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Definition: Rare chromosomal disorder with a characteristic phenotype caused by an additional copy, or a critical region, of chromosome 18.
Synonyms: Trisomy 18; Trisomy E syndrome
Overview
Edwards syndrome (trisomy 18) is the 2nd most common autosomal trisomy after Down syndrome (trisomy 21). The incidence of trisomy 18 is 1 in 6000 live births (taking into account prenatal diagnosis and termination of pregnancy).
Trisomy 18 predominately arises due to failure of duplicate chromosomes to separate correctly during meiosis (non-disjunction) while the remainder of cases are due to a chromosomal rearrangement (referred to as a translocation). In some cases, the chromosomal abnormality may be present in only a percentage of cells, whereas other cells contain the normal chromosomal pair (mosaicism).
The syndrome produces a recognisable constellation of both minor and major congenital abnormalities. However, symptoms may be variable from case to case depending on the chromosomal abnormality present.
Trisomy 18 is associated with significant morbidity and mortality. Typical life expectancy for liveborn infants is a few days. There is significant physical and cognitive impairment in those who survive.
Increased maternal age is associated with an increased risk of trisomy 18. Amniocentesis can be offered to women of an older age (usually over 35-37 years of age) due to the known increased risk of chromosomal abnormalities.
Diagnosis should be confirmed by cytogenetic testing.
Inheritance
This risk of trisomy 18 increases with maternal age (Table).
|
Maternal age (years) |
Trisomy 18 (rate per 1000) |
|
35 |
0.5 |
|
36 |
0.7 |
|
37 |
1.0 |
|
38 |
1.4 |
|
39 |
2.0 |
|
40 |
2.8 |
|
41 |
3.9 |
|
42 |
5.5 |
|
43 |
7.6 |
Maternal age and trisomy 18 found at amniocentesis (rate per 1000)
Based on Ferguson-Smith MA (1983). British Medical Journal. 39; pp 355-364
The majority of cases are due to non-disjunction during meiosis, where the affected child will have three complete copies of chromosome 18; the extra copy is usually of maternal origin. The recurrence risk is approximately 1-2%.
Other cases can be due to an unbalanced chromosomal translocation involving chromosome 18 and another chromosome. In this case, the extra copy of chromosome 18 is not entire but translocated onto another chromosome.
A chromosomal translocation may have arisen in the affected child de novo, or may be present in a balanced form in one of the parents. If this were the case, the recurrence risk would be significantly higher than that for non-disjunction. Prenatal testing could be offered in future pregnancies.
Mosaicism exists in approximately 10% of cases and may have a milder phenotype, depending on the degree of mosaicism.
Features
There is a recognisable pattern of physical features. The severity of the phenotype can be variable.
Typical features:
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Prenatal growth failure causing intrauterine growth retardation
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Craniofacial abnormalities including:
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prominent occiput
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low set, malformed ears
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smallness of one or both jaws
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small facial features
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narrow palate
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cleft lip and palate
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Short sternum
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Nail hypoplasia
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Short dorsiflexed hallux
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Prominent calcaneus (rocker bottom foot)
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Congenital heart defects
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Gastrointestinal abnormalities
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Urogenital abnormalities including:
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cryptorchidism
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prominent clitoris
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cystic kidneys
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horseshoe kidneys
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gonadal dysgenesis
Complications arising from trisomy 18 are related to birth defects e.g., congenital heart disease. Even those without severe congenital anomalies have a markedly reduced life expectancy. Central apnoea contributes to the increased occurrence of infant mortality. The median life expectancy for liveborn infants is 4 days, but due to a small minority (5-10%) who survive for a year or more, the mean age at death is reported as 48 days.
Mental disability is severe in surviving infants and seizures are common. Malignancies have also been reported in those who survive, including Wilms tumour and hepatoblastoma.
Diagnosis
Due to the constellation of features diagnosis is not usually confused with other conditions. However, two syndromes share a number of features with trisomy 18:
- Trisomy 13 (Patau syndrome). Specific differences that are seen in trisomy 13 include: dextrocardia, hypoplastic nipples, prominent nasal bridge, and short neck. Hypoplastic nails and a short sternum are seen more commonly in trisomy 18.
- Pena-Shokeir syndrome I, a fetal akinesia sequence, has been described as pseudo-trisomy 18. However, there is no congenital heart defect present and there are multiple contractures with overriding fingers observed with this syndrome.
If abnormalities are subtle clinical diagnosis may be difficult and therefore definitive diagnosis of trisomy 18 relies on cytogenetic tests.
Testing
Definitive diagnosis is by detection of a complete or partial trisomy of chromosome 18 using genetic techniques.
Chromosomal analysis can be carried out using fluorescence in situ hybridisation (FISH) technology, which gives a rapid result. However, a negative result is not definitive. Therefore, routine cytogenetic tests are conducted in parallel to confirm the results or detect any abnormalities not detected by rapid FISH analysis. As such, the full culture result should be awaited before confirming or excluding the diagnosis.
Prenatal genetic testing for trisomy 18 can be carried out on the foetus following chorionic villus sampling or amniocentesis. Amniocentesis can be offered to women of an older age (usually over 35-37 years of age) due to the known increased risk of chromosomal abnormalities. In others, amniocentesis may be offered due to a high composite risk for Down syndrome that may have been identified following routine antenatal blood testing or after an anomaly scan has revealed possible foetal abnormalities.
Management
Due to the significant morbidity and mortality of this condition, management is supportive. It is generally not deemed appropriate to aggressively treat babies with trisomy 18, (e.g., heart surgery) as life expectancy is limited and morbidity from other features of the condition is also present. Surviving infants should be followed up by a paediatrician.
Diagnosis should be made as soon as possible to avoid inappropriate intervention. If the condition is diagnosed antenatally and the parents wish to continue with the pregnancy, then the necessary measures should be in place to ensure that the birth is dealt with appropriately. These measures should be decided following discussion with an obstetrician and/or paediatrician/neonatologist.
Genetic counselling
If trisomy 18 is diagnosed antenally, couples should be offered the opportunity to discuss the findings with a clinical geneticist. It is important to stress that, although life expectancy is poor, 5 to 10% of babies are still alive after one year. This information may be important when parents are deciding whether to terminate or continue with a pregnancy.
Recurrence risk is approximately 1% for trisomy 18. With increasing maternal age the risk of trisomy 21 will be greater than the risk of a recurrence of trisomy 18.
Where trisomy 18 is caused by an unbalanced chromosomal translocation, chromosomal analysis should be carried out on both parents. A de novo translocation in the infant would suggest a low recurrence risk for future offspring. If a balanced translocation is found in a parent, the recurrence risk would be significantly higher. This would depend on the site of the break point. Prenatal testing should be offered in future pregnancies. Other family members should be alerted that they are also at risk of carrying the balanced form of the translocation.
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