Introduction
Down syndrome also referred to as trisomy 21 is a genetic abnormality that is associated with a chromosomal condition characterized by the availability of a third chromosome 21 copy either in part or fully . The disorder is usually manifested by slow cognitive capabilities, slight to moderate intellectual debility, hypotonia in infancy and weak muscle tenor. . Physical characteristics encompass distinctive facial characteristics such as a flat facial outline, eyes slanting upwards, macroglossia, epicanthic eyelids, flat nasal bridge, small limbs, petite body frame, palmer crease, microgenia and smaller heads compared to the body frame .
The slow cognitive capabilities are usually manifested by a major delay in body growth, delayed and slow development of language and speech with the developed speech being aberrant. Intellectual frailty is directly proportional to age given affected individuals display a steady decline in thinking and cognition capabilities as they grow older when compared to unaffected individuals. Moreover, a minimal fraction of individuals with the condition are predisposed to developing Alzheimer’s disease that leads to distorted judgment, memory loss and functional complications. In terms of behavioral issues, most patients display obsessive or compulsive disorder, throwing of tantrums, stubbornness and attention deficit disorders.
A substantial number of people with the condition are normally predisposed to an array of birth defects such as heart and digestive tract abnormalities. In addition affected individuals are normally inclined to developing severe medical complications such as celiac disease due to gluten intolerance, hypothyroidism that results in severe growth and metabolic effects, complications in vision and hearing and gastroesophageal reflux that lead to the release of acidified stomach innards back to the esophagus. Developmental problems such as autism that affect social and communication capabilities and adverse complications such as leukemia may also occur in a small proportion of children with Down syndrome . These medical conditions often result in premature death in individuals suffering from the disorder.
Genetically, Down Syndrome results due to a meiotic nondisjunction where an egg or sperm cell is generated with an additional copy of chromosome 21 resulting in Trisomy 21 i.e. (47, XX, +21) with 24 chromosomes in the gamete instead of the normal 23 chromosomes. When this gamete is linked with a typical gamete from the other parent, the resultant embryo acquires 47 chromosomes characterized by three copies of chromosome 21.Trisomy 21 has been implicated in majority of Down syndrome cases accounting for approximately 95% of the reported cases. 88% of these cases are related to nondisjunction in the maternal gamete and 8% due to nondisjunction in the paternal gamete. In essence the affected domain in this condition involves 21q22.1-q22.3 chromosomal bands.
Figure 1: Chromosomal arrangements during recombination indicating the extra chromosome 21 copy (http://downsyndromepbio.blogspot.com/, 2013).
Down syndrome due to trisomy 21ensues as a random occurrence during recombination in a parent reproductive cell.
Trisomy 21 is not the sole cause of the condition; Robertsonian translocation is also known to result in the extra chromosomal 21 copy. In this scenario, the elongated arm of chromosome 21is linked to a secondary chromosome and in most instances to chromosome 14 resulting in a phenomenon such as 45,XX,der(14;21)(q10;q10). In essence an individual with this kind of phenomenon is phenotypically normal. However, upon reproduction and recombination the genetic abnormality becomes apparent given there is a high chance that a gamete with an extra chromosome 21 may be generated resulting in translocation Down syndrome typically known as familial Down syndrome. Translocation Down syndrome accounts for approximately 3% of Down syndrome cases and it is inheritable.
The third form of Down syndrome is referred to as mosaic trisomy 21 which unlike trisomy 21 that occurs in an individual sperm or egg cell; this kind of trisomy occurs after fertilization during the early processes of cell division. Due to this, individuals with this abnormality possess two cell lines with one of them containing an extra chromosome 21 and the other with normal number of chromosomes . Mosaic trisomy 21 accounts for 2 to 4% of Down syndrome cases.
Generally, Down syndrome is stipulated to occur in 1:830 infants. Despite the colossal knowledge on the disorder, it is still unclear in human genetics why the abnormality occurs. There is no treatment or cure for the genetic disorder but the medical conditions that result due to the abnormality such as hypothyroidism can be treated. Interventions such as physical, speech and hearing therapies in addition to consistent medical screenings can allow affected individuals
The lack of treatment and cure for Down syndrome places emphasis on prenatal screening considering the fact that every woman is at risk of having a child with Down syndrome. This enables the mother to be mentally and emotionally prepared in case she is bound to have a baby with the condition. Two types of tests are usually explored in the prenatal diagnosis of Down syndrome; the first is a screening test that predicts the risk of a child being born with Down syndrome albeit it does not give a definitive diagnosis. The second is a diagnostic test which is more definitive and intrusive albeit safe and it is normally undertaken after the screening test indicates that the baby might be at risk of developing the condition.
This paper explores the various prenatal screening methods and highlights the current and emergent implications of prenatal screening on healthcare in detail in the discussion below:
Discussion:
Prenatal screening tests
Prenatal screening of Down syndrome can be done between 10 and 20 weeks which fall within the first and second trimesters of pregnancy. These tests vary in terms of accuracy and invasiveness but if combined the diagnostic/detection rate considerably amplifies. There are two fundamental methods used in the screening of Down syndrome and these encompass ultra sound and biochemical screening of blood and sera that are explained below in detail.
Nuchal translucency ultrasound scan (NT scan)
The NT scan is a unique imaging scan that is normally carried out between 11 and 14 weeks of pregnancy. The scan typically quantifies the accumulation of fluid beneath the skin at the rear of
the baby’s neck normally referred to as the nuchal translucency. It is normal for fetuses to have a collection of fluid in this particular region but fetuses with Down syndrome are inclined to have a higher volume of fluid than normal fetuses. However reviews have indicated that the test has a low sensitivity of only 75% to 80% and high false positive rates estimated at 5.8% to 6% at a 5% margin of error .
It is therefore evident that both the NT and biochemical methods if used independently are less sensitive and result in a high rate of false positive results that have been linked to anxiety, depression and high abortion rates in expectant women who have been falsely diagnosed. This has led to a lot controversies around these methods of screening. In as much as it is recommended that the two tests should be combined, the detection rate is still low at 85% with the false positive rate remaining constant at 5%. This is definitely an issue of concern especially when time, resources and emotional implications are brought forth due to the poor rates of specificity and sensitivity.
On the other hand, some ultrasound findings have associated Down syndrome with the lack of a
fetal nasal bone but the reproducibility of this finding has not been documented and it is indistinct how this can be used as a screening method .
Quad screen method
This method is also referred to as quadruple test or quad test. It is normally undertaken in the second trimester of pregnancy and involves the measurement of the serum levels of alpha-fetoprotein (AFP), beta-hCG, unconjugated estriol and inhibin-Alpha (INHA). AFP is usually generated by the liver and yolk sac during fetal development, estriol is a placental product and INHA is produced by the placenta. In essence, if a fetus is suspected to be at high risk of developing Down syndrome, the AFP and estriol levels would be low whereas the hCG and INHA levels would be high .
The estimated risk is weighted against the mother’s age, health condition, weight, ethnicity, lifestyle, chances of having twins and the fetus’ gestational age for a definitive result to be attained. However, the detection rate of the quad test is much lower than the combination of NT and biochemical tests at 60-70% at a false positive rate of 5% as well. This brings about the aforementioned issues associated with prenatal screening and their potential adverse effects to both the mother and unborn child.
Integrated test
This test utilizes both the first and second trimester prenatal screening tests i.e. combination of the NT, beta hcG and PAPP-A tests together with the quad screen test to generate a more tangible and precise result. The estimation of the results yielded by this test hugely relies on very
accurate calculation of the fetus’ gestational age or else the false positive rate may increase to 7.5%. The detection rate of this test is higher than all the aforementioned tests at 95% . Therefore, if the gestational age is accurately determined to minimize on the rate of generating false positives; this test is the best in screening prenatal Down syndrome. So far, no emergent issues or concerns have been associated with this test but the remaining 5% leaves a point of contention.
Sequencing of fetal DNA fragments
Most recently in October 2011, sequencing of fetal DNA fragments in the pursuit of prenatal screening of Down syndrome was developed by Sequenom. Several genomics firms such as Illumina and Ariosa Diagnostics have since then also developed and introduced the use of this method in prenatal screening to the market. In the initial clinical screening conducted by Sequenom, evidence indicated that the method identified Down syndrome in the fetal DNA of 209 out of 212 mothers yielding a high proportion of 98.6% .
Basically, this is a highly advanced screening test meant for effective diagnosis of Down syndrome and the International Society for Prenatal Diagnosis advices that this method should be used in combination with genetic counseling. However, in as much as the market for these tests have grown rapidly, there are fears that the tests yield poorly contemplated results that generate confusion among doctors and patients especially in cases of high risk pregnancies.
Some medical specialists have alluded to the fact that the tests yield inaccurate results leading to increase in abortion rates with some arguing whether the tests should be referred to as ‘screenings’ instead of ‘tests’ to show that they are used in risk prediction as opposed to ultimate
diagnosis. The test is estimated to have a detection rate of approximately 99% and it is gaining popularity as most doctors and patients prefer less invasive methods in prenatal screening .
Diagnostic tests
Two major tests are normally employed in the diagnosis of Down syndrome and these include amniocentesis and chorionic villus sampling (CVS). These tests are more intrusive and yield much lower false positive results when compared to screening tests and are therefore considered to be more reliable although they are associated with a higher risk of miscarriages.
Amniocentesis
This test is also referred to as the amniotic fluid test (AFT) and it is exploited in the prenatal determination of chromosomal abnormalities such as Down syndrome. The test is usually carried out between 15 and 18 weeks of pregnancy because evidence indicates that this period is the safest for performing the test but it can also be performed at later pregnancy stages .
The procedure basically involves the use of a fine needle in obtaining an amniotic fluid sample from the uterus. The fluid is usually targeted because it contains various waste products such as urine from the fetus’ developing kidneys and dead skin cells that contains the fetus’ genetic material. The genetic material is then analyzed in a laboratory setting to establish whether or not the fetus has Down syndrome or other genetic disorders .
In as much as there are various controversies surrounding the safety of the test, it has been established that the risk of developing complications is substantially low at approximately 1%
depending on how accurate and keenly the procedure is performed. The miscarriages after amniocentesis have been linked to the breakage of the amniotic sac that has been slightly disrupted and it is difficult to predict when one is most likely to develop the complications .
Chorionic villus sampling (CVS)
This method involves sampling of a placental tissue known as chorionic villus in order to diagnose genetic abnormalities. The test is usually performed earlier than amniocentesis at a gestation period of 10 to 12 weeks. This sample is preferentially taken because the villi typically contain genetic material that is identical to the developing fetus thus analyses can be carried out on these cells to explore the genetic makeup of the fetus making it easy for Down syndrome to be diagnosed. Like amniocentesis, CVS is carried out by the use of a fine needle into the uterus for sample collection from the placenta; this method is also referred to as transabdominal CVS.
However, the risk of having a miscarriage is low at approximately 1 to 2% and this has been linked to the leakage of amniotic fluid due to the disruption of the amniotic sac . In addition, the leakage may result in oligohydramnios that may cause the baby to develop hypoplastuc lungs if untreated and this may also occur in amniocentesis. There is also a slight risk of the child developing Limb Reduction Defects (LRD) and the risk is much higher in CVS than amniocentesis .
Conclusion
It is evident that screening tests are safer than diagnostic tests given they are less intrusive and no cases of miscarriages have been associated with these methods. From all the above methods, it is
evident that the integrated test and the novel sequencing of fetal DNA fragments are the safest and best methods to use due to safety, high specificity and high sensitivity. The 1% risk of miscarriages and other complications associated with amniocentesis and CVS have received a lot of criticism and if possible they should be totally avoided to totally reduce the high infant and maternal mortality rates that may occur due to these diagnostic tests.
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