Down Syndrome Assignment - Genetic Disorders PDF

Preview

Summary

A case study about an infant who has been admitted for examination as she has been showing signs of Downs Syndrome. This task involves answering a series of questions surrounding the diagnosis, prognosis, genetic causes and social issues surrounding Downs Syndrome....

Description

“BIO227-01 Down Syndrome In Course Assignment” “Chloe has just given birth to her first child, Mariam. The midwife examines Mariam and notices that she is floppy: when she holds her under the arms her body sags down as though she will slide through her hands. The midwife monitors Mariam’s breathing and is vigilant for signs of cyanosis. The delivery team suspect that Mariam has Down Syndrome (DS). A blood sample is taken from Mariam and sent to the lab for karyotype testing. Chloe is confused: she had the routine ultrasound scan at 12 weeks and her serum markers were tested but the results did not indicate that her baby had DS. Chloe decided not to have the cell-free fetal DNA test because her friend from ante-natal classes, Amina, had a positive result even though her baby did not have Down Syndrome. Chloe waits anxiously and 10 days later the test result confirms a trisomy of chromosome 21 (shown below) which was detected in all cells analysed.”

“Chloe tells the genetic counsellor that she is 43 and is the oldest of three children. Her sister, Sally, passed away last year at the age of 36 from breast cancer; she did not have any children. Her brother, John (36 years old), is married to Ann (35 years old) and they have two healthy children, Hana (2 years old) and Liam (5 years old). Chloe’s parents, Julian and Valerie, are 65 and 62 years old respectively and are both alive and well. Chloe is married to Amir (48 years old); they suffered one miscarriage before having Mariam.” “Answer the following questions by inserting text and/or figures into the boxes ONLY. Your answers should be in 11 point font and contained within the boxes. Marks are available for concise answers; you will not gain these marks if you expand the boxes. Where possible, your answers should be grounded in the scenario given above and draw on information from the scientific literature, rather than websites. As discussed in the first workshop, use the Vancouver style of referencing for in-text citations and include a list of references in the final box. Avoid using quotes from primary sources: this is poor practice. Instead, discuss any points you wish to make in your own words.” “Upload your work as a WORD file ONLY to QMplus by 17:30 on Wednesday 24th October.”

Page 1

“Question 1: When Mariam was born the midwife was vigilant for signs of cyanosis. What congenital condition seen in individuals with Down Syndrome (DS) might result in cyanosis? Your answer should also indicate which sub-types of this anomaly are most commonly found in DS Congenital Heart Disease can be seen in 40-50% of individuals who have Down syndrome, and can result in cyanosis. The different types of CHD include atrioventricular septal defects, which is the most common type in DS patients, ventricular septal defects and atrial septal defects [1]. Atrioventricular septal defects consist of abnormalities in the atrial and ventricular septa, as well as in the atrioventricular valves [1]. Ventricular septal defect is when there are holes in the walls between both ventricles, whereas atrial septal defect will show holes in the walls between the atria [1]. As the heart is weakened, the patient will have deoxygenated blood flowing in the circulation system, resulting in blueish skin or in other words cyanosis [2]. patients. [4 marks]”

“Question 2: Chloe underwent ultrasound screening: give details of the features which are commonly evaluated during ultrasound screening. [8 marks]” Nuchal translucency is measured in the first trimester, during an ultrasound screening, and it is the collection of fluid behind the neck of a foetus. Increased nuchal translucency may indicate trisomy 21, a measurement under 3mm is normal but over 3mm is deemed abnormal [3]. A second feature is the double bubble sign of duodenal atresia, where there is absence of two portions of the duodenum [4]. If duodenal atresia shows up in an ultrasound there may be a 30% chance of Down syndrome [4]. A third feature is cardiac defects, specifically structural congenital heart disease, for example atrioventricular septal defects, ventricular septal defects and atrial septal defects, which interfere with the normal flow of blood [1].

“Question 3: What is cell-free fetal DNA and why can it be used to detect fetal abnormalities? [4 marks]” Cell-free foetal DNA is the free DNA, not contained in cells, within the maternal blood. It can be used to for this purpose because during pregnancy the cell-free fetal DNA comes directly from the foetus itself, shed from syncytiotrophoblasts, located in the placenta [5]. It can be used for this because it allows the foetal DNA to be analysed, and is specific to the baby as cell-free DNA tends to disappear hours after pregnancy, making it more reliable to use [5]. It is also a method that has a lower risk of inducing miscarriages, and can be used effectively from as early as 10-11 weeks [5]. It has high sensitivity and specificity rates, making it a popular choice among expecting mothers.

“Question 4: What is a false-positive test result? [1 mark]” A false-positive test result is a result that indicates a certain condition is present when in actual fact it is not.

Page 2

“Question 5: What are the biological explanations for false positive results when cell-free fetal DNA is analysed. [12 marks]” Sometimes a transplant recipient may have a false positive result because the transplant (for instance an organ, donor egg or stem cell transplant) can transmit DNA that enters the blood stream, and when analysing the blood sample can make it look like there is trisomy 21 when there actually isn’t [6]. Secondly, it may result from placental mosaicism, because cell-free fetal DNA mainly comes from placental trophoblasts [7]. Placental mosaicism can give contradictory results, because there is a combination of affected cells with trisomy 21 and unaffected cells, making test results invalid. To be even more specific, cell free fetal DNA in maternal blood originates from the cytotrophoblast, this layer is derived from the trophoblast, and isn’t always consistent with true fetal DNA [8]. There will be a distribution of normal and abnormal cells over the different compartments (trophoblast, extraembryonic mesoderm and foetus), and if chronic villus testing is used as an alternative to amniocentesis, the test results may result in a false positive as it only using samples from the cytotrophoblasts [8]. Another reason is that Cell- free fetal DNA testing typically takes place in week 10/11 of pregnancy, which is fairly early. The amount of fetal DNA is very low in the first trimester as most cell-free circulating DNA is actually coming from the mother while cell-free fetal DNA is lower in abundancy, significantly increasing the occurrence of false positives because there isn’t a big enough sample [8]. Early death of an unaffected foetus and unknown chromosomal abnormality in the mother can also result in false positives .

“Question 6: What is the genetic basis and cause of the condition in this case? Justify your answer. [3 marks]” It is likely to be down to meiotic non-disjunction. This is due to the fact that Chloe is 43, so the risk of this is higher, as her oocytes will have been resting for a very long time in meiosis 1, before the baby was conceived [9]. Secondly, the likelihood of it being meiotic non-disjunction is 95% compared to only 4%, regarding Robertsonian translocation [9]. It cannot be mitotic non-disjunction because trisomy 21 was detected in all cells, instead of a mix of affected and unaffected cells [9].

“Question 7: The risk of having a child with DS increases with maternal age: briefly outline research which explains why. [3 marks]” A population-based, case-control study conducted in Atlanta investigated the effects of increased maternal age on DS. Mean parental ages were determined for trisomy 21 subgroups (parent and meiotic stage of origin), the control infants, and birth population. Nearly 90% of the cases had maternal origin, mostly from Meiosis I errors, increasing even more after the age of 35 [10]. They found older eggs have a higher risk of undergoing meiotic non-disjunction. This was down to the decay of cohesin and securin proteins within the egg over time, and with age, their levels declined causing chromosome pairs to be more loosely connected and further apart [10] . This causes instability in the chromosome pairs and a higher likelihood that chromosome division will occur unevenly, therefore, resulting in trisomy 21 after fertilisation [10] .

Page 3

“Question 8: Draw a pedigree from the family history information in this case, showing Chloe as having provided the information. (Insert in the box below either a photograph of the hand drawn pedigree, or an image file if you have drawn the pedigree using software such as PowerPoint. Credit will not be given for using a dedicated pedigree software package.) [6 marks]”

(Continued over page)

Page 4

“Insert your references in the text box below, using the Vancouver convention described in the first workshop. [7 marks]”

References 1. Sanaa, B, Abdenasser, D, Ayoub, E.H. Congenital heart disease and Down syndrome: various aspects of a confirmed association. Cardiovascular Journal of Africa. 2016; 27(5): 287-290. 2. Braam, R.L, Groenemeijer, B.E, Koomen, E.M, Snijder, R, Plokker, H.W.M. A 32-year-old woman with Down's syndrome and central cyanosis. Netherlands Heart Journal. 2009; 17(4): 171. 3. Mol, B.W.J. Down’s syndrome, cardiac anomalies, and nuchal translucency. BMJ: British Medical Journal. 1999; 318(7176): 70-71. 4. Al shahwani, N, Mandhan, P, Elkadhi, A, Ali, M.J, Latif, A. Congenital duodenal obstruction associated with Down's syndrome presenting with hematemesis. Journal of Surgical Case Reports. 2013; 1(12): 1. 5. Rafi, I, Chitty, L. Cell-free fetal DNA and non-invasive prenatal diagnosis. The British Journal of General Practice. 2009; 59(562): 146-148. 6. Hui, L. Noninvasive prenatal testing for aneuploidy using cell-free DNA – New implications for maternal health. Obstetric Medicine. 2016; 9(4): 148-152. 7. Dugo, N, Padula, F, Mobili, L, Brizzi, C, D’emidio, L, Cignini, P, Mesoraca, A, Bizzoco, D, Cima, A, Giorlandino, C. Six consecutive false positive cases from cell-free fetal DNA testing in a single referring centre. Journal of Prenatal Medicine. 2014; 8(1-2): 31-35 8. Taylor-phillips, S, Freeman, K, Geppert, J, Agbebiyi, A, Uthman, O.A, Madan, J, Clarke, J, Quenby, S, Clarke, A. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ Open. 2016; 6(1): 1. 9. Antonarakis, S.E, Petersen, M.B, Mcinnis, M.G, Adelsberger, P.A, Schinzel, A.A, Binkert, F, Pangalos, C, Raoul, O, Slaugenhaupt, S.A, Hafez, M, et al. The meiotic stage of nondisjunction in trisomy 21: Determination by using DNA polymorphisms. American Journal of Human Genetics. 1992; 50(3): 544-550 10. Yoon, P.W, freeman, S.B, Sherman, S.L, Taft, L.F, Gu, Y, Pettay, D, Flanders, W.D, Khoury, M.J, Hassold, T.J. Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study. American Journal of Human Genetics. 1996; 58(3): 628633.

“Marks for concise answers contained within the boxes provided. [2 marks]” Total mark out of 50

Page 5...