caused due to the presence of an extra 21st chromosome (triplication of chromosome 21). 95 percent of DS cases are due to meiotic non-disjunction during meiosis I. 4 percent of DS cases arise due to Robertsonian translocation and very rarely DS may be caused a post-fertilization mitotic error (mosaicism).

Differentiating Down syndrome from Other Diseases

The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination. Second quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. Pre-natal differentials of low AFP include Down syndrome, Edwards syndrome and Patau syndrome. In the newborn, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include isolated hypotonia, congenital hypothyroidism and Zellweger syndrome

Epidemiology and Demographics

Down syndrome is the most common chromosomal abnormality. Each year approximately 3,000 to 5,000 children are born with this chromosome disorder and it is believed there are about 250,000 families in the United States of America who are affected by Down syndrome. Birth rates are highest among mothers of advanced maternal age however 80% of all children with Down syndrome are born to mothers younger than 35 years. Down syndrome occurs in people of all races and economic levels.

Risk Factors

Common risk factors involved in the development of Down syndrome include maternal smoking, increased maternal age, impaired recombination of chromosome 21, impaired folate metabolism and oral contraceptive pills (OCPs). Less common risk factors leading to the development of Down syndrome include genomic instability in mothers, radiation exposure, low socioeconomic status and maternal obesity.

Screening

Standard prenatal screens can discover Down syndrome. Genetic counseling along with genetic testing, such as amniocentesis, chorionic villus sampling (CVS), or percutaneous umbilical blood sampling (PUBS) are usually offered to families who may have an increased risk of having a child with Down syndrome, or where normal prenatal exams indicate possible problems. Genetic screens are often performed on pregnant women older than 30 or 35. During the first trimester of pregnancy, increased nuchal translucency in the fetus on ultrasound and decreased levels of pregnancy associated protein- A (PAPP-A) suggest the diagnosis of a chromosomal abnormality. Quad screen results during the second trimester of pregnancy may show increased beta-hCG, increased inhibin A, decreased alfa-fetoprotein (AFP) and decreased estriol.

Natural History, Complications and Prognosis

3% of fetuses with Down’s syndrome diagnosed in utero at 16 weeks’ gestation would be lost spontaneously if termination of pregnancy was not performed. At birth, 50% of newborns with Down’s syndrome have one or more additional serious congenital abnormalities (in addition to intellectual disability). 96% without and 80% with heart defects survive the first year. At age 21 mean IQ is 42 (range 8–67) and mental age is 5 years (range 1–8 years). 11% develop Alzheimer’s disease by age 50 and 77% by age 70 (mean age of onset age 56). Common complication that may arise in patients suffering from Down syndrome include, congenital heart defects (ASD, VSD, PDA), hearing loss, diabetes, celiac disease, cataracts, endocarditis, atlantoaxial subluxation, hypo and hyperthyroidism, duodenal atresia, Hirschprung disease. Life expectancy is 50–55 years.

Diagnosis

History and Symptoms

Down syndrome is a congenital disorder. The symptoms of Down syndrome appear vary from person to person and range between mild to severe. The children with Down syndrome generally have a recognized appearance. The head is usually smaller than normal and abnormally shaped. For example, the head may be round with a flat area on the back. The inner corner of the eyes is usually round rather pointed. Children may also have delayed mental and social development.

Physical Examination

On physical examination, patients suffering from Down syndrome may exhibit dysmorphic facial features (flat face, epicanthal folds, hypotonia, enlarged protruded tongue), abnormal ophthalmologic examination including, Brushfield spots, cataracts, strabismus, amblyopia, impaired learning and decreased intelligence quotient. Cardiovascular examination may reveal heart murmurs (VSD, PDA) or fixed splitting of S2 (due to ASD). Examination of the extremities may reveal increased gap between the first and second fingers (sandal gap) and single palmar crease (simean crease).

Laboratory findings

Down syndrome is confirmed through cytogenetic studies which confirm trisomy 21. In addition complete blood count with differentials is performed to rule out leukemia, TSH and T4 are performed at birth, 6 months, 1 year and then annually to rule out hypothyroidism. Low level of IgG subclass 4 are correlated with bacterial infections. The mosaic trisomy 21 includes lymphocyte preparations, FISH, buccal mucosa cellular preparations and scoring frequency of trisomic cells.

Electrocardiogram

There are no ECG findings associated with Down syndrome however 40-60 percent of patients with Down syndrome suffer from congenital heart defects the most common being atrial septal defect, atrioventricular septal defect, ventricular septal defect, and patent ductus arteriosus. The ECG findings in Down syndrome are of the aforementioned underlying congenital heart defects. 

X-Ray

There are no x-ray findings associated with Down syndrome. However, an x-ray may be helpful in the diagnosis of complications of Down syndrome which include atrial septal defect, ventricular septal defect,atrioventricular septal defect, patent ductus arteriosus, 11 ribs, omphalocoele, mickey mouse pelvis, flaring of iliac wings, hyper-segmented sternum, joint laxity or dislocations, Developmental dysplasia of the hip, atlanto-axial subluxation, atlanto-occipital instability and hypoplastic posterior arch of C1. On X-ray of hands short hands with shortened phalanges and clinodactyly because of hypoplastic middle phalanx of the fifth finger can also be present.

CT scan

There are no CT scan findings associated with Down syndrome. However, a Multidetector-row CT (MDCT) scan may be helpful in the diagnosis of complications of Down syndrome, which include congenital heart diseases such as atrial septal defect, atrioventricular septal defect, ventricular septal defect, and patent ductus arteriosus.

MRI

There are no MRI scan findings associated with Down syndrome. However, a MRI scan may be helpful in the diagnosis of complications of Down syndrome, which include congenital heart diseases such as atrial septal defect, atrioventricular septal defect, ventricular septal defect, and patent ductus arteriosus. MRI is an expensive diagnostic method and is an expensive method of diagnostic study and the presence of ferromagnetic foreign bodies and some cardiac pacemakers are not compatible with MRI.

Echocardiogram/Ultrasound

The abnormalities that may be associated with Down syndrome on ultrasound include intrauterine growth restriction, mild cerebral ventriculomegaly, choroid plexus cysts, increased nuchal fold thickness,cystic hygromas, echogenic intracardiac foci, congenital heart defects, duodenal atresia (“double-bubble sign”) increased intestinal echogenicity, renal pelvis dilation, shortened humerus and femur, increased iliac wing angle, incurving (clinodactyly) and hypoplasia of the fifth finger, increased space between first and second toes and the two-vessel umbilical cord. There are no echocardiographic findings associated with Down syndrome however 40-60 percent of patients with Down syndrome suffer from congenital heart defects the most common being atrial septal defect, atrioventricular septal defect, ventricular septal defect, and patent ductus arteriosus. The echocardiographic findings in Down syndrome are of the aforementioned underlying congenital heart defects. 

Other Imaging Findings

Theradionuclide studies, which are used to measure ejection fractions and to investigate cardiac shunts and angiography for the assesment of blood flow, pressure, the hemodynamics of any defects and the anatomy of the pulmonary artery are performed.

Other Diagnostic Studies

There are no other diagnostic studies associated with Down syndrome.

Treatment

Medical Therapy

Treatment of individuals with Down Syndrome depends on the particular manifestations of the disease. For instance, individuals with congenital heart disease may need to undergo major corrective surgery soon after birth. Other individuals may have relatively minor health problems requiring no therapy. Patients suffering from Down syndrome require rigorous follow-up in order to prevent the complications associated with the syndrome. Close monitoring of growth, hearing evaluation, ophthalmologic evaluation, thyroid profile, cardiac evaluation, dental care and close monitoring of complete blood counts in order to identify hematological maliganancies should be a part of care for a Down syndrome patient.

Surgery

Treatment of individuals with Down Syndrome depends on the particular manifestations of the disease. For instance, individuals with congenital heart disease may need to undergo major corrective surgery soon after birth. Other individuals may have relatively minor health problems requiring no therapy.

Prevention

Primary Prevention

Experts recommend genetic counseling for persons with a family history of Down syndrome who wish to have a baby. A woman’s risk of having a child with Down syndrome increases as she gets older. The risk is significantly higher among women age 35 and older. Couples who already have a baby with Down syndrome have an increased risk of having another baby with the condition. Tests such as nuchal translucency ultrasound, amniocentesis, or chorionic villus sampling can be done on a fetus during the first few months of pregnancy to check for Down syndrome. The American College of Obstetricians and Gynecologists recommends offering Down syndrome screening tests to all pregnant women, regardless of age.

Secondary Prevention

The American Academy of Pediatrics, among other health organizations, has issued a series of recommendations for screening individuals with Down Syndrome for particular diseases.These guidelines enable health care providers to identify and prevent important aspects of DS. All other typical newborn, childhood, and adult screening and vaccination programs should also be performed.

References

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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Down syndrome (Trisomey 21 or Dow’s syndrome) is a genetic disorder is characterized by the presence of all or part of an extra 21st chromosome.[1] John Langdon Down, a British doctor described it first in 1866. JĂ©rĂŽme Lejeune in 1959 ascribed the features associated with Down’s syndrome to the presence of an extra 21st chromosome (trisomy 21). Based on anthropometric measurements and photographic appearance, John Landdon Down delineated a well-defined group of mentally disabled individuals, whose members all resembled the little girl very well. He called them, in concordance with the ethnical insights of the then famous dr. Blumenbach, mongoloid “idiots”. Today they are known by his own, more ethically correct name: Down’s syndrome. Until the middle of the 20th century, the cause of Down syndrome was largely. However, was known that it affected humans of all races, was associated with older maternal age and was rare. Standard medical texts assumed it was caused by a combination of inheritable factors which had not been identified. Other theories focused on injuries sustained during birth. In 1886 Shuttleworth referred to Langdon Down’s ethnic classification and he included the “Mongol type” in his publication. Beginning in 1888, John Langdon Down’s work became widely accepted and was consistently being referred to by scientists and physicians, beginning with Goodheart in 1888. By the 20th century, Mongolism had become a widely used descriptive term. This was the title used by Bertram Hill in 1908 and by Penrose as late as 1961. With the discovery of karyotype techniques in the 1950s, it became possible to identify abnormalities of chromosomal number or shape. In 1959, Professor JĂ©rĂŽme Lejeune discovered that Down syndrome resulted from an extra chromosome. The extra chromosome was subsequently labeled as the 21st, and the condition as trisomy 21.

Historical Perspective

  • An English physician John Langdon Down first characterized Down syndrome as a distinct form of mental disability in 1862, and in a more widely published report in 1866 entitled “Observations on an ethnic classification of idiots”.[2][3]
  • When John Down was 18 years old, he met a girl that appeared so odd and peculiar, that he felt sorry for her and, consciously or unconsciously, would spend the rest of his life deciphering and studying about what led to such a behavior and appearance in human beings. He decided to study Medicine, became the director of the largest “Asylum for Idiots” in England and became the pioneer of medical literature about the phenomena that he found so intriguing.[4]
  • Based on anthropometric measurements and photographic appearance, he delineated a well-defined group of mentally disabled individuals, whose members all resembled the little girl very well. He called them, in concordance with the ethnical insights of the then famous dr. Blumenbach, mongoloid “idiots”. Today they are known by his own, more ethically correct name: Down’s syndrome.
  • John Langdon Down was a pioneer of the use of photography in hospitals. Mongolian idiocy became a widely used term but in 1961 a group of genetic experts wrote to the Lancet suggesting four alternative names. Down syndrome was selected and was later adopted by the World Health Organization (WHO) in 1965.[5]
  • The majority of the physicians of his era thought the inhabitants of a lunatic asylum were incapable of learning and acquiring skills ascribed to normal human beings. John wanted to disprove this notion. He had noticed that his mongols were certainly able to be raised properly. He discovered that his patients were able to imitate normal human behavior. John and his wife Mary, who worked alongside him on the patients taught them how to ride a horse, clean the stables, grow vegetables and fruit, collect eggs and milk the cows. In the workshops, various skills were taught. Weaving and making puppets for the puppet play were the most popular activities. Here Down learned that if he divided patients with similar talents into groups, their ability to learn increased. Down also found that shopping is very useful in social training programs
  • Until the middle of the 20th century, the cause of Down syndrome was largely. However, was known that it affected humans of all races, was associated with older maternal age and was rare. Standard medical texts assumed it was caused by a combination of inheritable factors which had not been identified. Other theories focused on injuries sustained during birth.[6]
  • John Langdon Down’s son, Reginald Down was further able to carry his father’s work and made a further important observation in 1909 and contributed to discussion of a paper by Shuttleworth. He passed around hand prints of a number of patients with Down syndrome showing that “the bones of the palm differed from the normal in their extreme irregularity, and the tendency of the principal fold-lines to be two in number only, instead of three as was most commonly the case.” Reginald may have identified this peculiarity himself or his father may have shown it to him. A sketch of the palmar crease pattern dated 1908 was found in the historical literature and family archives.
  • In 1876, Mitchell and Fraser published an account of what they described as Kalmuc idiocy, claiming at the time that such a condition had never been reported in history. What they described was indeed Down’s syndrome and they had failed to note his earlier publication in the same journal in which their paper later appeared. The first reference to Langdon Down’s ethnic classification was probably in 1877 (Ireland). In 1879, Tanner and Meadows also acknowledged Down’s observations.
  • In 1886 Shuttleworth referred to Langdon Down’s ethnic classification and he included the “Mongol type” in his publication.
  • Beginning in 1888, John Langdon Down’s work became widely accepted and was consistently being referred to by scientists and physicians, beginning with Goodheart in 1888.
  • In 1891, Brush discussed John Down’s work at length in the ‘Cyclopedia of diseases of children’.[7]
  • By the 20th century, Mongolism had become a widely used descriptive term. This was the title used by Bertram Hill in 1908 and by Penrose as late as 1961.
  • With the discovery of karyotype techniques in the 1950s, it became possible to identify abnormalities of chromosomal number or shape. In 1959, Professor JĂ©rĂŽme Lejeune discovered that Down syndrome resulted from an extra chromosome. The extra chromosome was subsequently labeled as the 21st, and the condition as trisomy 21.
  • In his last years, Professor Lejeune did research into the question of metabolic abnormalities in persons with Down Syndrome. After his death in 1994, his research has been continued by Dr. Paddy Jim Baggot. Some success at identifying abnormalities and finding treatments has been experienced. In later research, it has been shown that measures to treat biochemical deficiencies should begin at about the 22nd week of pregnancy. Some parents are currently giving supplements to their children with Down Syndrome, which has resulted in some improvement of their capabilities.[8]

References

  1. ↑ “Trisomy 21: The Story of Down Syndrome paper”.
  2. ↑ Down, J.L.H. (1866). “Observations on an ethnic classification of idiots”. Clinical Lecture Reports, London Hospital. 3: 259–262. Retrieved 2006-07-14. For a history of the disorder, see OC Ward (1998). John Langdon Down, 1828–1896. Royal Society of Medicine Press. ISBN 1-85315-374-5. or Conor, Ward. “John Langdon Down and Down’s syndrome (1828–1896)”. Retrieved 2006-06-02.
  3. ↑ “John Langdon Down: The Man and the Message | Down Syndrome Education Online”.
  4. ↑ Dunn PM (July 1991). “Dr Langdon Down (1828-1896) and ‘mongolism‘“. Arch. Dis. Child. 66 (7 Spec No): 827–8. PMC 1590233. PMID 1830736.
  5. ↑ Ward OC (August 1999). “John Langdon Down: the man and the message”. Downs Syndr Res Pract. 6 (1): 19–24. PMID 10890244.
  6. ↑ Warkany, J. (1971). Congenital Malformations. Chicago: Year Book Medical Publishers, Inc. pp. 313–314. ISBN 0-8151-9098-0.
  7. ↑ Young, A. E. (1987). “The man behind the syndrome. P. Beighton and G. Beighton. 275 × 195 mm. Pp. 240. Illustrated. 1986. London: Springer Verlag. ÂŁ19.90”. British Journal of Surgery. 74 (1): 77–77. doi:10.1002/bjs.1800740143. ISSN 0007-1323.
  8. ↑ “The Anthropological Treatises of Johann Friedrich Blumenbach: With Memoirs … – Johann Friedrich Blumenbach, Karl Friedrich Heinrich Marx, Pierre Flourens, John Hunter, Rudolph Wagner – Google Books”.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome. Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle. Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.Immaturity of the feto–placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Down’s syndrome pregnancies. Reduced synthesis of AFP by the fetal liver is also thought to contribute to low AFP in Down’s syndrome pregnancies. Robertsonian translocation occurrs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromeres and the 2 short arms are lost. Mosaicism does not have any maternal association and it is a post-fertilization mitotic error. Disbilities found in Down syndrome patients are thought to arise secondary to varied genetic expression associated with the presence an extra 21st chromosome.

Pathophysiology

Mechanisms of trisomy 21

Meiotic non-disjunction

Robertsonian translocation

Mosaicism

Effects on increased gene dosage

Learning and memory

Neurodevelopment

  • DS patients have increased rates of neuronal apoptosis related to oxidative stress.[30]
  • Brain size of fetuses carrying trisomy 21 is smaller than euploid fetuses.
  • Murine models have suggested that disruption in expression of the following genes may play key roles in affecting neurodevelopment in DS patients:

Alzheimer’s disease

Cancer and leukemias

Genetics

Expression of the following genes may be disturbed in trisomy 21:

Table 1: Some genes located on the long arm of chromosome 21[50]
Gene OMIM Reference Location Purported Function
APP 104760 21q21 Amyloid beta A4 precursor protein. Suspected to have a major role in cognitive difficulties. One of the first genes studied with transgenic mice with Down syndrome.[51]
SOD1 147450 21q22.1 Superoxide dismutase. Possible role in Alzheimer’s disease. Anti-oxidant as well as possible affects on the immuno-system.
DYRK 600855 21q22.1 Dual-specificity Tyrosine Phosphorylation-Regulated Kinase 1A. May have an effect on mental development through abnormal neurogenesis. [52]
IFNAR 107450 21q22.1 Interferon, Alpha, Beta, and Omega, Receptor. Responsible for the expression of interferon, which affects the immuno-system.
DSCR1 602917 21q22.1–21q22.2 Down Syndrome Critical Region Gene 1. Possibly part of a signal transduction pathway involving both heart and brain.[53]
COL6A1 120220 21q22.3 Collagen, type I, alpha 1 gene. May have an effect on heart disease.
ETS2 164740 21q22.3 Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have “demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome.”[54]
CRYA1 123580 21q22.3 Crystallin, Alpha-A. Involved in the synthesis of Crystallin, a major component of the lens in eyes. May be cause of cataracts.

Associated Conditions

The following conditions may be associated with Down’s syndrome:

Gross Pathology

There are no gross pathological findings associated with Down syndrome.

Microscopic Pathology

There are no microscopic findings associated with Down syndrome.

References

  1. ↑ Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, Delorenzi M, Gehrig C, Descombes P, Sherman S, Dagna Bricarelli F, Baldo C, Novelli A, Dallapiccola B, Antonarakis SE (August 2007). “Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance”. Am. J. Hum. Genet. 81 (2): 252–63. doi:10.1086/519248. PMC 1950802. PMID 17668376.
  2. ↑ Sultan M, Piccini I, Balzereit D, Herwig R, Saran NG, Lehrach H, Reeves RH, Yaspo ML (2007). “Gene expression variation in Down’s syndrome mice allows prioritization of candidate genes”. Genome Biol. 8 (5): R91. doi:10.1186/gb-2007-8-5-r91. PMC 1929163. PMID 17531092.
  3. ↑ AĂŻt Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, BlĂ©haut H, Robin S, Delabar JM, Potier MC (September 2007). “Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes”. Am. J. Hum. Genet. 81 (3): 475–91. doi:10.1086/520000. PMC 1950826. PMID 17701894.
  4. ↑ Korbel JO, Tirosh-Wagner T, Urban AE, Chen XN, Kasowski M, Dai L, Grubert F, Erdman C, Gao MC, Lange K, Sobel EM, Barlow GM, Aylsworth AS, Carpenter NJ, Clark RD, Cohen MY, Doran E, Falik-Zaccai T, Lewin SO, Lott IT, McGillivray BC, Moeschler JB, Pettenati MJ, Pueschel SM, Rao KW, Shaffer LG, Shohat M, Van Riper AJ, Warburton D, Weissman S, Gerstein MB, Snyder M, Korenberg JR (July 2009). “The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies”. Proc. Natl. Acad. Sci. U.S.A. 106 (29): 12031–6. doi:10.1073/pnas.0813248106. PMC 2709665. PMID 19597142.
  5. ↑ Lyle R, BĂ©na F, Gagos S, Gehrig C, Lopez G, Schinzel A, Lespinasse J, Bottani A, Dahoun S, Taine L, Doco-Fenzy M, Cornillet-LefĂšbvre P, Pelet A, Lyonnet S, Toutain A, Colleaux L, Horst J, Kennerknecht I, Wakamatsu N, Descartes M, Franklin JC, Florentin-Arar L, Kitsiou S, AĂŻt Yahya-Graison E, Costantine M, Sinet PM, Delabar JM, Antonarakis SE (April 2009). “Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21”. Eur. J. Hum. Genet. 17 (4): 454–66. doi:10.1038/ejhg.2008.214. PMC 2986205. PMID 19002211.
  6. ↑ Antonarakis SE (March 1991). “Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group”. N. Engl. J. Med. 324 (13): 872–6. doi:10.1056/NEJM199103283241302. PMID 1825697.
  7. ↑ Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, Pangalos C, Raoul O, Slaugenhaupt SA, Hafez M (March 1992). “The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms”. Am. J. Hum. Genet. 50 (3): 544–50. PMC 1684265. PMID 1347192.
  8. ↑ Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, Masse N, Sherman SL (March 2008). “New insights into human nondisjunction of chromosome 21 in oocytes”. PLoS Genet. 4 (3): e1000033. doi:10.1371/journal.pgen.1000033. PMC 2265487. PMID 18369452.
  9. ↑ Hawley RS, Frazier JA, Rasooly R (September 1994). “Separation anxiety: the etiology of nondisjunction in flies and people”. Hum. Mol. Genet. 3 (9): 1521–8. PMID 7833906.
  10. ↑ Wolstenholme J, Angell RR (November 2000). “Maternal age and trisomy–a unifying mechanism of formation”. Chromosoma. 109 (7): 435–8. PMID 11151672.
  11. ↑ Yoon PW, Freeman SB, Sherman SL, Taft LF, Gu Y, Pettay D, Flanders WD, Khoury MJ, Hassold TJ (March 1996). “Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study”. Am. J. Hum. Genet. 58 (3): 628–33. PMC 1914585. PMID 8644722.
  12. ↑ Sherman SL, Allen EG, Bean LH, Freeman SB (2007). “Epidemiology of Down syndrome”. Ment Retard Dev Disabil Res Rev. 13 (3): 221–7. doi:10.1002/mrdd.20157. PMID 17910090.
  13. ↑ Koehler KE, Hawley RS, Sherman S, Hassold T (1996). “Recombination and nondisjunction in humans and flies”. Hum. Mol. Genet. 5 Spec No: 1495–504. PMID 8875256.
  14. ↑ Lamb NE, Freeman SB, Savage-Austin A, Pettay D, Taft L, Hersey J, Gu Y, Shen J, Saker D, May KM, Avramopoulos D, Petersen MB, Hallberg A, Mikkelsen M, Hassold TJ, Sherman SL (December 1996). “Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II”. Nat. Genet. 14 (4): 400–5. doi:10.1038/ng1296-400. PMID 8944019.
  15. ↑ Hawley RS, Frazier JA, Rasooly R (September 1994). “Separation anxiety: the etiology of nondisjunction in flies and people”. Hum. Mol. Genet. 3 (9): 1521–8. PMID 7833906.
  16. ↑ Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL (January 2005). “Association between maternal age and meiotic recombination for trisomy 21”. Am. J. Hum. Genet. 76 (1): 91–9. doi:10.1086/427266. PMC 1196437. PMID 15551222.
  17. ↑ Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL (January 2005). “Association between maternal age and meiotic recombination for trisomy 21”. Am. J. Hum. Genet. 76 (1): 91–9. doi:10.1086/427266. PMC 1196437. PMID 15551222.
  18. ↑ Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, Masse N, Sherman SL (March 2008). “New insights into human nondisjunction of chromosome 21 in oocytes”. PLoS Genet. 4 (3): e1000033. doi:10.1371/journal.pgen.1000033. PMC 2265487. PMID 18369452.
  19. ↑ Vicari S, Carlesimo GA (June 2006). “Short-term memory deficits are not uniform in Down and Williams syndromes”. Neuropsychol Rev. 16 (2): 87–94. doi:10.1007/s11065-006-9008-4. PMID 16967345.
  20. ↑ Carlesimo GA, Marotta L, Vicari S (January 1997). “Long-term memory in mental retardation: evidence for a specific impairment in subjects with Down’s syndrome”. Neuropsychologia. 35 (1): 71–9. PMID 8981379.
  21. ↑ Aylward EH, Li Q, Honeycutt NA, Warren AC, Pulsifer MB, Barta PE, Chan MD, Smith PD, Jerram M, Pearlson GD (April 1999). “MRI volumes of the hippocampus and amygdala in adults with Down’s syndrome with and without dementia”. Am J Psychiatry. 156 (4): 564–8. doi:10.1176/ajp.156.4.564. PMID 10200735.
  22. ↑ Di Filippo M, Tozzi A, Ghiglieri V, Picconi B, Costa C, Cipriani S, Tantucci M, Belcastro V, Calabresi P (April 2010). “Impaired plasticity at specific subset of striatal synapses in the Ts65Dn mouse model of Down syndrome”. Biol. Psychiatry. 67 (7): 666–71. doi:10.1016/j.biopsych.2009.08.018. PMID 19818432.
  23. ↑ Ahn KJ, Jeong HK, Choi HS, Ryoo SR, Kim YJ, Goo JS, Choi SY, Han JS, Ha I, Song WJ (June 2006). “DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects”. Neurobiol. Dis. 22 (3): 463–72. doi:10.1016/j.nbd.2005.12.006. PMID 16455265.
  24. ↑ Yu HH, Yang JS, Wang J, Huang Y, Lee T (February 2009). “Endodomain diversity in the Drosophila Dscam and its roles in neuronal morphogenesis”. J. Neurosci. 29 (6): 1904–14. doi:10.1523/JNEUROSCI.5743-08.2009. PMC 2671081. PMID 19211897.
  25. ↑ Best TK, Siarey RJ, Galdzicki Z (January 2007). “Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current”. J. Neurophysiol. 97 (1): 892–900. doi:10.1152/jn.00626.2006. PMID 17093127.
  26. ↑ Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K, Inokuchi K, Katsuki M, Fujii-Kuriyama Y (August 1999). “Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down’s syndrome”. Hum. Mol. Genet. 8 (8): 1409–15. PMID 10400987.
  27. ↑ Best TK, Cho-Clark M, Siarey RJ, Galdzicki Z (June 2008). “Speeding of miniature excitatory post-synaptic currents in Ts65Dn cultured hippocampal neurons”. Neurosci. Lett. 438 (3): 356–61. doi:10.1016/j.neulet.2008.04.039. PMID 18490108.
  28. ↑ Meng X, Shi J, Peng B, Zou X, Zhang C (April 2006). “Effect of mouse Sim2 gene on the cell cycle of PC12 cells”. Cell Biol. Int. 30 (4): 349–53. doi:10.1016/j.cellbi.2005.11.012. PMID 16530433.
  29. ↑ Rachidi M, Delezoide AL, Delabar JM, Lopes C (June 2009). “A quantitative assessment of gene expression (QAGE) reveals differential overexpression of DOPEY2, a candidate gene for mental retardation, in Down syndrome brain regions”. Int. J. Dev. Neurosci. 27 (4): 393–8. doi:10.1016/j.ijdevneu.2009.02.001. PMID 19460634.
  30. ↑ Busciglio J, Yankner BA (1995). “Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro”. Nature. 378 (6559): 776–9. doi:10.1038/378776a0. PMID 8524410.
  31. ↑ Micali N, Longobardi E, Iotti G, Ferrai C, Castagnaro L, Ricciardi M, Blasi F, Crippa MP (June 2010). “Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress”. Nucleic Acids Res. 38 (11): 3595–604. doi:10.1093/nar/gkq019. PMC 2887940. PMID 20110257.
  32. ↑ Suizu F, Hiramuki Y, Okumura F, Matsuda M, Okumura AJ, Hirata N, Narita M, Kohno T, Yokota J, Bohgaki M, Obuse C, Hatakeyama S, Obata T, Noguchi M (December 2009). “The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt”. Dev. Cell. 17 (6): 800–10. doi:10.1016/j.devcel.2009.09.007. PMID 20059950.
  33. ↑ Lepagnol-Bestel AM, Zvara A, Maussion G, Quignon F, Ngimbous B, Ramoz N, Imbeaud S, Loe-Mie Y, Benihoud K, Agier N, Salin PA, Cardona A, Khung-Savatovsky S, Kallunki P, Delabar JM, Puskas LG, Delacroix H, Aggerbeck L, Delezoide AL, Delattre O, Gorwood P, Moalic JM, Simonneau M (April 2009). “DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome”. Hum. Mol. Genet. 18 (8): 1405–14. doi:10.1093/hmg/ddp047. PMID 19218269.
  34. ↑ Canzonetta C, Mulligan C, Deutsch S, Ruf S, O’Doherty A, Lyle R, Borel C, Lin-Marq N, Delom F, Groet J, Schnappauf F, De Vita S, Averill S, Priestley JV, Martin JE, Shipley J, Denyer G, Epstein CJ, Fillat C, Estivill X, Tybulewicz VL, Fisher EM, Antonarakis SE, Nizetic D (September 2008). “DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome”. Am. J. Hum. Genet. 83 (3): 388–400. doi:10.1016/j.ajhg.2008.08.012. PMC 2556438. PMID 18771760.
  35. ↑ Kuhn DE, Nuovo GJ, Terry AV, Martin MM, Malana GE, Sansom SE, Pleister AP, Beck WD, Head E, Feldman DS, Elton TS (January 2010). “Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains”. J. Biol. Chem. 285 (2): 1529–43. doi:10.1074/jbc.M109.033407. PMC 2801278. PMID 19897480.
  36. ↑ Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, LaquerriĂšre A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D (January 2006). “APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy”. Nat. Genet. 38 (1): 24–6. doi:10.1038/ng1718. PMID 16369530.
  37. ↑ Cabrejo L, Guyant-MarĂ©chal L, LaquerriĂšre A, Vercelletto M, De la FourniĂšre F, Thomas-AntĂ©rion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D (November 2006). “Phenotype associated with APP duplication in five families”. Brain. 129 (Pt 11): 2966–76. doi:10.1093/brain/awl237. PMID 16959815.
  38. ↑ Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC (July 2006). “Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration”. Neuron. 51 (1): 29–42. doi:10.1016/j.neuron.2006.05.022. PMID 16815330.
  39. ↑ Seo H, Isacson O (June 2005). “Abnormal APP, cholinergic and cognitive function in Ts65Dn Down’s model mice”. Exp. Neurol. 193 (2): 469–80. doi:10.1016/j.expneurol.2004.11.017. PMID 15869949.
  40. ↑ Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, Lee HW, Kim IS, Cheon YH, Ahn YS, Chung SH, Song WJ (November 2007). “DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease”. J. Biol. Chem. 282 (48): 34850–7. doi:10.1074/jbc.M707358200. PMID 17906291.
  41. ↑ 41.0 41.1 Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD (September 2002). “Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome”. Nat. Genet. 32 (1): 148–52. doi:10.1038/ng955. PMID 12172547.
  42. ↑ Izraeli S, Rainis L, Hertzberg L, Smooha G, Birger Y (2007). “Trisomy of chromosome 21 in leukemogenesis”. Blood Cells Mol. Dis. 39 (2): 156–9. doi:10.1016/j.bcmd.2007.04.004. PMID 17532652.
  43. ↑ 43.0 43.1 Malinge S, Ben-Abdelali R, Settegrana C, Radford-Weiss I, Debre M, Beldjord K, Macintyre EA, Villeval JL, Vainchenker W, Berger R, Bernard OA, Delabesse E, Penard-Lacronique V (March 2007). “Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia”. Blood. 109 (5): 2202–4. doi:10.1182/blood-2006-09-045963. PMID 17068151.
  44. ↑ Groet J, McElwaine S, Spinelli M, Rinaldi A, Burtscher I, Mulligan C, Mensah A, Cavani S, Dagna-Bricarelli F, Basso G, Cotter FE, Nizetic D (May 2003). “Acquired mutations in GATA1 in neonates with Down’s syndrome with transient myeloid disorder”. Lancet. 361 (9369): 1617–20. doi:10.1016/S0140-6736(03)13266-7. PMID 12747884.
  45. ↑ Stepensky P, Brooks R, Waldman E, Revel-Vilk S, Izraeli S, Resnick I, Weintraub M (July 2010). “A rare case of GATA1 negative chemoresistant acute megakaryocytic leukemia in an 8-month-old infant with trisomy 21”. Pediatr Blood Cancer. 54 (7): 1048–9. doi:10.1002/pbc.22331. PMID 20108342.
  46. ↑ Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H, Miura M, Adachi S, Migita M, Morinaga S, Nakano T, Endo M, Kojima S, Kiyoi H, Mano H, Ito E (May 2008). “Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome”. Br. J. Haematol. 141 (5): 681–8. doi:10.1111/j.1365-2141.2008.07081.x. PMID 18397343.
  47. ↑ De Vita S, Mulligan C, McElwaine S, Dagna-Bricarelli F, Spinelli M, Basso G, Nizetic D, Groet J (May 2007). “Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome”. Br. J. Haematol. 137 (4): 337–41. doi:10.1111/j.1365-2141.2007.06574.x. PMID 17456055.
  48. ↑ Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, Plon SE, Basso G, Pession A, Rabin KR (March 2009). “Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia”. Br. J. Haematol. 144 (6): 930–2. doi:10.1111/j.1365-2141.2008.07552.x. PMC 2724897. PMID 19120350.
  49. ↑ Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, Shiloh R, Iacobucci I, Shochat C, Zeligson S, Cario G, Stanulla M, Strehl S, Russell LJ, Harrison CJ, Bornhauser B, Yoda A, Rechavi G, Bercovich D, Borkhardt A, Kempski H, te Kronnie G, Bourquin JP, Domany E, Izraeli S (February 2010). “Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group”. Blood. 115 (5): 1006–17. doi:10.1182/blood-2009-08-235408. PMID 19965641.
  50. ↑ See Leshin, L. (2003). “Trisomy 21: The Story of Down Syndrome”. Retrieved 2006-05-21.
  51. ↑ Chandra Shekhar (6 July 2006). “Down syndrome traced to one gene”. The Scientist. Retrieved 2006-07-11. Check date values in: |date= (help)
  52. ↑ Song, W.-J., Sternberg, L. R., Kasten-Sportes, C., Van Keuren, M. L., Chung, S.-H., Slack, A. C., Miller, D. E., Glover, T. W., Chiang, P.-W., Lou, L.; Kurnit, D. M. (1996). “Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome ‘critical region”. Genomics. 38: 331–339.
  53. ↑ Fuentes JJ, Pritchard MA, Planas AM, Bosch A, Ferrer I, Estivill X (1995). “A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart”. Hum Mol Genet. 4 (10): 1935–1944.
  54. ↑ OMIM, NIH. “V-ETS Avian Erythroblastosis virus E26 Oncogene Homolog 2”. Retrieved 2006-06-29.

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Causes

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Down’s syndrome (DS) is caused due to the presence of an extra 21st chromosome (triplication of chromosome 21). 95 percent of DS cases are due to meiotic non-disjunction during meiosis I. 4 percent of DS cases arise due to Robertsonian translocation and very rarely DS may be caused a post-fertilization mitotic error (mosaicism).

Causes

Down’s syndrome is caused by triplication of chromosome 21 (trisomy 21). The aneuploidy may occur in three possible ways:

For a detailed description on the mechanisms leading to Down’s syndrome, click here

References

  1. ↑ Antonarakis SE (March 1991). “Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group”. N. Engl. J. Med. 324 (13): 872–6. doi:10.1056/NEJM199103283241302. PMID 1825697.
  2. ↑ Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, Pangalos C, Raoul O, Slaugenhaupt SA, Hafez M (March 1992). “The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms”. Am. J. Hum. Genet. 50 (3): 544–50. PMC 1684265. PMID 1347192.
  3. ↑ Hook EB (October 1984). “Parental age and unbalanced Robertsonian translocations associated with Down syndrome and Patau syndrome: comparison with maternal and paternal age effects for 47, +21 and 47, +13”. Ann. Hum. Genet. 48 (Pt 4): 313–25. PMID 6238567.
  4. ↑ Zhao WW, Wu M, Chen F, Jiang S, Su H, Liang J, Deng C, Hu C, Yu S (2015). “Robertsonian translocations: an overview of 872 Robertsonian translocations identified in a diagnostic laboratory in China”. PLoS ONE. 10 (5): e0122647. doi:10.1371/journal.pone.0122647. PMC 4416705. PMID 25932913.
  5. ↑ Petersen MB, Adelsberger PA, Schinzel AA, Binkert F, Hinkel GK, Antonarakis SE (September 1991). “Down syndrome due to de novo Robertsonian translocation t(14q;21q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal”. Am. J. Hum. Genet. 49 (3): 529–36. PMC 1683126. PMID 1831959.
  6. ↑ Hsu LY, Gertner M, Leiter E, Hirschhorn K (November 1971). “Paternal trisomy 21 mosaicism and Down’s syndrome”. Am. J. Hum. Genet. 23 (6): 592–601. PMC 1706744. PMID 4257130.
  7. ↑ Modi D, Berde P, Bhartiya D (June 2003). “Down syndrome: a study of chromosomal mosaicism”. Reprod. Biomed. Online. 6 (4): 499–503. PMID 12831601.

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Differentiating Down syndrome from other Diseases

Differentiating Down syndrome from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination. Second quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. Pre-natal differentials of low AFP include Down syndrome, Edwards syndrome and Patau syndrome. In the newborn, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include isolated hypotonia, congenital hypothyroidism and Zellweger syndrome.

Differential Diagnosis

Pre-natal differentials

The diagnosis of Down syndrome should be suspected in pre-natal assessment of fetuses on ultrasound examination during first trimester of pregnancy. Second trimester quad screen showing decreased alfa-fetoprotein (AFP) should raise the suspicion of fetal chromosomal abnormlaity. The following are the differential diagnosis of decreased AFP levels during a first trimester quad screen:[1][2][3][4][5][6][7]

Fetal chromosomal abnormality Quad screen results Pregnancy associated protein-A (PAPP-A)
Alfa-fetoprotein (AFP) Beta human chorionic gonadotrpin (B-hCG) Estriol Inhibin A
Down syndrome (trisomy 21) ↓ ↑ ↓ ↑ ↓
Edwards syndrome (trisomy 18) ↓ ↓ ↓ ↓ or normal ↓
Patau syndrome (trisomy 13) ↓ ↓ ↓ ↓ ↓

Differentials in newborns and children

In the newborns and children, Down syndrome should be differentiated from other congenital conditions presenting with hypotonia, poor feeding, poor growth and dysmorphic facial features. The differentials include the following:[8][9][10][11][12][12][13][14]

Congenital condition Physical examination Karyotype examination Echocardiography
Hypotonia Poor feeding Poor growth Dysmorphic features (simian crease) Single palmar crease Epicanthal folds Flat occiput and face Seizures Dry skin Ophtalmologic examination Abundant neck skin Gap between first and second fingers (sandal gap) Protruding tongue Downward turned mouth Almond eyes Round face
Down syndrome + + + + + + + + – + Increased + + + +
  • Meiotic error:
    • 47,XX, +21 or 47, XY, +21 (meiotic I error leads to heterodisomy whereas meiotic II error leads to isodisomy)
  • Robertsonian translocation:
    • 46, XX, -14, +t(14q;21q) etc.
Congenital hypothroidism + + + + – – – + + – Increased + – – –
  • 46, XX or 46, XY
Zellwegger syndrome + + + + + + + + – – – – – – –
  • 46, XX or 46, XY
 –
Isolated hypotonia + – – – – – – – – – – – – – – –
  • 46, XX or 46, XY
 –

Down syndrome must be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, POEMS syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.[15][16][17][18][19]

Disease Addison’s disease Type 1 diabetes mellitus Hypothyroidism Other disorders present
APS type 1 + Less common Less common Hypoparathyroidism
Candidiasis
Hypogonadism
APS type 2 + + + Hypogonadism
Malabsorption
APS type 3 – + + Malabsorption
Thymoma + – + Myasthenia gravis
Cushing syndrome
Chromosomal abnormalities
(Turner syndrome,
Down’s syndrome) 		– + + Cardiac dysfunction
Kearns–Sayre syndrome – + – Myopathy
Hypoparathyroidism
Hypogonadism
Wolfram syndrome – + – Diabetes insipidus
Optic atrophy
Deafness
POEMS syndrome – + – Polyneuropathy
Hypogonadism
Plasma cell dyscrasias

References

  1. ↑ Benn PA, Ying J, Beazoglou T, Egan JF (January 2001). “Estimates for the sensitivity and false-positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustment for cross-identification and double-positive results”. Prenat. Diagn. 21 (1): 46–51. PMID 11180240.
  2. ↑ Yazdani S, Rouholahnejad R, Asnafi N, Sharbatdaran M, Zakershob M, Bouzari Z (2015). “Correlation of pregnancy outcome with quadruple screening test at second trimester”. Med J Islam Repub Iran. 29: 281. PMC 4764288. PMID 26913244.
  3. ↑ Reynolds T (August 2010). “The triple test as a screening technique for Down syndrome: reliability and relevance”. Int J Womens Health. 2: 83–8. PMC 2971727. PMID 21072301.
  4. ↑ Shaw SW, Lin SY, Lin CH, Su YN, Cheng PJ, Lee CN, Chen CP (March 2010). “Second-trimester maternal serum quadruple test for Down syndrome screening: a Taiwanese population-based study”. Taiwan J Obstet Gynecol. 49 (1): 30–4. doi:10.1016/S1028-4559(10)60005-8. PMID 20466289.
  5. ↑ Cuckle H (May 2014). “Prenatal Screening Using Maternal Markers”. J Clin Med. 3 (2): 504–20. doi:10.3390/jcm3020504. PMC 4449694. PMID 26237388.
  6. ↑ Shiefa S, Amargandhi M, Bhupendra J, Moulali S, Kristine T (January 2013). “First Trimester Maternal Serum Screening Using Biochemical Markers PAPP-A and Free ÎČ-hCG for Down Syndrome, Patau Syndrome and Edward Syndrome”. Indian J Clin Biochem. 28 (1): 3–12. doi:10.1007/s12291-012-0269-9. PMC 3547446. PMID 24381414.
  7. ↑ Park SY, Jang IA, Lee MA, Kim YJ, Chun SH, Park MH (September 2016). “Screening for chromosomal abnormalities using combined test in the first trimester of pregnancy”. Obstet Gynecol Sci. 59 (5): 357–66. doi:10.5468/ogs.2016.59.5.357. PMC 5028642. PMID 27668198.
  8. ↑ Devlin L, Morrison PJ (May 2004). “Accuracy of the clinical diagnosis of Down syndrome”. Ulster Med J. 73 (1): 4–12. PMC 2475449. PMID 15244118.
  9. ↑ Kurtul BE, Ozer PA, Kabatas EU, GĂŒrkan A, Aycan Z (2016). “Ophthalmic Manifestations in Children With Congenital Hypothyroidism”. J Pediatr Ophthalmol Strabismus. 53 (1): 29–34. doi:10.3928/01913913-20160113-06. PMID 26836000.
  10. ↑ Mutton D, Ide RG, Alberman E (October 1998). “Trends in prenatal screening for and diagnosis of Down’s syndrome: England and Wales, 1989-97”. BMJ. 317 (7163): 922–3. PMC 28676. PMID 9756810.
  11. ↑ Ozturk, Banu T; Kerimoglu, Hurkan; Dikbas, Oguz; Pekel, Hamiyet; Gonen, Mustafa S (2009). “Ocular changes in primary hypothyroidism”. BMC Research Notes. 2 (1): 266. doi:10.1186/1756-0500-2-266. ISSN 1756-0500.
  12. ↑ 12.0 12.1 Lee PR, Raymond GV (May 2013). “Child neurology: Zellweger syndrome”. Neurology. 80 (20): e207–10. doi:10.1212/WNL.0b013e3182929f8e. PMC 3908348. PMID 23671347.
  13. ↑ Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT (December 2015). “Zellweger spectrum disorders: clinical overview and management approach”. Orphanet J Rare Dis. 10: 151. doi:10.1186/s13023-015-0368-9. PMC 4666198. PMID 26627182.
  14. ↑ Reddy PA, Rajagopal G, Harinarayan CV, Vanaja V, Rajasekhar D, Suresh V, Sachan A (2010). “High prevalence of associated birth defects in congenital hypothyroidism”. Int J Pediatr Endocrinol. 2010: 940980. doi:10.1155/2010/940980. PMC 2864451. PMID 20454578.
  15. ↑ Sherer Y, Bardayan Y, Shoenfeld Y (1997). “Thymoma, thymic hyperplasia, thymectomy and autoimmune diseases (Review)”. Int. J. Oncol. 10 (5): 939–43. PMID 21533467.
  16. ↑ Nozza, Andrea (2017). “POEMS SYNDROME: AN UPDATE”. Mediterranean Journal of Hematology and Infectious Diseases. 9 (1): e2017051. doi:10.4084/mjhid.2017.051. ISSN 2035-3006.
  17. ↑ Maceluch JA, Niedziela M (2006). “The clinical diagnosis and molecular genetics of kearns-sayre syndrome: a complex mitochondrial encephalomyopathy”. Pediatr Endocrinol Rev. 4 (2): 117–37. PMID 17342029.
  18. ↑ Rigoli L, Di Bella C (2012). “Wolfram syndrome 1 and Wolfram syndrome 2”. Curr. Opin. Pediatr. 24 (4): 512–7. doi:10.1097/MOP.0b013e328354ccdf. PMID 22790102.
  19. ↑ Husebye, Eystein S.; Anderson, Mark S. (2010). “Autoimmune Polyendocrine Syndromes: Clues to Type 1 Diabetes Pathogenesis”. Immunity. 32 (4): 479–487. doi:10.1016/j.immuni.2010.03.016. ISSN 1074-7613.
Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Down syndrome is the most common chromosomal abnormality. Each year approximately 3,000 to 5,000 children are born with this chromosome disorder and it is believed there are about 250,000 families in the United States of America who are affected by Down syndrome. Birth rates are highest among mothers of advanced maternal age however 80% of all children with Down syndrome are born to mothers younger than 35 years. Down syndrome occurs in people of all races and economic levels.

Epidemiology and Demographics

Prevalence

  • Down syndrome is the most common chromosomal abnormality.
  • The prevalence of Down syndrome 691 live births, worldwide; prevalence of 100.3 per 100,000)[1]

Incidence

  • The estimated incidence of Down Syndrome is between 100 in 100,000 live births worldwide.[2] 
  • Each year approximately 3,000 to 5,000 children are born with this chromosome disorder and it is believed there are about 250,000 families in the United States of America who are affected by Down syndrome.[3]

Maternal age

  • Birth rates are highest among mothers of advanced maternal age however 80% of all children with Down syndrome are born to mothers younger than 35 years.[4]
  • Maternal age influences the chances of conceiving a baby with Down syndrome. At maternal age 20 to 24, the probability is 1/1490; at age 40 the probability is 1/60, and at age 49 the probability is 1/11.[5] Although the probability increases with maternal age, 80% of children with Down syndrome are born to women under the age of 35,[6] reflecting the overall fertility of that age group. Recent data also suggest that paternal age also increases the risk of Down Syndrome manifesting in pregnancies in older mothers.[7]

Race

  • Down syndrome occurs in people of all races and economic levels.[8]

Gender

  • Down syndrome affects both genders equally.[9]

Prevalence of congenital malformations

  • Sixty to 80 percent of children with Down syndrome have hearing deficits. 
  • Forty to 45 percent of children with Down syndrome have congenital heart disease.
  • Intestinal abnormalities also occur at a higher frequency in children with Down syndrome. 
  • Children with Down Syndrome often have more eye problems than other children who do not have this chromosome disorder.


References

  1. ↑ Sherman SL, Allen EG, Bean LH, Freeman SB (2007). “Epidemiology of Down syndrome”. Ment Retard Dev Disabil Res Rev. 13 (3): 221–7. doi:10.1002/mrdd.20157. PMID 17910090.
  2. ↑ “WHO | Genes and human disease”.
  3. ↑ “Down Syndrome Facts | National Down Syndrome Society”.
  4. ↑ “WHO | Genes and human disease”.
  5. ↑ Hook, E.B. (1981). “Rates of chromosomal abnormalities at different maternal ages”. Obstet Gynecol. 58: 282. PMID 6455611
  6. ↑ Estimate from “National Down Syndrome Center”. Retrieved 2006-04-21.
  7. ↑ Warner, Jennifer. “Dad’s Age Raises Down Syndrome Risk, Too”, “WebMD Medical News”. Retrieved 2007-09-29.
  8. ↑ “WHO | Genes and human disease”.
  9. ↑ “WHO | Genes and human disease”.

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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Common risk factors involved in the development of Down syndrome include maternal smoking, increased maternal age, impaired recombination of chromosome 21, impaired folate metabolism and oral contraceptive pills (OCPs). Less common risk factors leading to the development of Down syndrome include genomic instability in mothers, radiation exposure, low socioeconomic status and maternal obesity.

Risk factors

The following are the risk factors for developing Down syndrome:

Common risk factors

Common risk factors in the mother leading to the development of Down syndrome include the following:[1][2][3][4][5][6][7]

Less common risk factors

Less common risk factors involved in the development of Down syndrome include the following:[8]

References

  1. ↑ Morris JK, Mutton DE, Alberman E (2002). “Revised estimates of the maternal age specific live birth prevalence of Down’s syndrome”. J Med Screen. 9 (1): 2–6. doi:10.1136/jms.9.1.2. PMID 11943789.
  2. ↑ Yang Q, Sherman SL, Hassold TJ, Allran K, Taft L, Pettay D, Khoury MJ, Erickson JD, Freeman SB (1999). “Risk factors for trisomy 21: maternal cigarette smoking and oral contraceptive use in a population-based case-control study”. Genet. Med. 1 (3): 80–8. doi:10.1097/00125817-199903000-00004. PMID 11336457.
  3. ↑ Ghosh S, Hong CS, Feingold E, Ghosh P, Ghosh P, Bhaumik P, Dey SK (November 2011). “Epidemiology of Down syndrome: new insight into the multidimensional interactions among genetic and environmental risk factors in the oocyte”. Am. J. Epidemiol. 174 (9): 1009–16. doi:10.1093/aje/kwr240. PMID 21957181.
  4. ↑ Sperling K, Neitzel H, Scherb H (January 2012). “Evidence for an increase in trisomy 21 (Down syndrome) in Europe after the Chernobyl reactor accident”. Genet. Epidemiol. 36 (1): 48–55. doi:10.1002/gepi.20662. PMID 22162022.
  5. ↑ Hunter JE, Allen EG, Shin M, Bean LJ, Correa A, Druschel C, Hobbs CA, O’Leary LA, Romitti PA, Royle MH, Torfs CP, Freeman SB, Sherman SL (September 2013). “The association of low socioeconomic status and the risk of having a child with Down syndrome: a report from the National Down Syndrome Project”. Genet. Med. 15 (9): 698–705. doi:10.1038/gim.2013.34. PMC 4122862. PMID 23558253.
  6. ↑ Alverson CJ, Strickland MJ, Gilboa SM, Correa A (March 2011). “Maternal smoking and congenital heart defects in the Baltimore-Washington Infant Study”. Pediatrics. 127 (3): e647–53. doi:10.1542/peds.2010-1399. PMID 21357347.
  7. ↑ Bergström S, Carr H, Petersson G, Stephansson O, Bonamy AK, Dahlström A, Halvorsen CP, Johansson S (July 2016). “Trends in Congenital Heart Defects in Infants With Down Syndrome”. Pediatrics. 138 (1). doi:10.1542/peds.2016-0123. PMID 27252035.
  8. ↑ Hildebrand E, KĂ€llĂ©n B, Josefsson A, Gottvall T, Blomberg M (April 2014). “Maternal obesity and risk of Down syndrome in the offspring”. Prenat. Diagn. 34 (4): 310–5. doi:10.1002/pd.4294. PMID 24327477.

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Screening

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Standard prenatal screens can discover Down syndrome. Genetic counseling along with genetic testing, such as amniocentesis, chorionic villus sampling (CVS), or percutaneous umbilical blood sampling (PUBS) are usually offered to families who may have an increased risk of having a child with Down syndrome, or where normal prenatal exams indicate possible problems. Genetic screens are often performed on pregnant women older than 30 or 35. During the first trimester of pregnancy, increased nuchal translucency in the fetus on ultrasound and decreased levels of pregnancy associated protein- A (PAPP-A) suggest the diagnosis of a chromosomal abnormality. Quad screen results during the second trimester of pregnancy may show increased beta-hCG, increased inhibin A, decreased alfa-fetoprotein (AFP) and decreased estriol.

Screening

Prenatal screening

  • Pregnant women can be screened for various complications during pregnancy. Many standard prenatal screens can discover Down syndrome. Genetic counseling along with genetic testing, such as amniocentesis, chorionic villus sampling (CVS), or percutaneous umbilical blood sampling (PUBS) are usually offered to families who may have an increased chance of having a child with Down syndrome, or where normal prenatal exams indicate possible problems. Genetic screens are often performed on pregnant women older than 30 or 35.
  • Amniocentesis and CVS are considered invasive procedures, in that they involve inserting instruments into the uterus, and therefore carry a small risk of causing fetal injury or miscarriage. There are several common non-invasive screens that can indicate a fetus with Down syndrome. These are normally performed in the late first trimester or early second trimester. Due to the nature of screens, each has a significant chance of a false positive, suggesting a fetus with Down syndrome when, in fact, the fetus does not have this genetic abnormality. Screen positives must be verified before a Down syndrome diagnosis is made. Common screening procedures for Down syndrome are given in Table 1.
Common first and second trimester Down syndrome screens
Screen When performed (weeks gestation) Detection rate False positive rate Description
Triple screen 15–20 75% 8.5% This test measures the maternal serum alpha feto protein (a fetal liver protein), estriol (a pregnancy hormone), and human chorionic gonadotropin (hCG, a pregnancy hormone).[1]
Quad screen 15–20 79% 7.5% This test measures the maternal serum alpha feto protein (a fetal liver protein), estriol (a pregnancy hormone), human chorionic gonadotropin (hCG, a pregnancy hormone), and high inhibin-Alpha (INHA).[1]
AFP/free beta screen 13–22 80% 2.8% This test measures the alpha feto protein, produced by the fetus, and free beta hCG, produced by the placenta.
Nuchal translucency/free beta/PAPPA screen 10–13.5 91%[2] 5%[2] Uses ultrasound to measure Nuchal Translucency in addition to the freeBeta hCG and PAPPA (pregnancy-associated plasma protein A). NIH has confirmed that this first trimester test is more accurate than second trimester screening methods.[3]

Postnatal Screening

Persons with Down syndrome need to be closely screened for certain medical conditions. They should have:

  • Eye exam every year during infancy
  • Hearing tests every 6 – 12 months, depending on age
  • Dental exams every 6 months
  • X-rays of the upper or cervical spine between ages 3 – 5 years
  • Pap smears and pelvic exams beginning during puberty or by age 21
  • Thyroid testing every 12 months

References

  1. ↑ 1.0 1.1 For a current estimate of rates, see Benn, PA, J Ying, T Beazoglou, JFX Egan. “Estimates for the sensitivity and false-positive rates for second trimester serum screening for Down syndrome and trisomy 18 with adjustments for cross-identification and double-positive results”. Prenatal Diagnosis. 21 (1): 46–51. PMID 11180240
  2. ↑ 2.0 2.1 Some practices report adding Nasal Bone measurements and increasing the detection rate to 95% with a 2% False Positive Rate.
  3. ↑ NIH FASTER study (NEJM 2005 (353):2001). See also J.L. Simplson’s editorial (NEJM 2005 (353):19).

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Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

3% of fetuses with Down’s syndrome diagnosed in utero at 16 weeks’ gestation would be lost spontaneously if termination of pregnancy was not performed. At birth, 50% of newborns with Down’s syndrome have one or more additional serious congenital abnormalities (in addition to intellectual disability). 96% without and 80% with heart defects survive the first year. At age 21 mean IQ is 42 (range 8–67) and mental age is 5 years (range 1–8 years). 11% develop Alzheimer’s disease by age 50 and 77% by age 70 (mean age of onset age 56). Common complication that may arise in patients suffering from Down syndrome include, congenital heart defects (ASD, VSD, PDA), hearing loss, diabetes, celiac disease, cataracts, endocarditis, atlantoaxial subluxation, hypo and hyperthyroidism, duodenal atresia, Hirschprung disease. Life expectancy is 50–55 years.

Natural History, Complications and Prognosis

Natural history

The natural history of Down syndrome consists of the following findings:

Inutero

  • 3% of fetuses with Down’s syndrome diagnosed in utero at 16 weeks’ gestation would be lost spontaneously if termination of pregnancy was not performed; at 10 weeks’ gestation the figure is 43%

At birth

Infancy and early childhood

  • 96% without and 80% with heart defects survive the first year
  • 20% of live borns die before age 5; after age 5 survival to adulthood is likely
  • More than 50 % of live borns survive to age 60

Adulthood

  • At age 21 mean IQ is 42 (range 8–67) and mental age is 5 years (range 1–8 years)
  • 11% develop Alzheimer’s disease by age 50 and 77% by age 70 (mean age of onset age 56)

Complications

Common complications that may develop in patients suffering from Down syndrome include the following:

Prognosis

These factors can contribute to a shorter life expectancy for people with Down syndrome. One study, carried out in the United States in 2002, showed an average lifespan of 49 years, with considerable variations between different ethnic and socio-economic groups. However, in recent decades, the life expectancy among persons with Down syndrome has increased significantly up from 25 years in 1980. The causes of death have also changed, with chronic neurodegenerative diseases becoming more common as the population ages. Most people with Down Syndrome who survive into their 40s and 50s begin to suffer from an Alzheimer’s disease-like dementia.

References

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Diagnosis

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Treatment

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies | Sociological and Cultural Aspects

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