New Delhi: Scientists have observed trisomy 21, the extra copy of chromosome 21 known to cause the genetic condition Down syndrome, to impair heart formation during embryonic development, a malfunction found to cause a hyperactive cellular response when attacked by viruses.
Using stem cells obtained from research participants with Down syndrome and a mouse model of the syndrome, the scientists at the University of Colorado Anschutz Medical Campus, US, modelled cardiogenesis, or heart formation, in the lab.
The scientists demonstrated that blocking the antiviral cellular response, or the interferon response, improved cardiogenesis.
Medical conditions common in children with Down syndrome include hearing loss (75%), obstructive sleep apnea (50%–79%), otitis media (50%–70%), eye problems (60%–80%), including cataracts (<1%–3%), nasolacrimal duct obstruction (3%–36%), and strabismus and severe refractive errors (36%–80%), congenital heart defects (50%), neurologic dysfunction (1%–13%), gastrointestinal atresia (12%), hip dislocation and hip abnormalities (2%–8%), symptomatic atlantoaxial instability (1%–2%), thyroid disease (24%–50%) and, less commonly, transient abnormal myelopoiesis (4%–10%) and later leukemia (1%), autoimmune diseases, including Hashimoto thyroiditis (13%–39%), with incidence dependent on age, celiac disease (1%–5%), Hirschsprung disease (<1%), and autism (7%–19%).
People with Down syndrome often function more effectively in social situations than would be predicted based on cognitive assessment results, unless there is presence of cooccurring autism. Although the level of social–emotional functioning may vary, these skills may be improved with early intervention and therapy through early adulthood.
In 96% of children with Down syndrome, the condition is sporadic because of nonfamilial trisomy 21, in which there are 47 chromosomes with the presence of a free extra chromosome 21. In 3% to 4% of people with the Down syndrome phenotype, the extra chromosomal material is the result of an unbalanced translocation between chromosome 21 and another acrocentric chromosome, usually chromosome 14 or 21.
Approximately three-quarters of these unbalanced translocations are de novo, and the remainder result from translocation inherited from a parent. If the child has a translocation, the parents should be offered a karyotype to determine whether the translocation is familial or de novo. In the remaining 1% to 2% of people with the Down syndrome phenotype, a mix of 2 cell lines is present: 1 normal and the other with trisomy 21.
This condition is called mosaicism. People with mosaicism may be more mildly affected than people with complete trisomy 21 or translocation chromosome 21, but this is not always the case, and their condition may include any of the associated medical problems and may be indistinguishable from trisomy 21.
The chance of recurrence for families with an affected child depends on many factors and vary greatly, from 1% in most families to 100% in some circumstances. Table 2 describes the different chromosomal characteristics of Down syndrome.
The American College of Obstetricians and Gynecologists recommends that all pregnant women, regardless of age or risk status, be offered the option of screening and diagnostic testing for Down syndrome.17,18
A wide variety of screening test options exist in the first and second trimester using maternal serum and ultrasonography.
Each offers varying levels of sensitivity and specificity. No 1 screening test is superior to other screening tests in all characteristics. In recent years, noninvasive prenatal testing by cell-free DNA (cfDNA) has become available and is the most sensitive method for screening for Down syndrome.
cfDNA screening for Down syndrome is significantly more sensitive and specific than conventional screening methods, with a 2017 meta-analysis reporting a detection rate of 99.7%, with a false-positive rate of 0.04% in singleton pregnancies. cfDNA uses a maternal blood sample to analyze free-floating small fragments of DNA from the placenta. Because cfDNA is from the placenta and not directly from the fetus, it is a screening test and not diagnostic. cfDNA analysis can be performed as early as 9 to 10 weeks’ gestation depending on the laboratory, and a high-risk result from cfDNA would require confirmation by diagnostic testing with chorionic villus sampling (CVS) or amniocentesis. Screening for trisomy 21 by cfDNA in twin pregnancies can be performed, but total number of reported cases is small.20
Other screening tests for Down syndrome include first-trimester screening, which incorporates maternal age, nuchal translucency ultrasonography, and measurement of maternal serum β human chorionic gonadotropin and pregnancy-associated plasma protein A. Second-trimester screening is available for patients who first seek medical care in the second trimester or in locations where first-trimester screening is not available.
The second-trimester serum screening, often called the quad screen, incorporates maternal age risk with measurement of maternal serum β human chorionic gonadotropin, unconjugated estriol, α-fetoprotein, and inhibin concentrations. The detection rate of Down syndrome by first-trimester screening is 82% to 87%, by second trimester screening is 80%, and by combined first- and second-trimester screening (referred to as integrated screening) is 95%. These screening tests are reported to have a 5% false-positive rate.
Ultrasonography is an additional screening tool for Down syndrome because structural changes, including congenital heart defects, increased nuchal skin fold, “double bubble” sign suggestive of duodenal atresia, ventriculomegaly, and short–long bones, may be identified by prenatal imaging. Although ultrasonography is an additional screening tool, it is not diagnostic for Down syndrome.
Diagnostic testing for Down syndrome includes CVS or amniocentesis. CVS has the benefit of being performed earlier in pregnancy, between 10 and 14 completed weeks’ gestation. A placental sample is obtained either transabdominally or transcervically, depending on provider preference and placental location. Amniocentesis is a transabdominal procedure to remove a sample of amniotic fluid performed after 15 weeks’ gestational age. Risk for procedure-related loss of pregnancy from CVS or amniocentesis is comparable in recent studies when performed by providers with expertise, 0.22% for amniocentesis and 0.11% for CVS.
Pediatricians may be asked to counsel a family whose fetus has been identified with or is at increased chance of having Down syndrome. Families may have a great number of questions during any pregnancy and especially when the child will have Down syndrome.
They may have received counseling from a certified genetic counselor, a clinical geneticist, maternal–fetal medicine specialist, obstetrician, or developmental specialist. In addition, parents may have received information and support from a family-led organization such as Parent to Parent USA, a local Down syndrome group, a national Down syndrome organization, social media, or possibly an Internet site with inaccurate information. Pediatricians who often have a previous relationship with the family may be the natural source of support for and guidance in the context of the medical home.