Down syndrome overview

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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]

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. Jérôme 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. Jérôme 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 Jérôme 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