Down Syndrome Workup

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Nov 29, 2011
 

Laboratory Studies

A complete blood count (CBC) count with differential and bone marrow examination is indicated. Thyroid-stimulating hormone (TSH) and thyroxine (T4) levels should be obtained at birth and annually thereafter. Perform Papanicolaou smears every 1-3 years in sexually active women starting at the age of first intercourse.

In addition, the following studies should be considered.

Cytogenetic studies

The clinical diagnosis should be confirmed with cytogenetic studies. Karyotyping is essential to determine the risk of recurrence. In translocation Down syndrome, karyotyping of the parents and other relatives is required for proper genetic counseling (see the images below).

G-banded karyotype showing trisomy 21 (47,XY,+21).G-banded karyotype showing trisomy 21 (47,XY,+21). G-banded karyotype showing trisomy 21 of isochromoG-banded karyotype showing trisomy 21 of isochromosome arm 21q type [46,XY,i(21)(q10)].

Interphase fluorescence in situ hybridization

Fluorescence in situ hybridization (FISH) may be used for rapid diagnosis. It can be successful in both prenatal diagnosis and diagnosis in the neonatal period.

Occult mosaicism for trisomy 21 may partially explain the previously described association between family history of Down syndrome and risk of Alzheimer disease. Screening for mosaicism with FISH is indicated in selected patients with mild developmental delay and those with early-onset Alzheimer disease.[44]

Evaluation of the proportion of cells with trisomy 21 in mosaic trisomy 21 includes the following[45] :

  • Lymphocyte preparations
  • Buccal mucosa cellular preparations
  • FISH
  • Scoring frequency of trisomic cells

Measurement of immunoglobulin G

Measurement of immunoglobulin (Ig) G levels focuses on identifying deficiencies of subclasses 2 and 4. Decreased levels of IgG subclass 4 is significantly correlated with bacterial infections. These deficits in cellular immunity have also been documented in individuals with gingivitis and periodontal disease.

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Radiography and Ultrasonography

Skull series show evidence of flattened facial features (including small or absent nasal bones), hypoplastic sinuses, a flat occiput, microcephaly, and brachycephaly.

Cervical radiography (with lateral flexion and extension views) is required to measure the atlantodens distance and to rule out atlantoaxial instability at the age of 3 years. Radiography is also used before anesthesia is given if signs suggest spinal cord compression.

Yearly mammograms should be obtained in women older than 50 years.

Reduced iliac and acetabular angles may be present in young infants. Short hands with shortened digits and clinodactyly due to hypoplastic middle phalanx of the fifth finger may be present.

Echocardiography should be performed on all infants with Down syndrome to identify congenital heart disease, regardless of findings on physical examination.

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Prenatal Screening and Diagnosis

The first prenatal diagnosis of Down syndrome was made in 1968, and screening women on the basis of advanced maternal age with amniocentesis was gradually introduced into medical practice. Low maternal serum alpha-fetoprotein (MSAFP) levels were associated with Down syndrome in 1983. Later, elevated human chorionic gonadotropin (hCG) and low unconjugated estriol (uE3) levels were found to be markers for Down syndrome.

By 1988, use of the 3 biochemical markers, together with maternal age, had been accepted as a method of prenatal screening for Down syndrome in the general population. Currently, in the general population, maternal age, ultrasound findings, and maternal serum markers (in the first or second trimester) are used alone or in combination for risk calculation.[56]

Ultrasonography

With prenatal ultrasonography, trisomy 21 may be diagnosed in the second and third trimester of pregnancy. Suggestive prenatal ultrasound findings may be followed with amniocentesis and fetal chromosome analysis. Prenatal ultrasonography may reveal the following:

  • Ultrasonography soft markers observed in the second trimester for Down syndrome include absent or hypoplastic nasal bone, thickened nuchal fold, echogenic bowel, shortened long bones, and pyelectasis
  • Absent or hypoplastic nasal bone is observed in 43-62% of trisomy 21 fetuses, compared with 0.5-1.2% of normal fetuses
  • A thickened nuchal fold has been associated with a greatly increased risk of trisomy 21 and may be an early feature of fetal hydrops or cystic hygroma
  • Echogenic bowel has been observed in approximately 15% of fetuses with trisomy 21, compared with 0.6% of normal fetuses; about 35% of fetuses with true echogenic bowel have some underlying pathology, such as first trimester bleeding, fetal infections, and cystic fibrosis due to meconium ileus
  • Shortened long bones (humerus and femur) have been associated with an increased risk of chromosomal abnormalities; the humerus is a more reliable discriminator for Down syndrome than the femur and appears to be the next most important marker after nasal bone and nuchal fold; other possible causes include skeletal dysplasia, especially if the long bones are severely shortened or abnormal in appearance (eg, bowing fractures or reduced mineralization)
  • Pyelectasis has been observed in approximately 17% of fetuses with trisomy 21, and approximately 1 in every 300 fetuses with isolated pyelectasis has aneuploidy; pyelectasis has been associated with an increased risk of hydronephrosis and postnatal urinary reflux
  • Other ultrasonographic abnormalities include cystic hygroma, duodenal atresia or stenosis (double-bubble sign), cardiac defects (endocardial cushion defect with atrial and ventricular septal defects and abnormal mitral and tricuspid valves), intracardiac echogenic focus, and prune belly anomaly

Ultrasonography should not be relied on as the primary method of diagnosing Down syndrome; the diagnosis can be missed in affected families.

Maternal serum biochemical markers

When ultrasonography is used to estimate gestational age, the detection rate is about 20% when only the MSAFP test is used, 59% when the double test (MSAFP and hCG) is used, and 69% when the triple test (MSAFP, hCG, uE3) is used. The false-positive rate is 5%. Other factors for adjustment are maternal age and weight, insulin-dependent diabetes mellitus, multiple pregnancies, racial background, previous pregnancy with Down syndrome, and first or repeat test in a pregnancy.

A positive screening result only suggests an increased risk for Down syndrome, and definitive testing with amniocentesis and chromosomal analysis is indicated.

In a retrospective study of first-trimester screening for free beta-hCG and pregnancy-associated plasma protein A (PAPP-A), detection rates were as high as those associated with MSAFP, hCG, or uE3 testing in the second trimester.[57] Prospective studies are needed to further assess first-trimester screening. Second-trimester maternal serum marker screening allows the detection of 60-70% of Down syndrome cases, with a false positive rate of 5%.[57]

Effective screening for trisomy 21 is provided by assessment of a combination of maternal age, fetal nuchal translucency thickness, and maternal serum free β-hCG and pregnancy-associated plasma protein-A (PAPP-A) at 10-14 weeks’ gestation.[58] Prospective studies have demonstrated that combined screening can identify about 90% of affected fetuses, with a false-positive rate of 5%.[59]

In nonstandard Down syndrome (ie, mosaicism and translocation) cases, second-trimester maternal serum marker screening gives the same detection rate as for standard trisomy 21, except in cases with low-level mosaicism (< 10%).[56]

After fetal nucleated red blood cells (RBCs) are sorted by using different cell transferrin and glycophorin-A receptors on the cell surface, interphase FISH can be used to determine the chromosomal constitution. Chromosome-specific probes available for X, Y, 13, 18, and 21 permit diagnosis. The FISH finding should be confirmed by using standard cytogenetic techniques.

Invasive diagnostic tests

Amniocentesis, routinely performed at 14-16 weeks’ gestation, remains the criterion standard of invasive diagnostic tests. Testing for chromosomal disorders is 99.5% accurate. Rare cases of mosaicism are missed, and results can be inaccurate if maternal-cell contamination occurs. The procedure is associated with a small risk of pregnancy loss (1:200-300).

Chorionic villus sampling (CVS) is performed at 10-13 weeks’ gestation; earlier testing is thought to be associated with a 1 in 300-1000 risk of fetal transverse limb deficiency, a small risk of maternal cell contamination, and a 0.5-1% risk of a fetal loss after the procedure. The accuracy of CVS (96-98%) is less than that of midtrimester amniocentesis, because of confined placental mosaicism and maternal-cell contamination.

Percutaneous umbilical blood sampling (PUBS) is approximately 95% successful in obtaining a blood sample for cytogenetic testing. The pregnancy-loss rate is 3.25% for PUBS done for chromosomal indications, compared with 1.25% and 2.75% for PUBS done for nonchromosomal indications. The indication for the procedure greatly increases the risk of procedure-related pregnancy loss.

The availability of in vitro fertilization has allowed preimplantation diagnosis of single-gene disorders, sex selection for X-linked disorders, and identification of chromosomal aneuploidies. After a biopsy sample is obtained from the first polar body, the blastocyst, or the 6-cell to 8-cell embryo, FISH can then be used to diagnose fetal aneuploidy. However, standard cytogenetic confirmation is not possible for the preimplantation diagnosis.

Noninvasive diagnostic tests

A major goal in the field of prenatal screening has been to reduce the need for invasive procedures.

Among high-risk pregnancies clinically indicated for invasive prenatal diagnosis, noninvasive detection of fetal trisomy 21 can be achieved by using multiplexed, massively parallel sequencing of maternal plasma DNA, which has 100% sensitivity and 97.9% specificity; this provides a 96.6% positive predictive value and 100% negative predictive value.[60]

The sequencing test could be used to rule out trisomy 21 in high-risk pregnancies before proceeding to invasive diagnostic testing to reduce the number of cases that require amniocentesis or chorionic villus sampling. However, its diagnostic performance and practical feasibility in the clinical setting have not been tested on a large scale.

Offering noninvasive massively parallel shotgun sequencing (MPSS) to women already at high risk for Down syndrome can reduce procedure-related losses by up to 96%, while maintaining high detection.[61] Currently, MPSS testing cannot yet be considered diagnostic. Confirmation by invasive testing is still needed.

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Other Tests

The auditory brainstem response (ABR), also known as the brainstem auditory evoked response (BAER) may be tested to demonstrate hearing loss. Evaluation of the ABR in 47 nonselected children with Down syndrome aged 2 months to 3.5 years indicated some hearing loss in 66% (28% unilateral, 38% bilateral). Speech evaluation may also be indicated.

Pediatric ophthalmic examination should be performed for vision screening and for detecting ophthalmologic disorders.

Growth charts are available for children with Down syndrome. A developmental chart for noninstitutionalized children based on a modified Denver Developmental Screening Test is available for assessing developmental milestones.

Rigorous dental hygiene and dental evaluation are indicated beginning after tooth eruption.

Histologic findings

In patients with Down syndrome who have clinical signs of dementia associated with Alzheimer disease, postmortem histopathologic findings of the brains show the typical microscopic findings of Alzheimer disease.

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Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG  Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

James Bowman, MD Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Infant with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, flat nasal bridge, open mouth with tendency for tongue protrusion, and small ear with overfolded helix.
Child with Down syndrome. Note up-slanting palpebral fissures, bilateral epicanthal folds, small nose with flat nasal bridge, open mouth with tendency for tongue protrusion, and small ears with overfolded helix.
G-banded karyotype showing trisomy 21 (47,XY,+21).
G-banded karyotype showing trisomy 21 of isochromosome arm 21q type [46,XY,i(21)(q10)].
Hand of infant with Down syndrome. Note transverse palmar crease and clinodactyly of fifth finger.
Ear of infant with Down syndrome. Note characteristic small ear with overfolded helix.
Characteristic flat facies with hypertelorism, depressed nasal bridge, and protrusion of tongue, as well as single palmar simian crease in 2-year-old girl with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Small auricle and anomalies of folds in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Palmar simian crease in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Patient with Down syndrome with protuberant abdomen and umbilical hernia. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Wide gap between first and second toes and onychomycosis in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
Hypodontia in patient with Down syndrome. Image courtesy of L. Dourmishev, MD, PhD, DSc.
 
 
 
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