EDWARDS SYNDROME (TRISOMY 18)

Scientific background

Edwards syndrome, which is based on trisomy 18, has an average incidence of 1:3,000 in newborns. In 80% a free trisomy 18 is found, in 10% a mosaic trisomy and in another 10% there is an unbalanced translocation. There is clear gynecotrophy in 75% of female patients. External symptoms are variable; they include dolichocephaly with prominent occiput and a small face, ear dysplasia, microcephaly, microretrognathia, and a prominent calcaneus. Overlapping of the 3rd and 4th fingers by the 2nd and 5th fingers is characteristic, especially in newborns. Furthermore, heart defects, horseshoe kidney, muscle hypertonia and joint contractures are found. Psychomotor development is also severely delayed. Mortality usually occurs within the first few months of life, with over 90% dying within the first year of life. As with all autosomal trisomies, there is a maternal age effect.

References

Vendola et al. 2010, Am J Med Genet 152A:360 / Baty et al. 1994, Am J Med Genet 49:175 / Van Dyke and Allen 1990, Pediatrics 85:753 / Carter et al. 1983, Clin Genet 27:59

Edwards syndrome - March 18 is Trisomy 18 Awareness Day

Trisomy 18 is the second most common and second most severe trisomy [1]. The condition arises if the egg or the sperm carries an extra chromosome 18, that when combined passes 3 copies of chromosome 18 instead of 2 to the developing baby. Trisomy 18 was first described in 1960 by two groups; John Edwards, whom the disease is named after, and by Smith, Patau, Therman and Inhorn – the team that also described Trisomy 13, Patau syndrome [2, 3].

Globally, the condition occurs in approximately 1 in 5,000 live births [4]. The prevalence is greater, estimated to be around 1 in 2,500, but fetal loss during pregnancy and selective terminations after diagnosis due to the severity of the condition is high [1, 5]. Maternal age plays a factor in trisomy 18, and with the mean maternal age increased during the last 20 years, prevalence rates of trisomy 18 have risen [5].

Trisomy 18 is considered less severe than trisomy 13, but the mortality rates are still high with many stillbirths and miscarriages during the first pregnancy months. The chance of spontaneous fetal loss rises from 28% to 41% from weeks 12 to 20 [5]. Survival after birth is challenging, with 50% of children sadly dying within their first week of life [1, 6]. Individual symptoms can vary greatly in severity and complexity as 95% of the patients have full trisomy 18. Others have a mosaic form (some cells are trisomic for chromosome 18 and others carry the normal amount) or a partial form (only a section of chromosome 18 is duplicated) [1, 6]. The latter form arises mostly when the parents unknowingly have a translocation (structural rearrangement of chromosomes) concerning chromosome 18 [7].  The risk of recurrence is around 1%, and it primarily applies to translocation carriers. Mosaic and partial forms of trisomy 18 are the ones with the best chances of survival. Patients having these forms are the small percentage that may survive well into adulthood, although with significant developmental and physiological delays. Interestingly, girls with trisomy 18 are found to respond better to treatment and survive longer than boys with trisomy 18 [6, 7].

Trisomy 18 is characterized by major and minor abnormalities, affecting all organs and systems. 90% of patients have heart defects, bone abnormalities, and kidney, respiratory, and intestinal problems, resulting in feeding difficulties, also being common [4, 6, 8]. Severe developmental delays, delayed growth, and distinct characteristics like a small jaw, low-set ears, clenched fists, strawberry-shaped head, and rocker bottom feet (resembling a rocking chair) may also exist [4, 6, 8]. Failure to thrive (gain weight) is seen from the prenatal period, with fetuses affected being smaller than average, and with the mean birth weight being 1,700-1,800g [4, 8].

No specific treatment is available for trisomy 18. Care for trisomy 18 children is usually palliative and conservative, depending on the severity of the symptoms, the parent’s wishes, and the doctor’s medical judgment. Respiratory insufficiency and apnea are the major causes of death due to the breathing and feeding problems the patient experience [8]. Sadly, only around 10% of children with trisomy 18 pass their first birthday, and continuous support and health supervision are needed throughout their lives [4, 9].

Prenatal detection of trisomy 18 can be achieved through 1st and 2nd-trimester screening, and routine ultrasounds as the presence of one or multiple findings are evident. These can include omphalocele (the baby’s organs are outside of the belly, covered in a sac), excess amniotic fluid, very little fetal activity, and lower maternal hormone levels. A positive screening test should always be confirmed by a diagnostic test, like chorionic villus sampling (CVS) or amniocentesis. Combined prenatal screening for trisomy 18 is at least 78% accurate [10]. Non-Invasive Prenatal Testing (NIPT), analyzing the fetal blood through a blood sample taken from the expecting mother from the 10th week of pregnancy, is the most sensitive-detecting method, with over 97% accuracy [11]. Thus, NIPT can reduce the number of unnecessary invasive procedures, and give parents invaluable time to think and research their options regarding clinical management and care.

Several support groups for families with children with trisomy 18 exist, providing precious emotional support and information by sharing experiences, health problems, and advances in research. Trisomy 18 is a life-threatening condition, but it is not ‘universally lethal’. Spreading awareness about the condition, the different forms and the variability of symptoms is useful for expecting parents to receive an accurate image of trisomy 18 and be able to make their own informed decisions.

VERACITY and VERAgene both detect Trisomy 18, amongst other common genetic disorders, from the 10th week of pregnancy.

For more information on support groups for trisomy 18, please visit http://www.chromosome18eur.org or http://www.soft.org.uk.

References

1. Trisomy 18 Foundation (2019) https://www.trisomy18.org/
2. Edwards JH et al. (1960) ‘A new trisomic syndrome’. Lancet; April 9;1(7128): 787-790. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(60)90674-7/fulltext
3. Smith DW et al. (1960) ‘A new autosomal trisomy syndrome: multiple congenital anomalies caused by an extra chromosome’. The Journal of Pediatrics; Sep; 57:338-345. https://www.jpeds.com/article/S0022-3476(60)80241-7/pdf
4. Genetics Home Reference (2019) https://ghr.nlm.nih.gov/condition/trisomy-18#genes
5. Morris JK et al. (2008) ‘The risk of fetal loss following a prenatal diagnosis of trisomy 13 or trisomy 18’. American Journal of Medical Genetics; 146A:827–832. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.32220
6. MSD Manuals Professional Version (2019) https://www.msdmanuals.com/professional/pediatrics/chromosome-and-gene-anomalies/trisomy-18
7. Rasmussen SA et al. (2003) ‘Population-based analyses of mortality in trisomy 13 and trisomy 18’. Pediatrics; 111:777–784. https://publications.aap.org/pediatrics/article-abstract/111/4/777/63087/Population-Based-Analyses-of-Mortality-in-Trisomy?redirectedFrom=fulltext
8. Cereda A. and Carey JC. (2012) ‘The trisomy 18 syndrome’. Orphanet Journal of Rare Diseases; 7:81 https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-81
9. The chromosome 18 Registry & Research Society (2018) https://www.chromosome18.org/
10. Breathnach FM et al. (2007) ‘First, second trimester evaluation of risk (FASTER) research consortium: first- and second-trimester screening: detection of aneuploidies other than down syndrome.’ Obstetrics and Gynecology; 110:651–657. https://journals.lww.com/greenjournal/Abstract/2007/09000/First__and_Second_Trimester_Screening__Detection.18.aspx
11. Mackie FL et al. (2017) ‘The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis’. BJOG, 2017;124:32-46. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.14050

Last updated in March 2019